Giuseppe PennoDipartimento di Medicina Clinica e

SperimentaleUniversitagrave di Pisa

I FENOTIPI DI MALATTIA RENALE

NEL DIABETICO DAL RIACE ALLA

NEFROPROTEZIONE

Dichiarazione esplicita di trasparenza delle fonti di finanziamentoe dei rapporti con soggetti portatori di interessi commerciali

Il sottoscritto Dr Giuseppe Penno

in qualitagrave diModeratore Relatore

ai sensi dellrsquoart 33 sul Conflitto di Interessi pag 17 del Reg Applicativo dellrsquoAccordo Stato-Regione del 5 novembre 2009

dichiarache negli ultimi due anni ha avuto i seguenti rapporti anche di finanziamento con soggetti

portatori di interessi commerciali in campo sanitario

AstraZeneca Boerhinger Ingelheim Eli-Lilly Janssen Merck Sharp amp Dohme

Novo Nordisk Takeda

Ancona 7 ottobre 2017

The changing face of DKD in diabetes

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Prevalent cases of diabetic kidney disease in the United States accounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

p=039 plt0001

plt0001

Afkarian M et al JAMA 316 602-610 2016USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

40 30 20

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

1

099

095

1

093

086

076

1

133

138

161

Sheet1

p=0001 p=015plt0001

plt0001

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Adults aged lt65 Adults aged ge65 Adults aged lt65 Adults aged ge65

Prevalent cases of albuminuria and reduced eGFR in the United States by ageaccounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Afkarian M et al JAMA 316 602-610 2016

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

089

08

07

1

094

096

084

1

145

162

195

1

126

128

153

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 15
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• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
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• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
All diabetic kidney disease		100		100		099		095					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		093		086		076					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		133		138		161					024		030		029		037		028		034

All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034

Dichiarazione esplicita di trasparenza delle fonti di finanziamentoe dei rapporti con soggetti portatori di interessi commerciali

Il sottoscritto Dr Giuseppe Penno

in qualitagrave diModeratore Relatore

ai sensi dellrsquoart 33 sul Conflitto di Interessi pag 17 del Reg Applicativo dellrsquoAccordo Stato-Regione del 5 novembre 2009

dichiarache negli ultimi due anni ha avuto i seguenti rapporti anche di finanziamento con soggetti

portatori di interessi commerciali in campo sanitario

AstraZeneca Boerhinger Ingelheim Eli-Lilly Janssen Merck Sharp amp Dohme

Novo Nordisk Takeda

Ancona 7 ottobre 2017

The changing face of DKD in diabetes

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Prevalent cases of diabetic kidney disease in the United States accounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

p=039 plt0001

plt0001

Afkarian M et al JAMA 316 602-610 2016USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

40 30 20

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

1

099

095

1

093

086

076

1

133

138

161

Sheet1

p=0001 p=015plt0001

plt0001

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Adults aged lt65 Adults aged ge65 Adults aged lt65 Adults aged ge65

Prevalent cases of albuminuria and reduced eGFR in the United States by ageaccounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Afkarian M et al JAMA 316 602-610 2016

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

089

08

07

1

094

096

084

1

145

162

195

1

126

128

153

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
All diabetic kidney disease		100		100		099		095					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		093		086		076					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		133		138		161					024		030		029		037		028		034

All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034

The changing face of DKD in diabetes

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Prevalent cases of diabetic kidney disease in the United States accounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

p=039 plt0001

plt0001

Afkarian M et al JAMA 316 602-610 2016USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

40 30 20

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

1

099

095

1

093

086

076

1

133

138

161

Sheet1

p=0001 p=015plt0001

plt0001

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Adults aged lt65 Adults aged ge65 Adults aged lt65 Adults aged ge65

Prevalent cases of albuminuria and reduced eGFR in the United States by ageaccounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Afkarian M et al JAMA 316 602-610 2016

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

089

08

07

1

094

096

084

1

145

162

195

1

126

128

153

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
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• Diapositiva numero 5
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
All diabetic kidney disease		100		100		099		095					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		093		086		076					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		133		138		161					024		030		029		037		028		034

All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Prevalent cases of diabetic kidney disease in the United States accounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

p=039 plt0001

plt0001

Afkarian M et al JAMA 316 602-610 2016USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

40 30 20

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

1

099

095

1

093

086

076

1

133

138

161

Sheet1

p=0001 p=015plt0001

plt0001

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Adults aged lt65 Adults aged ge65 Adults aged lt65 Adults aged ge65

Prevalent cases of albuminuria and reduced eGFR in the United States by ageaccounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Afkarian M et al JAMA 316 602-610 2016

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

089

08

07

1

094

096

084

1

145

162

195

1

126

128

153

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
All diabetic kidney disease		100		100		099		095					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		093		086		076					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		133		138		161					024		030		029		037		028		034

All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

1

099

095

1

093

086

076

1

133

138

161

Sheet1

p=0001 p=015plt0001

plt0001

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Adults aged lt65 Adults aged ge65 Adults aged lt65 Adults aged ge65

Prevalent cases of albuminuria and reduced eGFR in the United States by ageaccounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Afkarian M et al JAMA 316 602-610 2016

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

089

08

07

1

094

096

084

1

145

162

195

1

126

128

153

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
All diabetic kidney disease		100		100		099		095					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		093		086		076					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		133		138		161					024		030		029		037		028		034

All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		All diabetic kidney disease		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034

Sheet1

p=0001 p=015plt0001

plt0001

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Adults aged lt65 Adults aged ge65 Adults aged lt65 Adults aged ge65

Prevalent cases of albuminuria and reduced eGFR in the United States by ageaccounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Afkarian M et al JAMA 316 602-610 2016

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

089

08

07

1

094

096

084

1

145

162

195

1

126

128

153

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
All diabetic kidney disease		100		100		099		095					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		093		086		076					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		133		138		161					024		030		029		037		028		034

p=0001 p=015plt0001

plt0001

Adjusted for age sex and raceethnicity p-values are for trendUACR urine albumin-to-creatinine ratio

Adults aged lt65 Adults aged ge65 Adults aged lt65 Adults aged ge65

Prevalent cases of albuminuria and reduced eGFR in the United States by ageaccounting for persistence

Clinical manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Afkarian M et al JAMA 316 602-610 2016

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

089

08

07

1

094

096

084

1

145

162

195

1

126

128

153

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)

Chart1

1988ndash1994(reference)

1999ndash2004

2005ndash2008

2009ndash2014

Adjusted prevalence ratio (95 CI)

1

089

08

07

1

094

096

084

1

145

162

195

1

126

128

153

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
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• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		01		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		Albuminuria (UACR ge30 mgg)		014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		024		03		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)		Impaired eGFR (lt60 mlmin173 msup2)

Sheet1

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
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• Diapositiva numero 5
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

	1988ndash1994(reference)		1999ndash2004		2005ndash2008		2009ndash2014					1999ndash2004			2005ndash2008			2009ndash2014
Albuminuria (UACR ge30 mgg)		100		089		080		070					010		011		011		011		009		011
Albuminuria (UACR ge30 mgg)		100		094		096		084					014		013		011		015		011		013
Impaired eGFR (lt60 mlmin173 msup2)		100		145		162		195					024		030		029		037		028		034
Impaired eGFR (lt60 mlmin173 msup2)		100		126		128		153

Vol 1 CKD Ch 1 6

Data Source National Health and Nutrition Examination Survey (NHANES) 2007ndash2012 participants aged 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation

Afkarian M et al JAMA 316 602-610 2016

Clinical Manifestations of Kidney Disease among US Adults with Diabetes 1988-2014

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Patientsn

DM

Follow-upyears

Renal impairment

No-albuminuric renal

impairment

Renal impairment with no albuminuria nor retinopathy

UKPDS Diabetes 55 1832-1839 2006

4006 100 15 28 67 (51) ---

MacIsaac RJ et al Diabetes Care 27 195-200 2004

301 100 --- 36 39 29

Kramer HJ et al NHANES III JAMA 289 3273-3277 2003

1197 100 --- 13 36 30

Thomas MC et al NEFRONDiabetes Care 32 1497-1502 2009

3893 100 --- 23 55 ---

Ninomiya T et al ADVANCEJ Am Soc Nephrol 20 1813-1821 2009

10640 100 --- 19 62 ---

Bakris GL et al ACCOMPLISHLancet 375 1173-1181 2010

11482 60 --- 95 468 ---

Tube SW et al ONTARGET TRASCENDCirculation 123 1098-1107 2011

23422 37 --- 24 68 ---

Drury PL et al FIELDDiabetologia 54 32-43 2011

9765 100 --- 53 590 ---

RIACE Study Group RIACEJ Hypertens 29 1802-1809 2011

15773 100 --- 188 566 432

In the last years progression of AER as an obligatorypredictorstep of DKD has been challenged

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Schematic presentation of variable clinical courses of diabetic kidney disease

Boger CA et al PLOS Genetics 8 e1002989 2012 (modified)

Normoalbuminuria

Normal GFR

Normoalbuminuria

Normal GFR

0 5 10 15 20Duration of diabetes (years)

Increased GFR (hyperfiltration)

Reduced GFR ESRD

crosstalk between the two channels

Normoalbuminuria

Microalbuminuria

Macroalbuminuria

Normal GFR

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
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• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The changing face of DKD in diabetes

RIACE and DKD phenotypes

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

30-59 mlmin173 m2

171Normo 731

Micro222

Macro47

60-89 mlmin173 m2

517

ge90 mlmin173 m2

296

lt30 mlmin173 m2

17

eGFR strata(mlmin173 m2)

Albuminuria strata(mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

30 20

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
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• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
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162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
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451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
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745714285714		28318688036
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797142857143		30833147299
801428571429		31462068034
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808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
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0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
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161428571429		161428571429
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164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
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174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
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302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
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39		39
421428571429		421428571429
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444285714286		444285714286
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452857142857		452857142857
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465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
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69		69
781428571429		781428571429
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798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

625120

67

171

17

No CKD

CKD stage 1

CKD stage 2

CKD stage 3

CKD stages 45

Approximately 40 of patients with T2DM show signs of CKD (stages 1-5)

Approximately 20 of patients with T2DM show signs of renal failure (eGFRlt60 mlmin173 m2)

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

40

20

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
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• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Severe(A3)

Mild(A2)

Normal(A1)

15-29

30-44

45-59

60-89

gt90

Albuminuria

Stage 2

Stage 1Stage 0(no CKD)

625

Stage 3

Stage 4

Stage 5

Stage 1-2albuminuric phenotype

187

Penno G et al J Hypertens 29 1802-1809 2011

Renal dysfunction is common in patients with T2DMThe RIACE Study 15773 patients with T2DM

eGFRmlmin173 m2

MDRD

lt15

G4

G3b

G3a

G2

G1

G5

Stage 35Non

albuminuricCKD

Phenotype

106

Stages 35

AlbuminuricCKD

Phenotype

82

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Distribution of markers of CKD in RIACE and in NHANES participants with diabetes hypertension self-reported cardiovascular

disease amp obesity 2011ndash2014

Data Source National Health and Nutrition Examination Survey (NHANES) 2011ndash2014 participants age 20 amp older Single-sample estimates of eGFR amp ACR eGFR calculated using the CKD-EPI equation Abbreviations ACR urine albumincreatinine ratio BMI body mass index CKD chronic kidney disease SR CVD self-reported cardiovascular disease eGFR estimated glomerular filtration rate HTN hypertension

USRDS - 2016 Annual Data Report Vol 1 CKD Ch 1

106

82

187

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
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• Diapositiva numero 5
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

De Cosmo S et al The AMD-Annals Study Group Nephrol Dial Transplant 29 657-662 2014

Kidney dysfunction and related cardiovascular risk factorsamong patients with type 2 diabetesClinical features of 120903 patients with type 2 diabetes whole sample and

divided according to the presenceabsence of albuminuria or low eGFR

106 187 82625

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
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• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Penno G et al The RIACE Study Group Diabetes Care 36 2301-2310 2013

HbA1c Variability as an Independent Correlate of Nephropathy but Not Retinopathy in Patients With Type 2 Diabetes

8260 patients with type 2 diabetes from Italy

106187 82

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
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814285714286		814285714286
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158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
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174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
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302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
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39		39
421428571429		421428571429
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452857142857		452857142857
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467142857143		467142857143
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605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
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798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

De Cosmo S et al The AMD-Annals Study Group Medicine 2016

Predictors of chronic kidney disease in type 2 diabetesA longitudinal study from the AMD Annals initiative

27029 patients with type 2 diabetes estimated eGFR ge60 mlmin173m2

and normoalbuminuria ndash observation over a period of 4 years

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
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• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Independent correlates of nonalbuminuric and albuminuric renal impairment (eGFR lt60 mlmin per 173m2 stage ge3 CKD) and albuminuria with nonreduced eGFR (eGFR ge60 mlmin per 173m2 stages 1-2 CKD) vs no CKD (eGFR ge60 mlmin per 173m2 without albuminuria)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

106 187 82

Penno G et al The RIACE Study Group J Hypertens 29 1802-1809 2011

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

0

10

20

30

40

50

CKD stages 1-2

n 2949

No CKD

n 9865

Maj

or C

VD e

vent

s

794(269)

1756(178)

Any CVD event by CKD phenotype

Chi square plt00001

CKD stages 3-5nonalbuminuric

n 1673

528(316)

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

CKD stages 3-5albuminuric

n 1286

576(448)

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Solini A et al The RIACE Study Group Diabetes Care 35 143-149 2012

Logistic regression analysis of CVD events by vascular bed with CKD phenotypes as covariates

The RIACE (Renal Insufficiency and Cardiovascular Events) Italian Multicenter Study

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Cumulative survival by Kaplan Mayer analysis (A)

and Cox proportional hazards regression unadjusted (B)

and adjusted by age (C)

and multiple confounders (D)

according to DKD phenotypes

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
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441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
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811428571429		811428571429
814285714286		814285714286
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157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
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164285714286		164285714286
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167142857143		167142857143
168571428571		168571428571
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174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
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39		39
421428571429		421428571429
432857142857		432857142857
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444285714286		444285714286
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452857142857		452857142857
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605714285714		605714285714
612857142857		612857142857
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798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Penno G et al The RIACE Study Group Diabetes Care submitted

Nonalbuminuric renal impairment is a strong predictior of all-cause mortality in patients with in type 2 diabetes The RIACE Italian Multicentre Study

Survival analysis by Cox proportional hazards regression adjusted for confounders according to DKD phenotypes and age categories

A lt55 years

B 55-64 years

C 65-74 years

D gt75 years

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
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• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
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• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 27
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• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes

1 117

31

20 2431

76

012345678

CV events415 (115)

All-cause mortality406 (107)

no CKDStages 1-2 CKDStages 3-5 CKD Alb-Stages 3-5 CKD Alb+

Development of CV events and all-cause mortality 129 and 131 years of median follow-up respectively

HR

Thorn LM et al Diabetes Care 38 2128-2133 2015

Adjusted for sex age BMI sBP HbA1c non-HDL cholesterol history of retinal laser tx and current smoking Adjusted for age

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

0

5

10

50

75

100

No DKD

n 692

DKD stadi 1-2

n 53

DKDstadi ge3 Alb-

n 17

DKDstadi ge3 Alb+

n 12

894

68

22 16

207 of all subjects with DKD 586 of DKD stages ge3

774 patients with T1DM

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

Cum

ulat

ive

surv

ival

Follow-up years

K-M Log Rank testplt00001

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

30 Ref

500HR 20683

(8292-51587)

151HR 4504

(1992-10186)

294HR 8573

(3222-22815)

40 di 77452

626 x 1000anno

774 patients with T1DM follow-up 83plusmn23 years

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 7441(2781-19911)

plt00001

HR 2970(1018-8662)

p=0046

Cum

ulat

ive

surv

ival

Follow-up years

No DKD (n 692)DKD stages 1-2 (n 53)DKD stages ge3 Alb- (n 17)DKD stages ge3 Alb+ (n 12)

Cox regression adjusted byage and gender

Ref

HR 3841(1686-8750)

p=0001

HR 95CI p

Age 1070 1044-1098 lt00001

Gender (M) 1922 0969-3813 =0061

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 10
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• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The presence and consequence of nonalbuminuric chronic kidney disease in patients with type 1 diabetes all-cause mortality

M Garofolo et al unpublished data

HR 458(169-1242)

p=0003

HR 277(097-794)

p=0058

Cum

ulat

ive

surv

ival

Follow-up years

No DKDDKD stages 1-2DKD stage ge3 Alb-DKD stage ge3 Alb+

Ref

HR 257(111-594)

p=0027

HR 95CI p

Gender (M) 152 077-301 0225

EURODIAB risk scoreLow riskIntermediate riskHigh risk

13351174

---120-932

444-3104

lt00001

0021lt00001

p=0008

Cox regression adjusted byGender and EURODIAB risk score

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
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• Diapositiva numero 5
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• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

DKD diabetic kidney disease T1D type 1 diabetes T2D type 2 diabetes IDNT Irbesartan Type 2 Diabetic Nephropathy Trial RAAS reninndashangiotensin-aldosterone system RENAAL

1 Mogensen CE et al Br Med J (Clin Res Ed)1982285685 2 Parving HH et al Lancet 198311175 3 Lewis EJ et al N Engl J Med 19933291456 4 Lewis EJ et al N Engl J Med 2001345851 6 Brenner BM et al N Engl J Med

2001345861

Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

1980 1990 2010 20152000

No new DKD-specific treatment in the last 15 years

High blood pressure

identified as DKD risk factor

szlig-blockers1

Hydralazine2

Captopril3

T1D

IDNT4 IRMA 25

Irbesartan T2D

RENAAL6

LosartanT2D

RAAS blockade

No new DKD-specific treatment in the last 15 years

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Glucoseloweringagents

Glitazones(ADOPT)

Sulphonylureas(ADOPT)

Metiglinides andAlpha-Glucosidase

Inhibitors

Metformin(ADOPT)

GLP-1agonists

Insulin(ORIGIN)

DPP-4inhibitors

Key question are glucose-lowering agents able to improverenal end-points beyond their antihyperglycemic effect

SGLT-2inhibitors

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
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• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

∆ HbA1c 030

Worsening or improvement are defined as a shift from baseline ACR category (lt34 ge34 to le339 or gt339 mgmmol) Plt0001 vs placebo

16492 patients who had a history or were at risk for CV events

Scirica BM et al N Engl J Med 369 1317-326 2013

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
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• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
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445714285714		445714285714
448571428571		448571428571
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491428571429		491428571429
525714285714		525714285714
55		55
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557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
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1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
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39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
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45		45
452857142857		452857142857
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467142857143		467142857143
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55		55
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69		69
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811428571429		811428571429
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831428571429		831428571429
922857142857		922857142857

16492 patients who had a history or were at risk for CV events

Mosenzon O et al on behalf of the SAVOR-TIMI 53 Investigators EASD Stockholm 2015

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
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462857142857			42927873673
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467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
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798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
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818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
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158571428571		158571428571
16		16
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164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
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168571428571		168571428571
17		17
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242857142857		242857142857
274285714286		274285714286
28		28
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16492 patients who had a history or were at risk for CV events

Mosenzon O et al Diabetes Care 40 69-76 2017

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Difference in mean change in ACR (mgg) as continuous variable among treatment arms by eGFR baseline categories

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
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		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Beneficial non-insulin CV Outcomes Trials in T2DM

Outcomes

LEADERLiraglutide

9340 T2DM at high CV risk

SUSTAIN-6 Semaglutide3297 T2DM

at high CV riskThree-point MACE -13 -26CV death -22 -2

Fatal and non-fatal MI-14

non-fatal -12 not significant

non-fatal -26 not significant

Fatal and non-fatalstroke

-14non-fatal -11

both not significantnon-fatal -39

Heart failure -13 +11All-cause mortality -15 +5Nephropathy -22 -36

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016 Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

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• No new DKD-specific treatment in the last 15 years
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• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death

The cumulative incidences were estimated with the use of the KaplanndashMeier method and the hazard ratios with the use of the Cox proportional-hazard regression model The data analyses are truncated at 54 months because less than 10 of the patients had anobservation time beyond 54 months CI confidence interval ESRD end-stage renal disease HR hazard ratio

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Marso SP et al for the LEADER Trial Investigators N Engl J Med 375 311-322 2016

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Liraglutide and Renal Outcomes in Type 2 Diabetes

Mann JFE et al for the LEADER Steering Committee and Investigators N Engl J Med 377 839-848 2017

Composite Renal Outcome and Individual Components of the Composite Outcome

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
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• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Supplementary Figure 5B Kaplan Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using lsquoin-trialrsquo data from subjects in the full analysis set HR is from a proportional hazard model CI confidence interval EAC (external) event adjudication committee HR hazard ratio

Semaglutide 38

HR 064 (95 CI 046 088)Events 62 Semaglutide 100 PlaceboP=0005

Number of patients at risk

Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518

Placebo 1649 1629 1570 1545 1518 1498 1471 1465

Placebo 61

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

New or worsening nephropathy

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
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• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
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• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Chart1

Semaglutide

Placebo

Weeks since randomisation

Patients with an event ()

0

00609013398

01218026797

01827783801

02439783934

03051784066

06111781131

08559779816

09172157963

0978453611

10398432864

11626226135

12854019407

13468298175

14082959671

14698388535

15315358862

15932329189

16550462148

17168595107

19641124989

2025925795

2087739091

2149552387

2211365683

22731789791

23350313974

23969622589

24589324416

25209026243

2582872807

26448429897

27068921656

27691796867

28318688036

30204226564

30833147299

31462068034

32719909239

33349239162

33978569084

34607899007

35237228929

35868618177

36500007425

37136401079

37774059092

38411717104

0

00606428138

01212856277

01821131029

02430519838

03651534885

04873298561

15258291761

17092074409

18314596468

20148379113

20759640261

2137090141

22593423468

23204684617

23815945765

24430284377

25045010096

25659735815

26274461533

27503912726

28733363918

30577540245

31807771545

3242288732

33039178474

34271760533

34889233832

35506707131

36124972062

39216292751

39834557684

41071884029

42309210373

42927873673

43546536974

44165200275

44785872223

45406544171

46027216119

47889231076

4913057471

49751652061

50373135611

50996250352

51619365092

52247016075

52877590249

53508584526

54139999746

56034244459

5666565968

59193009968

59824848108

60457111156

6109022631

61727207161

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

0		0
41428571429		41428571429
47142857143		47142857143
81428571429		81428571429
158571428571		158571428571
16		16
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
294285714286		294285714286
30		30
301428571429		301428571429
311428571429		311428571429
32		32
34		34
38		38
382857142857		382857142857
431428571429		431428571429
438571428571		438571428571
441428571429		441428571429
442857142857		442857142857
444285714286		444285714286
445714285714		445714285714
448571428571		448571428571
451428571429		451428571429
491428571429		491428571429
525714285714		525714285714
55		55
551428571429		551428571429
557142857143		557142857143
56		56
581428571429		581428571429
681428571429		681428571429
745714285714		745714285714
781428571429		781428571429
797142857143		797142857143
801428571429		801428571429
802857142857		802857142857
808571428571		808571428571
81		81
811428571429		811428571429
814285714286		814285714286
921428571429		921428571429
941428571429		941428571429
1068571428571		1068571428571
1075714285714		1075714285714
1091428571429		1091428571429
0		0
01428571429		01428571429
24285714286		24285714286
102857142857		102857142857
127142857143		127142857143
157142857143		157142857143
158571428571		158571428571
161428571429		161428571429
162857142857		162857142857
164285714286		164285714286
165714285714		165714285714
167142857143		167142857143
168571428571		168571428571
17		17
174285714286		174285714286
178571428571		178571428571
242857142857		242857142857
274285714286		274285714286
28		28
287142857143		287142857143
288571428571		288571428571
298571428571		298571428571
301428571429		301428571429
302857142857		302857142857
311428571429		311428571429
328571428571		328571428571
331428571429		331428571429
39		39
421428571429		421428571429
432857142857		432857142857
441428571429		441428571429
444285714286		444285714286
45		45
452857142857		452857142857
462857142857		462857142857
465714285714		465714285714
467142857143		467142857143
541428571429		541428571429
55		55
551428571429		551428571429
561428571429		561428571429
565714285714		565714285714
571428571429		571428571429
581428571429		581428571429
605714285714		605714285714
612857142857		612857142857
69		69
781428571429		781428571429
791428571429		791428571429
798571428571		798571428571
801428571429		801428571429
802857142857		802857142857
811428571429		811428571429
814285714286		814285714286
818571428571		818571428571
831428571429		831428571429
922857142857		922857142857

Sheet1

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

X-Values		Semaglutide		Placebo
0		0
41428571429		00609013398
47142857143		01218026797
81428571429		01827783801
158571428571		02439783934
16		03051784066
161428571429		06111781131
162857142857		08559779816
164285714286		09172157963
165714285714		0978453611
294285714286		10398432864
30		11626226135
301428571429		12854019407
311428571429		13468298175
32		14082959671
34		14698388535
38		15315358862
382857142857		15932329189
431428571429		16550462148
438571428571		17168595107
441428571429		19641124989
442857142857		2025925795
444285714286		2087739091
445714285714		2149552387
448571428571		2211365683
451428571429		22731789791
491428571429		23350313974
525714285714		23969622589
55		24589324416
551428571429		25209026243
557142857143		2582872807
56		26448429897
581428571429		27068921656
681428571429		27691796867
745714285714		28318688036
781428571429		30204226564
797142857143		30833147299
801428571429		31462068034
802857142857		32719909239
808571428571		33349239162
81		33978569084
811428571429		34607899007
814285714286		35237228929
921428571429		35868618177
941428571429		36500007425
1068571428571		37136401079
1075714285714		37774059092
1091428571429		38411717104
0			0
01428571429			00606428138
24285714286			01212856277
102857142857			01821131029
127142857143			02430519838
157142857143			03651534885
158571428571			04873298561
161428571429			15258291761
162857142857			17092074409
164285714286			18314596468
165714285714			20148379113
167142857143			20759640261
168571428571			2137090141
17			22593423468
174285714286			23204684617
178571428571			23815945765
242857142857			24430284377
274285714286			25045010096
28			25659735815
287142857143			26274461533
288571428571			27503912726
298571428571			28733363918
301428571429			30577540245
302857142857			31807771545
311428571429			3242288732
328571428571			33039178474
331428571429			34271760533
39			34889233832
421428571429			35506707131
432857142857			36124972062
441428571429			39216292751
444285714286			39834557684
45			41071884029
452857142857			42309210373
462857142857			42927873673
465714285714			43546536974
467142857143			44165200275
541428571429			44785872223
55			45406544171
551428571429			46027216119
561428571429			47889231076
565714285714			4913057471
571428571429			49751652061
581428571429			50373135611
605714285714			50996250352
612857142857			51619365092
69			52247016075
781428571429			52877590249
791428571429			53508584526
798571428571			54139999746
801428571429			56034244459
802857142857			5666565968
811428571429			59193009968
814285714286			59824848108
818571428571			60457111156
831428571429			6109022631
922857142857			61727207161

Semaglutide Placebo HR(95 CI)

P valueNo () Incidence rate per 100 PYR

No () Incidence rate per 100 PYR

Retinopathy complications 50 (30) 149 29 (18) 086 176 111 278 002

Need for retinal

photocoagulation38 (23) 113 20 (12) 059 191 111 328 002

Vitreous haemorrhage 16 (10) 047 7 (04) 021 229 094 557 007

Need for treatment with

intravitreal agent16 (10) 047 13 (08) 038 125 059 256 058

Onset of diabetes-related

blindness5 (03) 015 1 (01) 003 501 059 4288 014

New or worsening

nephropathy62 (38) 186 100 (61) 306 064 046 088 0005

Persistent

macroalbuminuria44 (27) 131 81 (49) 247 054 037 077 0001

Persistent doubling of serum creatinine level and creatinine clearance per MDRD lt45 mlmin173m2

18 (11) 053 14 (08) 041 128 064 258 048

Need for continuous

renal-replacement therapy11 (07) 032 12 (07) 035 091 040 207 083

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP et al for the SUSTAIN-6 Investigators N Engl J Med 375 1834-1844 2016

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Differences in glycaemic control with the study drug versus placebo in cardiovascular outcome studies assessing the safety of incretin‐based

therapies in patients with type 2 diabetes mellitus at high risk of cardiac events

Muskiet MHA et al Nature Review 4 september 2017

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

The changing face of DKD in diabetes

RIACE and DKD phenotypes

Different correlates for different phenotypes

Consequences of different phenotypes

(hellip and type 1 diabetes)

Nephroprotection

DPP4-i and GLP-1 RA

SGLT2-i

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

The effect of dapagliflozin on renal function in patientswith type 2 diabetes

Twelve double-blind placebo-controlled randomized clinical trials were analyzed up to 24 weeks (N = 4545) Six of the 12 studies included long-term data for up to 102 weeks (N = 3036)

Kohan DE et al J Nephrol 29 391-400 2016

Small transient reduction

Returned to near baseline by week 24

Returned to near baseline by week 24

gt90 of subjects had baselineeGFR gt60 mlmin173m2

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment

minus264 (minus550 205)minus439 (minus643 minus120)

310 (minus190 1119)

Week 104 ∆ UACR

158

273

396

43

339

147

0

5

10

15

20

25

30

35

40

45Placebo DAPA 5 mg DAPA 10 mg

Shift to higher UACR level

Patients shifting UACR category ()

Shift to lower UACR level

Post hoc analysis included 166 patients with stage 3 chronic kidney disease (CKD) and increased albuminuria (ge34 mgmmol)

Fioretto P et al Diabetologia 59 2036-2039 2017

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al

J Am Soc Nephrol 28 368-375 2017

Patients with an eGFR of lt55 mlmin per 173 m2 (or lt60 mlmin per 173 m2 if based on restriction of metformin use in the local label) or serum creatinine concentrations ge124 mmolL for men and ge115 mmolL for women were excluded

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Canagliflozin slows progression of renal function decline independently of glycemic effects

Heerspink HJL et al J Am Soc Nephrol 28 368-375 2017

1450 T2DM patients receiving metforminEnd points were annual change in eGFR and albuminuria over 2 years of follow-up

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Change in eGFR over 192 weeks

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

-39 -46New-onset or worsening nephropathy including new onset of macroalbuminuria (UACR gt300 mgg)

reduction started very early with curves separating after 3 months

Composite outcome bull Doubling of serum creatinine accompanied by

an eGFR of 45 mlmin173 m2 or lessbull Initiation of renal replacement therapybull Death due to renal disease

Wanner C et al N Engl J Med 375 323-334 2016

Incident or Worsening Nephropathy Renal Composite Outcome

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Empagliflozin Placebo

no with event

analyzed ()

rate1000pt-yr

no with event

analyzed ()

rate1000pt-yr

Hazard Ratio (95 CI)

p-value

Incident or worsening nephropathy or CV death

6754170(162)

607 4972102(236)

959 061 (055ndash069) lt0001

Incident or worsening nephropathy 5254124(127)

478 3882061(188)

760 061 (053ndash070) lt0001

Progression to macroalbuminuria 4594091(112)

418 3302033 (162)

649 062 (054ndash072) lt0001

Doubling of serum creatinine 704645(15)

55 602323(26)

97 056 (039ndash079) lt0001

Initiation of renal replacement therapy 134687(03)

10 142333(06)

21 045 (021ndash097) 004

Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

814645(17)

63 712323(31)

115 054 (040ndash075) lt0001

Incident albuminuria in patients with normoalbuminuria at baseline

14302779(515)

2525 7031374(512)

2660 095 (087ndash104) 025

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Chart1

1

2

3

4

5

6

8

6272

6185

6124

6968

7020

6968

4053

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

061		008		006
061		009		008
062		01		008
056		023		017
045		052		024
054		021		014
095		009		008
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

CVd

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
											0		0		0
	New or worsening of nephropathy or cardiovascular death		6272		061		055		069					061		1		6272		006		008
	New or worsening of nephropathy		6185		061		053		07					061		2		6185		008		009
	New onset of macroalbuminuria		6124		062		054		072					062		3		6124		008		01
	Doubling of serum creatinine accompanied by eGFR (MDRD) le45 mlmin173m2		6968		056		039		079					056		4		6968		017		023
	Initiation of renal replacement therapy		7020		045		021		097					045		5		7020		024		052
	Doubling of serum creatinine (accompanied by eGFR [MDRD] le45mlmin173m2) initiation of renal replacement therapy or death due to renal disease		6968		054		04		075					054		6		6968		014		021
	New onset of microalbuminuria		4053		095		087		104					095		8		4053		008		009

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

Wanner C et al N Engl J Med 375 323-334 2016

Pre-specified subgroup analyses for incident or worsening nephropathy

HR 061 (95CI 053-070) plt0001

-39

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease

Empagliflozin Placebop-value for interactionPatients analyzed

All patients 4645 2323Urine albumin-to-creatinine ratio 051lt30 mgg 2766 1376ge30 to 300 mgg 1325 671gt300 mgg 504 260

Estimated glomerular filtration rate 018ge90 mLmin173m2 1043 48660 to lt90 mLmin173m2 2406 123245 to lt60 mLmin173m2 822 416lt45 mLmin173m2 374 189

Favors placeboFavors empagliflozin

Hazard ratio (95 CI)

Wanner C et al N Engl J Med 375 323-334 2016

054 (040ndash075)

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

HR 054 (95CI 040-075) plt0001

-46

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

Grafico1

1

2

3

4

5

6

7

8

9

10

6968

0

4142

1996

764

0

1529

3638

1238

563

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

0		0		0
054		021		014
0		0		0
041		031		018
067		059		031
051		034		02
0		0		0
021		032		012
061		041		024
068		06		032
063		066		033
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN
0		NaN		NaN

CVd

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
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• Diapositiva numero 15
• Diapositiva numero 16
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• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

		Number of patients		HR		Lower 95 CI		Upper 95 CI					HR			N=		Lower plot value		Upper plot vale
Doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease												0		0		0
All patients			6968		054		04		075					054		1		6968		014		021
UACR										0		2		0		0		0
lt30 mgg			4142		041		023		072					041		3		4142		018		031
ge30 to 300 mgg			1996		067		036		126					067		4		1996		031		059
gt300 mgg			764		051		031		085					051		5		764		02		034
eGFR										0		6		0		0		0
ge90			1529		021		009		053					021		7		1529		012		032
60 to lt90			3638		061		037		102					061		8		3638		024		041
45 to lt60			1238		068		036		128					068		9		1238		032		06
lt45			563		063		03		129					063		10		563		033		066

Sheet2

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Sheet3

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

4171 with normo- (A) 2013 with micro- (B) 769 with macro-albuminuria (C)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

-7 p=0013

-25 plt00001

-32 plt00001

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Cherney D et al Lancet Diabetes Endocrinol June 27 2017

2013 with microalbuminuria (A) 769 with macroalbuminuria (B)

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

new onset of sustainednormoalbuminuria in patientswith microalbuminuria atbaseline

new onset of sustainednormoalbuminuria or microalbuminuria in patientswith macroalbuminuria atbaseline

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
• Diapositiva numero 14
• Diapositiva numero 15
• Diapositiva numero 16
• Diapositiva numero 17
• Diapositiva numero 18
• Diapositiva numero 19
• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Cherney D et al Lancet Diabetes Endocrinol

June 27 2017

4171 with normo- 2013 with micro- 769 with macro-albuminuriaEstimated eGFR over 192 weeks by albuminuria categories

Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory

analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
• Diapositiva numero 10
• Diapositiva numero 11
• Diapositiva numero 12
• Diapositiva numero 13
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• Diapositiva numero 15
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• Diapositiva numero 20
• Diapositiva numero 21
• Diapositiva numero 22
• Diapositiva numero 23
• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Contribution of changes in HbA1c body weight systolic blood pressure (SBP) to changes in UACR with empagliflozin macroalbuminuria

Cherney D et al Diabetologia 59 1860-1870 2016

HbA1c Weight

SBP

Similar in patients with microalbuminuria

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
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• Diapositiva numero 11
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• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
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• Diapositiva numero 9
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• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
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• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Neal B et al N Engl J Med June 12 2017

Canagliflozin and Cardiovascular and Renal Eventsin Type 2 Diabetes

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
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• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Neal B et al N Engl J Med June 12 2017Wanner C et al N Engl J Med 375 323-334 2016

054040 075

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
• Diapositiva numero 2
• Diapositiva numero 3
• Diapositiva numero 4
• Diapositiva numero 5
• Diapositiva numero 6
• Diapositiva numero 7
• Diapositiva numero 8
• Diapositiva numero 9
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• Diapositiva numero 24
• Diapositiva numero 25
• Diapositiva numero 26
• Diapositiva numero 27
• Diapositiva numero 28
• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
• Diapositiva numero 58
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• Diapositiva numero 61
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• Diapositiva numero 63
• Diapositiva numero 64

Take home message

Non-albuminuric renal impairment is the predominant clinical DKD phenotype in type 2 DM patients particularly women with reduced eGFR

Progression of DKD confers independent increased risk for CVD events and all-cause mortality

Also the non-albuminuric form is associated with a significant prevalence of CVD especially at the level of the coronary vascular bed

Non-albuminuric renal function impairment is also detectable among patients with type 1 diabetes

Different DKD phenotypes (in both type 2 and type 1 DM) are associated with different covariates indicating that increased albuminuria and reduced GFR at least partly reflect separate phenomena

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

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• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

A New Chapter for Diabetic Kidney Disease

Some recently developed medications that control glycemia in patientswith T2DM appear to have opened a new chapter for the prevention and treatment of DKD

Specifically DPP4-i GLP-1 RA and SGLT2-i may help prevent and treatDKD by allowing tighter and safer control of the blood glucose level and by exerting beneficial direct effects on the kidney

For patients with T2DM and prevalent kidney disease the existing data suggest that GLP-1 RA and SGLT2-i may slow the progression of kidneydisease

Currently it is logical to consider including a GLP-1 RA or SGLT2-i in the glucose-lowering regimen of patients with T2DM and mild-to-moderate DKD with the anticipation of salutary renal and particularly cardiovascular effects

Thank for your attention

• Diapositiva numero 1
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• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Diapositiva numero 57
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• Diapositiva numero 59
• Diapositiva numero 60
• Diapositiva numero 61
• Diapositiva numero 62
• Diapositiva numero 63
• Diapositiva numero 64

Thank for your attention

• Diapositiva numero 1
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• Diapositiva numero 29
• Diapositiva numero 30
• Diapositiva numero 31
• No new DKD-specific treatment in the last 15 years
• Diapositiva numero 33
• Diapositiva numero 34
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Changes in Microalbuminuria
• Diapositiva numero 38
• Time to first renal eventMacroalbuminuria doubling of serum creatinine ESRD renal death
• Diapositiva numero 40
• New or worsening nephropathy
• Diapositiva numero 42
• Diapositiva numero 43
• Diapositiva numero 44
• The effect of dapagliflozin on renal function in patientswith type 2 diabetes
• Diapositiva numero 46
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Canagliflozin slows progression of renal function decline independently of glycemic effects
• Diapositiva numero 49
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Diapositiva numero 51
• Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes
• Composite of doubling of serum creatinine initiation of renal replacement therapy or death due to renal disease
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
• Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease an exploratory analysis from the EMPA-REG OUTCOME randomised placebo-controlled trial
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