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NEFROPROTEZIONE NEL PAZIENTE DIABETICO

Paola FiorettoDipartimento di Medicina

Università di PadovaDiapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.

Per ricevere la versione originale si prega di scrivere a [email protected]

La dr./sa Fioretto Paola dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche:

- ASTRA ZENECA- JANSSEN- BOEHRINGER INGHELEIM- LILLY

Diapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.


Incident counts and adjusted rates of ESRD, by primary diagnosis

United States Renal Data System. 2014 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2014. Available at: https://www.usrds.org/2014/download/V2_Ch_01_ESRD_Incidence_Prevalence_14.pdf. Accessed March 2017

USRDS annual data report 2014

Diabetes

Hypertension

GN

Cystic kidney

Rat

e pe

r mill

ion

popu

latio

n

0

50

100

150

200Rates

81 84 87 90 93 96 99 02 05 08 11

Year

Diabetes

Hypertension

GN

Cystic kidney

Num

ber o

f pat

ient

s (in

thou

sand

s)

0

10

20

30

40

50 Counts

81 84 87 90 93 96 99 02 05 08 11

YearDiapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.


Trends in diabetes-related complications among U.S. adults with diagnosed diabetes 1990–2010

ESRD, end-stage renal diseaseGregg EW, et al. New Engl J Med 2014;370:1514–1523

150

125

100

75

50

25

420

Even

ts p

er 1

0,00

0 ad

ult p

opul

atio

nw

ith d

iagn

osed

dia

bete

s

1990 1995 2000 2005 2010

Acute myocardial infarction

Stroke

Amputation

ESRD

Death from hyperglycaemic crisis

YearDiapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.


The incidence of low eGFR and albuminuria increased during follow up of patients with Type 2 diabetes in an Italian network

De Cosmo S, et al. Medicine 2016;95:e4007

The incidence of low eGFR and albuminuria was assessed in patients with Type 2 diabetes in the Italian Association of Clinical Diabetologists network

5,0%6,7%

8,6%10,1%

7,8%

10,3%

13,1%15,0%

0,5% 0,9% 1,5%2,3%

0%2%4%6%8%

10%12%14%16%18%20%

1 2 3 4

Prop

ortio

n of

pat

ient

s

Years from baseline

Low eGFR (<60 mL/min/1.73 m2)

8,0%9,6%

13,1%14,5%

8,2%10,0%

13,5%

15,5%

7,7%9,0%

12,4% 13,0%

0%2%4%6%8%

10%12%14%16%18%20%

1 2 3 4Pr

opor

tion

of p

atie

nts

Years from baseline

Albuminuria

Overall populationeGFR 60–90 mL/min/1.73 m2

eGFR >90 mL/min/1.73 m2



60

Natural history of diabetic nephropathy

*Whole-kidney hyperfiltration is generally defined as a GFR that exceeds approximately 135 mL/min, and is indicated with the red lineGFR, glomerular filtration rate; UAE, urinary albumin excretionTonneijck L, et al. J Am Soc Nephrol 2017;28:1023–1039

~Nephron mass 100% 100% 50% 0%

Renal functional reserve

GFR

UAE

Impr

oved

H

bA1c

20

200

1000

5000

30

90

120

150

135*

180

Urinary album

in excretion(m

g/24 hours)W

hole

kid

ney

GFR

(m

L/m

in/1

.73m

2 )

Normal filtration Phase 1

Hyperfiltration at whole-kidney level

Normal filtrationPhase 2

Hypofiltration



Clinical manifestations of kidney disease in patients with Type 2 diabetes

• Among US adults with diabetes from 1988–2014, the overall prevalence of DKD did not change significantly, whereas the prevalence of albuminuria declined and the prevalence of reduced eGFR increased

ACR, albumin:creatinine ratio; CI, confidence interval; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rateAfkarian M, et al. JAMA 2016;316:602–610

0 0,2 0,4 0,6 0,8 1

1988–1994

1999–2004

2005–2008

2009–2014

1 (reference)

0.93 (0.79, 1.06)

0.86 (0.75, 1.01)

0.76 (0.65, 0.89)

1 (reference)

1.86 (0.87, 3.98)

1.93 (0.90, 4.11)

2.86 (1.38, 5.91)

0 2 4 6

Albuminuria (ACR ≥30 mg/g) eGFR <30 mL/min/1.73 m2

Adjusted prevalence ratio (95% CI)





CVD and renal outcomes by eGFR and albuminuriaThe Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) Study

CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; UAE, urinary albumin excretionNinomiya T, et al. J Am Soc Nephrol 2009;20:1813–1821

• 10,640 patients with Type 2 diabetes, median follow-up of 4.3 years

Macro Micro Normo >90

60–89<60

0

5

10

15

20

25

UAE eGFR

Haz

ard

ratio

Renal events

Macro Micro Normo >90

60–89<60

012

3

4

5

6

UAE eGFR

Cardiovascular deaths

Haz

ard

ratio



Presence and severity of CKD are associated with adverse outcomes

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; MI, myocardial infarctionTonelli M, et al. Lancet 2012;380:807–814

19

15

75

1,20

5

10

15

20

Previous MI Diabetes & eGFR<60 eGFR<60 Diabetes No diabetes & no GFR <60

40

71

47

19

6

0

10

20

30

40

50

60

70

80

Previous MI Diabetes and eGFR <60 eGFR <60 Diabetes No diabetes and no eGFR<60

All-cause mortality

Myocardial infarction

Rat

e pe

r 100

0-pe

rson

yea

rs



1. Blockade of the RAAS

2. Blood pressure control

3. Glucose control

4. Lipid control

Treatment of DKD in patients with Type 2 diabetes



RENAAL study: Losartan conferred significant renal benefits in patients with Type 2 diabetes and nephropathy

ESRD, end-stage renal disease; NIDDM, non-insulin-dependent diabetes mellitusBrenner BM. N Engl J Med 2001;345:861–869

• Mean treatment duration 3.4 years; N=1513

• Primary composite endpoint was doubling of serum creatinine, ESRD or death

Months

Prim

ary

com

posi

te e

ndpo

int

patie

nts

with

eve

nt (%

)

P=0.024Risk reduction: 16%

Placebo

Losartan

0 12 24 36 480

10

20

30

40

50



STENO-2: 21-year follow-up demonstrated intensive intervention reduces CKD progression in patients with Type 2 diabetes

CI, confidence interval; CVD, cardiovascular disease; ESRD, end-stage renal disease; HR, hazard ratio Gæde P, et al. Diabetologia 2016;59:2298–2307

• The original intervention (mean treatment duration 7.8 years) involved 160 patients with Type 2 diabetes and microalbuminuria randomly assigned to receive either conventional therapy or intensified, multifactorial treatment

• Progression to diabetic nephropathy was reduced by 48% in the intensive therapy group

• Ten patients in the conventional therapy groups versus five patients in the intensive therapy group progressed to ESRD (P=0.061)

0.2 0.5 1.0 2.0

Event

All-cause mortality

CVD mortalityNon-CVD mortality

Death | CVD stateCVD event | CVD state

Retinopathy progressionAutonomic neuropathyPeripheral neuropathy

Macroalbuminuria

95% CI P valueHR

0.55

0.380.70

0.830.55

0.670.591.120.52

(0.36, 0.83)

(0.19, 0.75)(0.41, 1.20)

(0.54, 1.30)(0.39, 0.77)

(0.51, 0.89)(0.40, 0.89)(0.71, 1.77)(0.32, 0.84)

0.005

0.0060.195

0.4250.001

0.0050.0110.6300.008

HR – intensive vs conventionalDiapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.


The legacy effect: Strict glycaemic control can result in sustained reductions in renal complications

ESRD, end-stage renal disease; GFR, glomerular filtration rate1. The DCCT/EDIC Research Group. New Engl J Med 2011;365:2366–2376; 2. Holman RR, et al. New Engl J Med 2008;359;1577–1589; 3. Zoungas S, et al. New Engl J Med 2014;371:1392–1403; 4. Bilous R. Diabet Med 2008;25(Suppl) 2:25–29

TrialDiabetes

type

Initial treatment

period (years)

Follow-up period(years) Sustained beneficial renal function observations

DCCT-EDIC1 Type 1 6.5 22 (median) Risk for impaired GFR reduced by 50% in the intensive-treatment group compared with the control group

UKPDS2 Type 2 10 10

25% risk reduction for microvascular outcomes observed in the intensive-treatment group33% reduction in microalbuminuria or proteinuria at 12 years4

ADVANCE-ON3 Type 2 5 6Intensive treatment was associated with a significant cumulative benefit with respect to ESRD, but had no effect on the rate of death from renal disease

• Long-term follow-ups from several trials have shown that intensive glycaemic control can result in sustained reductions in diabetic renal complications that last for many years



DCCT/EDIC: Early intensive glycaemic control reduces long-term risk of impaired eGFR in patients with Type 1 diabetes

aImpaired eGFR was defined as a sustained estimated GFR <60 mL/min/1.73m2 of body surface areaCI, confidence interval; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; eGFR, estimated glomerular filtration rate DCCT/EDIC Research Group. N Engl J Med 2011;365:2366–2376

• Intensive diabetes therapy reduced the risk of an impaired eGFRa by 50% in patients with Type 1 diabetes

Median follow-up period 22 years; impairment of GFR developed in 24 patients assigned to intensive therapy and in 46 assigned to conventional therapy

151050 20 25Years since randomisation

0

5

10

15

Cum

ulat

ive

inci

denc

e of

impa

ired

GFR

(%)

Number at riskIntensive therapy

Conventional therapy711730 719

704 684697

672657

619594

10890

Risk reduction with intensive therapy: 50% (95% CI: 18, 69)P=0.006

Conventional diabetes therapy

Intensive diabetes therapy



Action in Diabetes and Vascular Disease: Preterax and DiamicronModified Release Controlled Evaluation (ADVANCE): 6-year follow-up

CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratioZoungas, et al. N Engl J Med 2014;371:1392–1406

HR: 0.54 (95% CI: 0.34, 0.85)P=0.007

Patie

nts

with

eve

nt (%

)

100908070605040302010

00 2 4 6 8 10

Follow-up (year)

2

1

00 2 4 6 8 10

55715569

5402 5186 4124 3764 2811Intensive5400 5173 4041 3681 2683Standard

Patients

53 (1.0%)29 (0.5%)

Intensive glycaemic control

Standard glycaemic control

Significant cumulative benefit with respect to ESRD for patients in the intensive glycaemic control group vs standard glycaemic control group

Median post-trial follow-up was 5.4 years for the glycaemic control comparison (N=8494)



What about individual antidiabetes agents?

– GLP-1 receptor agonists



Effects of incretin-based therapies on renal risk factors

DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonistMuskiet MH, et al. Nat Rev Nephrol 2014;10:88–103

Diabetic kidney disease

GLP-1 RADPP-4 inhibitor




Metformin, sulphonylurea, thiazolidinedione, insulin

Thiazolidinedione

Cytokines and growth factors

Glomerular hypertension

Hyperglycaemia

Metabolic syndrome

SystemichypertensionDiapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.


GLP-1 and the kidney

GLP-1, glucagon-like peptide-1

Potential mechanisms

Blood glucose reduction

Blood pressure reduction

Increased sodium excretion

Renin-angiotensin pathway

Reduced glucose-induced oxidative stress

Reduced inflammation



2400 12060

1.2

0.2

5

2

50

20

10

Effects of GLP-1 in healthy subjects

GLP-1, glucagon-like peptide-1; proANB, pro-atrial natriuretic peptide; proBNP, pro B-type natriuretic peptideSkov J, et al. Endocrin Conn 2014;3:11–16

• Healthy young males (N=12) were evaluated in a RCT to evaluate the effects of a 2-hour native GLP-1 infusion on atrial natriuretic peptide

• GLP-1 infusion increased plasma GLP-1 concentration, but had no significant effect on proANB or proBNP, despite increases in urinary sodium excretion

0 40 80 120Time (min)

0

20

40

60

80

100

GLP

-1 (p

mol

/L)

P<0.001

0 40 80 120Time (min)

0

40

60

proA

NP

(pm

ol/L

)

P=0.32

30

6

3

1

0 40 80 120Time (min)

0

7

proB

NP

(pm

ol/L

)

P=0.67

4

0 40 80 120Time (min)

0

0.4

0.6

0.8

Na+

excr

etio

n (m

mol

/min

)P<0.001

1.0

1.2

0.2

Time (min)

0

0.4

0.6

0.8

Na+

excr

etio

n (m

mol

/min

)

1.0

180

GLP-1 infusion

Washout

PlaceboGLP-1GLP-1 in first period (n=6)



Acute exenatide administration was shown to increase proximal sodium excretion in overweight patients with Type 2 diabetes

BMI, body mass index; GFR, glomerular filtration rate; HbA1c, glycated haemoglobinTonnejick L, et al. Diabetologia 2016;59:1412–1421

127,0 134,0

153,0

189,0

0

40

80

120

160

200

Placebo (N=28) Exenatide (N=24)

Na+

excr

etio

n (μ

mol

/min

/1.7

3 m

2 )

Baseline

Intervention

• Study included overweight men (BMI 25–40 kg/m2) and postmenopausal women aged 35–75 years with Type 2 diabetes (HbA1c 6.5–9.0%) and estimated GFR ≥60 mL/min/1.73 m2

P<0.01



RAAS hormones in patients with Type 2 diabetes before and after 12 weeks’ treatment with liraglutide

Data are presented as geometric mean [interquartile range] or mean (95% CI)CI, confidence interval; RAAS, renin-angiotensin-alterosterone systemVon Scholten BJ, et al. Diabetes Obes Metab 2017;19:239–247

Before liraglutide

After liraglutide

Change for liraglutide

group (95% CI)

Before placebo After placebo

Change for placebogroup

(95% CI)

P value for comparison

between therapies

(end vs end)

p-Renin concentration, mU/L

83.7[34.5, 322.0]

52.4[14.0, 204.1]

–37%(–59, –5)P=0.030

81.9[30.0, 241.0]

60.1[15.9, 242.3]

–27%(–56, 18)P=0.22

0.57

p-Renin activity, mIU/L

67.7[24.5, 252.5]

44.0[11.0, 146.5]

–35%(–59, 2)P=0.060

65.8[20.0, 181.8]

46.9[13.0, 153.1]

–29%(–59, 19)P=0.21

0.80

p-Angiotensin II, pmol/L

9.7[3.0, 50.5]

5.5[1.1, 29.4]

–43%(–64, –9)P=0.022

9.0[4.0, 39.0]

6.4[1.6, 33.9]

–28%(–57, 17)P=0.20

0.53

p-Aldosterone,ng/L

214.9[161.8, 292.2]

213.6[158.0, 319.9]

–1(–19, 18)P=0.95

225.0[182.0, 299.0]

206.4[157.8, 293.5]

–6(–20, 13)P=0.45

0.53



Acute renal effects of liraglutide in patients with Type 2 diabetes

*P<0.05; **P<0.01FE, fractional excretion; GFR, glomerular filtration rate; NS, not significant; RBF, renal blood flowSkov J, et al. Diabetes Obes Metab 2016;18:581–589

GFR RBF FE of lithium Angiotensin II

NS NS ** *

In patients with Type 2 diabetes (N=11), a single dose of liraglutide 1.2 mg had no effect on renal haemodynamics but increased the proximal tubular sodium reabsorption

Placebo Liraglutide0

20

40

60

80

100

120

140

GFR

(mL/

min

/1.7

3m2 )

Placebo Liraglutide0

200

400

600

800

1000

RB

F (m

L/m

in)

Placebo Liraglutide

0.0

0.1

0.2

0.3

0.4

FE li

thiu

mPlacebo Liraglutide

0

4

6

8

10

ANG

II (p

g/m

L)

2



Acute exenatide administration does not affect eGFR in overweight patients with Type 2 diabetes, compared with placebo

eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; MTD, mean treatment differenceTonnejick L, et al. Diabetologia 2016;59:1412–1421

MDT= +2±3 mL/min/m2

P=0.489

ExenatidePlacebo40

60

80

100

120

140G

FR (m

L/m

in/1

.73m

2 )Baseline

Acute stimulation

NS



GLP-1 and the kidney

GLP-1, glucagon-like peptide-1

Potential mechanisms

Blood glucose reduction

Blood pressure reduction

Increased sodium excretion

Renin–angiotensin pathway

Reduced glucose-induced oxidative stress

Reduced inflammation



Exendin-4 suppressed the inflammatory axis in the kidney

**P<0.01 and ***P<0.001 vs non-diabetes and non-diabetes + exendin-4; †P<0.05 and ‡P<0.001 vs diabetesICAM, intercellular adhesion molecule-1; STZ, streptozotocinKodera R, et al. Diabetologia 2011;54:965–978

• Exendin-4 was administered at 10 μg/kg daily for 8 weeks to a STZ-induced rat model of Type 1 diabetes

• Markers of inflammation were significantly up-regulated in the diabetes group and significantly downregulated by exendin-4 treatment

Mac

roph

ages

ICAM

-1Ty

pe IV

col

lage

n

3

2

1

0ND ND+EX DM DM+EXR

elat

ive

expr

essi

on o

f Ic

amIm

RN

A (fo

ld) **

†

3

2

1

0ND ND+EX DM DM+EXR

elat

ive

expr

essi

on o

f Tg

fbIm

RN

A (fo

ld) **

†

3

2

1

0ND ND+EX DM DM+EXR

elat

ive

expr

essi

on o

f

C

dl4

mR

NA

(fold

) ***

‡



GLP-1 receptor agonists and oxidative stress

***P<0.001 vs vehiclecAMP, cyclic adensosine monophosphate; GLP-1, glucagon-like peptide-1Fujita H, et al. Kidney Int 2014;85:579–589

• Treatment with liraglutide in Akita mice reduced albuminuria and mesangial expansion

• These effects were abolished by cAMP inhibitor SW22536 and PKA inhibitor H-89

1.0

1.5

0.5

0.0

Mes

angi

al

expa

nsio

n sc

ores

VehicleLiraglutide

***

100

150

50

0Fibr

onec

tin s

tain

ing

inte

nsity

(% v

ehic

le)

***

80

100

40

0

Podo

cyte

num

ber

(/glo

mer

ulus

)

***60

20

400

500

200

0

GBM

(nm

)

***300

100

SQ22536H-89

––

+–

–+

––



GLP-1 receptor agonists and oxidative stress

cAMP, cyclic adenosine monophosphate; NADPH, nicotinamde adenine dinucleotide phosphate; PKA, protein kinase AFujita H, et al. Kidney Int 2014;85:579–589

• Treatment with liraglutide in Akita mice decreased levels of superoxide and renal NAD(P)H oxidase and elevated renal cAMP and PKA activity

• These effects were abolished by cAMP inhibitor SW22536 and PKA inhibitor H-89



The protective roles of GLP-1 R signaling in diabetic nephropathy

cAMP, cyclic adenosine monophosphate; NADPH, nicotinamde adenine dinucleotide phosphate; PKA, protein kinase A; SOD, superoxide dismutaseFujita H, et al. Kidney Int 2014;85:579–589

GLP-1

GLP-1 receptor

Renal glomerulus and blood vessels

GLP-1 receptorsignalling

cAMP PKA

NAD(P)H oxidase

Diabetes

Oxidative renal injury O2

.‒

H2O2

H2O

Catalase GSH peroxidase

SOD



Exenatide reduced 24-hour UAE, TGF-β1 and type IV collagen excretion in patients with Type 2 diabetes and microalbuminuria

Col, collagen; TGF, transforming growth factor; UAE, urinary albumin excretionZhang H, et al. Kidney Blood Press Res 2012;35:483–488

• The levels of 24-hour urinary albumin in the exenatide group dropped significantly by 37.97% from 107 to 65 mg/L after 16 weeks of treatment (P<0.01)

• The levels of urinary TGF-β1 were significantly reduced following treatment with exenatide (P<0.01)

• A significant reduction was also observed for urinary type IV collagen in the exenatide group (P<0.01)

–40

–35

–30

–25

–20

–15

–10

–5

0

5

Cha

nge

(%)

24-UAE uTGF-β1 ulV-Col

Glimepiride groupExenatide group

P<0.005

P<0.001 P<0.001Diapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.


DURATION-2: switch from sitagliptin and pioglitazone to exenatide QW

*P<0.05Data are presented as mean±standard error, or geometric least square mean % change (95% confidence interval)ACR, uinary abumin:creatinine ratio; BNP, B-type natriuretic peptide; hsCRP, high-sensitivity C-reactive protein; PAI-1, plasminogen activator inhibitor 1; QW, once weeklyWysham C, et al. Diabetic Med 2017

Exenatide QW exenatide QW (N=103)

Sitagliptin exenatide QW (N=116)

Pioglitazone exenatide QW (N=100)

ACR (baseline) 15.31±2.37 11.46±1.27 13.23±1.92

∆ weeks 26–52 –19% (–31, –5)* –14% (–26, 0) –12% (–25, 4)

∆ weeks 0–52 –34% (–45, –20)* –18% (–31, –3)* –23% (–36, –7)*

BNP (baseline, pg/mL) 9.66±1.00 11.69±1.03 9.60±0.84

∆ weeks 26–52 –10% (–23, 6) –16% (–27, –3)* –26% (–37, –14)*

∆ weeks 0–52 –18% (–31, –3)* –15% (–28, –1)* –13% (–26, 3)

hsCRP (baseline, mg/L) 2.50±0.24 2.35±0.18 2.33±0.24

∆ weeks 26–52 –2% (–15, 12) –8% (–20, 5) 37% (19, 58)*

∆ weeks 0–52 –25% (–35, –13)* –17% (–27, –4)* –5% (–18, 11)

PAI-1 (baseline, ng/mL) 39.14±2.29 32.97±1.71 36.18±1.95

∆ weeks 26–52 16% (4, 30)* –3% (–12, 8) 27% (14, 42)*

∆ weeks 0–52 4% (–8, 16) –8% (–18, 2) 12% (0, 25)Diapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.


10

8

6

4

2

060 12 18 24 30 36 42 48 54

HR: 0.7895% CI (0.67, 0.92)

P=0.003

Liraglutide

Placebo

46684672

46354643

45614540

44924428

44004316

43044196

LiraglutidePlacebo

Patients at risk42104094

41143990

16321613

454433

Patie

nts

with

an

even

t (%

)

Time since randomisation (months)

LEADER: renal endpointMacroalbuminuria, doubling of serum creatinine, ESRD, renal death

The cumulative incidences were estimated with the use of the Kaplan–Meier 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 an observation time beyond 54 monthsCI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratioMarso SP, et al. N Eng J Med 2016;375:311–322



Liraglutide PlaceboHazard ratio

(95% CI) N % N %Number of patients 4668 100 4672 100Microvascular endpoint 0.84 (0.73, 0.97) 355 7.6 416 8.9Renal event 0.78 (0.67, 0.92) 268 5.7 337 7.2New onset of persistent macroalbuminuriaa 0.74 (0.60, 0.91) 161 3.4 215 4.6Persistent doubling of serum creatinineb 0.88 (0.66, 1.18) 87 1.9 97 2.1Need for continuous renal replacement therapy 0.87 (0.61, 1.24) 56 1.2 64 1.4Death due to renal disease 1.59 (0.52, 4.87) 8 0.2 5 0.1

Eye event 1.15 (0.87, 1.52) 106 2.3 92 2.0Vitreous haemorrhage 1.45 (0.84, 2.50) 32 0.7 22 0.5Treatment with photocoagulation or intravitreal agent 1.16 (0.87, 1.55) 100 2.1 86 1.8

2 310.50.2

Favours liraglutide Favours placeboHazard ratio (95% CI)

LEADER: Time to first microvascular endpoints

Full analysis set. EAC-confirmed microvascular events including events with onset between date of randomisation and date of follow-up; Cox proportional hazard model adjusted for treatment; development of diabetes-related blindness was not analysed as an individual component because only one event was observed; aNew onset of persistent macroalbuminuria: urine albumin ≥300 mg/g creatinine; bPersistentdoubling of serum creatinine level and eGFR ≤45 mL/min/1.73 m2 per MDRD CI, confidence interval; EAC, event adjudication committee; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal diseaseMarso SP, et al. N Eng J Med 2016;375:311–322



SUSTAIN-6: Semaglutide reduced the risk of new or worsening nephropathy compared with placebo

Kaplan–Meier plot for time from randomisation to first EAC-confirmed new or worsening nephropathy using ‘in-trial’ data from subjects in the full analysis set; HR is from a proportional hazard modelCI, confidence interval; EAC, (external) event adjudication committee; HR, hazard ratioVilsbøll T. Presented at the 52nd EASD Annual Meeting 2016. Munich, Germany; 16th September 2016; OP S35.3

Time since randomisation (weeks)8 16 24 32 40 48 56 64 72 80 88 96 1040

0

2

4

8

6

3.8%

6.1%

Patie

nts

with

an

even

t (%

) HR: 0.64 (95% CI: 0.46, 0.88)Events: 62 semaglutide; 100 placebo

P=0.005

Semaglutide Placebo

No. of patients at risk

Placebo 1649 1629 1570 1545 1518 1498 1471 1465Semaglutide 1648 1630 1605 1580 1563 1541 1525 1518



SUSTAIN-6: New or worsening nephropathy: Benefit driven by reduction in persistent macroalbuminuria

MDRD, Modification of Diet in Renal DiseaseVilsboll T. Presented 16th September at the 52nd EASD Annual Meeting 2016, Munich, Germany; OP S35.3

0

1

2

3

4

5

6

7

New or worseningnephropathy

Persistentmacroalbuminuria

Need for continuous renal-replacement therapy

Persistent doubling ofserum creatinine level andcreatinine clearance perMDRD <45 mL/min/1.73m

Patie

nts

with

eve

nt (%

)

SemaglutidePlacebo

2Diapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.



– DPP4 inhibitors



*

*

Growth factorsChemokinesVasoactive peptides

Potential GLP-1-independent effects of DPP-4 inhibitors on renal outcomes

ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; DPP-4, dipeptidyl peptidase-4; GIP, gastric inhibitory polypeptide; GLP-1, glucagon0like peptide 1; HMGB1, high-mobility group protein B1; NPY, neuropeptide Y; PYY, peptide YY; RAAS, renin-angiotensin-aldosterone system; SDF-1α, stromal cell-derived factor 1α; SP, substance PMuskiet MH, et al. Nat Rev Neprhol 2014;10:88–103



Effects of sitagliptin on fractional excretion of sodium

LovshinJA et al, Diabetes Care, 2017



Effects of sitagliptin on intact plasma SDF-1a




DPP-4 inhibitors are associated with a reduction in albuminuria

DPP-4, dipeptidyl peptidase-4; UACR, urinary albumin:creatinine ratioGroop P-H, et al. Diabetes Care 2013;36:3460–3468

Linagliptin(n=170)

12 weeks

Placebo(n=56)

Linagliptin(n=162)

24 weeks

Placebo(n=55)

20

0

–20

–40P<0.05P<0.05

• Retrospective data showed a significant decrease in albuminuria in patients who had Type 2 diabetes and were treated with linagliptin compared with those on placebo

Cha

nge

in U

ACR

(%)



Effects of linagliptin on UACR in the Marlina study

CI, confidence interval; UACR, urinary albumin:creatinine ratioGroop PH, et al. ADA 2016, Poster 17-LB

Placebo (N=173)(gMean baseline UACR: 132.2 mg/gCr)

Linagliptin (N=178) (gMean baseline UACR: 120.5 mg/gCr)

There was no significant difference between linagliptinand placebo in the change in UACR from baseline over time

6Baseline 12 18 24

Week

0.6

0.7

0.8

0.9

1.0

1.1Ad

just

ed g

Mea

nra

tio ±

95%

CI o

f re

lativ

e ch

ange

from

bas

elin

e in

UAC

R



Effects of saxagliptin on ACR at 2 years in the SAVOR study

*P<0.05; **P<0.01ACR, albumin:creatinine ratio; HbA1c, glycated haemoglobinMosenzon O, et al. Diabetes Care 2017;40:69–70

Saxagliptin improved ACR compared with placebo, and this was irrespective of changes in HbA1c

30

25

20

15

10

5

0HbA1c improvement HbA1c improvement HbA1c improvement HbA1c improvement

Worsening of microalbuminuria to macroalbuminuria

Improvement of microalbuminuria to normoalbuminuria

Patie

nts

with

cha

nge

in A

CR

cat

egor

y fr

om b

asel

ine

cate

gory

at 2

yea

rs (%

)

27

19.4

24.8

20.3

11.9

17.3

12.2

18.6

***

*

*

*

**

Saxagliptin

Placebo



0

5

10

15

20

25

30

Baseline 8 weeks ∆ from Baseline

Urinary Albumin to Creatinine (mg/g/Cr)

44.6% ∆ from Baseline

N=47 single arm study P<0.0001

4Tami et al, Am J Cardiovasc Drugs, 2013

Effects of Vildagliptin on ACR (8 weeks)




– SGLT2 inhibitors



SGLT2 inhibition and potential renal protection

RAS, renin-angiotensin system; SGLT2, sodium–glucose co-transporter 2

Indirect benefits for the kidney• Improved glycaemic control• Reduced insulin levels• Increased insulin sensitivity• Reduced blood pressure• Reduced body weight/fat• Reduced plasma uric acid

Potential direct benefits• Reduction in hyperfiltration• Inhibition of intra-renal RAS?• Attenuation of renal

hypertrophy• Reduction in tubulotoxicity of

glucose



SGLT2

ElevatedGFR

DecreasedNa+ deliveryto macula densa

Afferent arteriolevasodilation

Hyperfiltration in earlystages of diabetic nephropathy

Impaired TGFB

IncreasedNa+ /glucosereabsorption

Na+ /glucosereabsorption

Macula densaAppropriateafferent arterioletone

NormalGFR

SGLT2

Normal physiology

Normal TGFA

IncreasedNa+ deliveryto maculadensa

SGLT2inhibitionin proximaltubule

Glucosuria

Afferent arterioleconstriction

Normalisationof GFR

SGLT2 inhibition reduceshyperfiltration via TGF

Restored TGF

Na+

3

45

12

C

Tubuloglomerular feedback and SGLT2 inhibition

GFR, glomerular filtration rate; SGLT, sodium–glucose co-transporter; TGF, tubuloglomerular feedbackCherney D, et al. Circulation 2014;129:587–597



Type 1 diabetes – Reduced hyperfiltration was mediated by effects on renal blood flow and vascular resistance

* p<0.01Patients with type 1 diabetes and hyperfiltration at baseline. RBV and RVR recorded in euglycaemic state. RBF, renal blood flow; RVR, renal vascular resistanceCherney D, et al. Circulation 2014;129:587–597

• Reduced renal blood flow (RBF) & increased renal vascular resistance (RVR) after empagliflozin treatment are consistent with afferent arteriole vasoconstriction

172,0

139.0

0

20

40

60

80

100

120

140

160

180

200

T1D-H (Euglycemia)

Mea

n G

FR (m

l/min

/1.7

3 m

2 )

Baseline Empagliflozin

1641

1156

0

200

400

600

800

1000

1200

1400

1600

1800

RBF

Mea

n R

BV

(ml/m

in/1

.73

m2 )


0,054

0,072

0

0,01

0,02

0,03

0,04

0,05

0,06

0,07

0,08

RVR

Mea

n RV

R (m

mH

g/L/

min

)


*

*

Renal blood flow Renal vascular resistance Glomerular filtration rate



Empagliflozin reduces intraglomerular pressure

T1D-H, Type 1 diabetes and renal normofiltration; T1D-H, Type 1 diabetes and renal hyperfiltrationSkrtic M, et al. Diabetologia 2014;57:2599–2602

Intraglomerular pressure recorded at baseline and after 8 weeks treatment with empagliflozin

40

45

50

55

60

65

70

75

80

T1D-N T1D-H

Mea

n in

tra-

glom

erul

ar p

ress

ure,

eu

glyc

aem

ia, m

mH

g

BaselineEmpagliflozin

*

Glomerular pressure T1D-H (mmHg) Baseline EMPA P value Change from baseline

Euglycaemia (mmHg) 67.4 ± 5.4 61.0 ± 5.2 <0.0001 9.5%

Hyperglycaemia (mmHg) 69.3 ± 6.5 61.6 ± 6.3 <0.0001 11.1%

*P<0.0001

►~6–8 mmHG



SGLT2 and RAAS inhibition

RAAS, renin-angiotensin-aldosterone inhibitor; SGLT2, sodium–glucose co-transporter 2Adapted from: Cherney D et al. Circulation 2014;129:587

Pharmacological actions:

SGLT2 inhibition

Afferent vasomodulation

Haemodynamic effects and clinical implications:

• Decreased glomerular pressure due to increased afferent resistance

• Decreased hyperfiltration

SGLT2 inhibition &RAAS blockadeAfferent modulation & Efferent dilation

• Potential for normalisation of intra-glomerular pressure

• Additive intra-glomerular pressure reduction (?)

• Potential for long-term renal protection (?)

RAAS blockade

Efferent vasodilation

• Decreased glomerular pressure due to decreased efferent resistance

• Decreased hyperfiltration• Renal protection proven in clinical trials



Possible mechanisms responsible for cardiovascular and renal protection with SGLT2 inhibition

ACE, angiotensin-converting enzyme; HbA1c, glycated haemoglobin; SGLT2, sodium–glucose co-transporter 2Heerpsink HJ, et al. Circulation 2016;134:752–772

SGLT2 inhibition

↑Tubuloglomerularfeedback

↓Bloodpressure

↓Arterialstiffness

Glycosuria

↓HbA1c

↑Uricosuria

↓Plasma uric acid

↓Inflammation↓Glucose toxicity

Negative caloricbalance

↓Total body fat mass

↓Epicardial fat

↑Cardiaccontractility

Cardiac and renal protection

↓Atherosclerosis

Afferentarteriole

constriction

↓Intraglomerular hypertension

↓Hyperfiltration

↓Myocardial stretch

↓Ventriculararrhythmias

Activation of ACE2 – Ang1/7

No sympathetic nervous system

activation

↓Plasma volume

↑

↓ ↓↓

Natriuresis

↓Inflammation↓Fibrosis



Additional mechanisms of SGLT2i-mediated organ protection

ECV, extracellular volume; GFR, glomerular filtration rate; HIF, hypoxia-inducible factor; MD, macula densa; NHE, sodium-hydrogen exchanger; PBow, hydrostatic pressure in Bowman’s capsuleVallon V, et al. Diabetologia 2017;60:215–225

Kidney protectionTransport work

Renal O2 consumptionAlbuminuria

Kidney growth AlbuminuriaInflammation

GFR

1PBow

Kidney/heartprotection

Blood glucose

Insulin need/levelsGlucagon

5

SGLT2 NHE3

GlucosuriaOsmotic diuresis

NatriuresisUricosuria

2

2

4

ECV/blood pressureUric acid levels

Body fat and weight

33

3

HIF

6?Lipolysis and hepatic

gluconeogenesis

5

Mild ketosis

5

5?

[NA+/CI‒/K+]MD

?



Adjusted percent change from baseline in ACR over time

0 2 4 6 8 10 12 140

-10

-20

-30

-40

-50

-60

-70

WeekC

hang

e fr

om b

asel

ine

in A

CR

, % (9

5% C

I)

DAPA 5 mg + ACEi/ARBDAPA 10 mg + ACEi/ARBPBO + ACEi /ARB

n Baseline Week 4 Week 8 Week 12Follow-up (Week 13)

DAPA 5 mg + ACEi/ARB 85 81 79 73 74DAPA 10 mg + ACEi/ARB 165 160 124 153 144PBO + ACEi /ARB 185 182 172 163 158

SGLT2 inhibitors lowered albuminuria in patients with Type 2 diabetes and hypertension

ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin:creatinine ratio; ARB, angiotensin II receptor blocker; DAPA, dapagliflozin; PBO, placebo; SGLT2, sodium–glucose co-transporter 2Lambers Heerspink Y, et al. Diabetes Obes Metab 2016;18:590–597



SGLT2 inhibitors are associated with an initial reduction in eGFR

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; SGLT2, sodium-glucose cotransporter 2Lambers Heerspink Y, et al. Diabetes Obes Metab 2016;18:590–597

Adjusted percent change from baseline in eGFR over time

4

2

0

–2

–4

–6

–8

0 2 4 6 8 10 12 14

Cha

nge

from

bas

elin

e in

eG

FR,

mL/

min

/1.7

3m2 (9

5% C

I)DAPA 5 mg + ACEi/ARBDAPA 10 mg + ACEi/ARBPBO + ACEi /ARB

n Baseline Week 8 Week 12Follow-up (Week 13)

DAPA 5 mg + ACEi/ARB 85 79 74 74DAPA 10 mg + ACEi/ARB 165 154 153 147PBO + ACEi /ARB 186 172 163 157

Week



• This post-hoc analysis included 166 patients with CKD stage 3 and increased albuminuria (≥3.4 mg/mmol)

Effects of dapagliflozin on UACR in patients with CKD stage 3

CI, confidence interval; CKD, chronic kidney disease; DAPA, dapagliflozin; PBO, placebo; UACR, urine albumin:creatinine ratioFioretto P, et al. Diabetologia 2016;59:2036–2039

–80

–40

0

40

80

120

0 4 52 104

Adju

sted

cha

nge

(95%

CI)

in U

ACR

(%)

Weeks

PlaceboDapagliflozin 5 mgDapagliflozin 10 mg

–26.4%

–43.9%

31.0%

PlaceboDAPA 5 mg

DAPA 10 mg 56 52 40 2953 50 39 2056 49 31 25

No. of patients



Effects of dapagliflozin on UACR in patients with CKD stage 3

CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; DBP, diastolic blood pressure; HbA1c, glycated haemoglobin; UACR, urinary albumin:creatinine ratioFioretto P, et al. Diabetologia 2016;59:2036–2039

Placebo-corrected UACR reductions20

0

–20

–40

–60

–80

–100

Diff

eren

ce v

s pl

aceb

o, %

(95%

CI)

n=29 n=20 n=29 n=20

–53.6–47.4–43.8

–57.2

Not adjusted for sex, or change in HbA1c, SBP, DBP,

uric acid and eGFR

Adjusted for sex, or change in HbA1c, SBP, DBP, uric

acid and eGFR

Dapagliflozin 5 mg

Dapagliflozin 10 mg



Effects of dapagliflozin on eGFR in patients with CKD stage 3

BL, baseline; CI, confidence interval; CKD, chronic kidney disease; DAPA, dapaglilfozin; eGFR, estimated glomerular filtration rateFioretto P, et al. Diabetologia 2016;59:2036–2039

0 4 52 104–8

–6

–4

–2

0

2

4

6

Adju

sted

mea

n ch

ange

in c

GFR

,m

L/m

in/1

.73m

2 (9

5% C

I)

PlaceboDapagliflozin 5 mgDapagliflozin 10 mg

WeeksPlacebo

DAPA 5 mgDAPA 10 mg 56 52 41 30

53 52 39 2056 50 31 25

No. of patients45.143.944.1

BL eGFR, mL/min/1.73 m2



There was a temporary initial reduction in eGFR with SGLT2 inhibitors

DAPA, dapagliflozin; eGFR, estimated glomerular filtration rate; PBO, placebo; RCT, randomised controlled trial; SGLT2, sodium–glucose co-transporter 2 Kohan D, et al. J Nephrol 2016;29:391–400

4

2

0

-2

-4

-61 4 8 12 16 20 24 37 50 63 76 89 102eG

FR (m

L/m

in/1

.73m

2 ) m

ean

chan

ge fr

om b

asel

ine

DAPA 5 mgPBO

DAPA 10 mgDAPA 2.5 mg

Study weekPBO 683 666 649 626 616 598 598 578 546 266 219 148 107

DAPA 2.5 mg 623 611 593 583 574 561 555 548 525 349 284 199 136DAPA 5 mg 748 740 714 705 696 681 669 659 628 354 288 208 159

DAPA 10 mg 744 740 728 717 706 681 676 670 646 367 310 220 166

2

1 4 8 12 16 20 24

0

–2

–4

–6

DAPA 5 mg DAPA 10 mg

PBO DAPA 2.5 mg

eGFR

(mL/

min

/1.7

3m2 )

mea

n ch

ange

from

bas

elin

e

Study week

∆ baseline after 102 weeks:PBO: 1.31DAPA 2.5 mg: –0.74 DAPA 5 mg: 2.52 DAPA 10 mg: 1.38

Analysis of 12 RCTs (N=4545)

No. of patientsDiapositiva preparata da Paola Fioretto e ceduta alla Società Italiana di Diabetologia.


Effects of Empagliflozin on Albuminuria

**P<0.01; ***P<0.001CV, cardiovascular; gCV, geometric coefficient of variation; gMean, geometric mean; UACR, urine albumin:creatinine ratioCherney D, et al. Diabetologia 2016;59:1860–1870

Mean ratio of relative change from baseline in UACR

0 0

–10

–20

–30

–40

–50

–10

–20

–30

–40

–50***

Placebo(n=248)

73.1 (69.1)

Empaglifiozin(n=388)

73.2 (69.8)

Treatment difference for empagliflozin

vs placeboBaselinegMean (gCV (%))

Adju

sted

gM

ean

ratio

of r

elat

ive

chan

ge fr

om b

asel

ine

in U

ACR

(%) Adjusted gM

eanratio of relative

change from baseline in U

ACR

for em

pagliflozinvs placebo (%

)

0 0

–10–10

–20

–30

–40

–50

–60

–70

–80

BaselinegMean (gCV (%))

Placebo(n=87)

1068.0 (116.1)

Empaglifiozin(n=128)

988.3 (96.6)

Treatment difference for empagliflozin

vs placebo

**

Adju

sted

gM

ean

ratio

of r

elat

ive

chan

ge fr

om b

asel

ine

in U

ACR

(%) Adjusted gM

eanratio of relative

change from baseline in U

ACR

for em

pagliflozinvs placebo (%

)

–20

–30

–40

–50

–60

–70

–80



Effect of canagliflozin vs glimepiride on UACR

BL, baseline; HbA1c, glycated haemoglobin; UACR, urine albumin:creatinine ratioHeerspink HJ, et al. J Am Soc Nephrol 2016;28:368–375

• Patients with Type 2 diabetes (N=1450) treated with metformin were given either glimepiride or canagliflozin

% change(95% CI) P value

CANA 100 mg vs glimepiride

–37.7%(8.6, 48.9) 0.01

CANA 300 mg vs glimepiride

–49.3 (31.9, 62.2) <0.001

Changes in UACR relative to glimepiride

1047852260–70

–50

–40

0

10

Time (weeks)

Cha

nge

in U

ACR

(%)

Glimepiride

Canagliflozin 100 mg


Least squares mean

–20

–30

–60

Glimepiride



N

65

68

66

65

68

66

57

64

63

52

56

52

45

52

45

–10

UACR ≥30 mg/g subgroup



Mean eGFR in Patients with T2DM Treated with Canagliflozin

CANA, canagliflozin; eGFR, estimated glomerular filtration rate; GLIM, glimepiride; LOCF, last observation carried forward; SE, standard error; T2DM, type 2 diabetes mellitus; wk, week Leiter LA, et al. Diabetes Care 2015;38:355–364

Patients with T2DM were treated with canagliflozin (100 or 300 mg) or glimepiride (N=1,450)

100

95

90

85

80

75

70

65

650 4 12 26 36 44 52 64 78 88 104 104

(LOCF)Time point (wk)

Mea

n (±

SE) e

GFR

(mL/

min

/1.7

3m2 ) Mean change from

baseline (LOCF)

–2.0 mL/min/1.73 m2

–6.2 mL/min/1.73 m2

Baseline (mL/min/1.73 m2)

GLIM88.6

CANA 100 mg90.1

CANA 300 mg93.5

–3.8 mL/min/1.73 m2



EMPA-REG: New-onset or worsening of nephropathy

• Incident or worsening nephropathy occurred in 12.7% and 18.8% of patients in the empagliflozin and placebo groups, respectively; a significant relative risk reduction of 39%

CI, confidence interval; HR, hazard ratioWanner C, et al. N Engl J Med 2016;375:323–334

Cum

ulat

ive

prob

abili

ty o

f eve

nt (%

) 30

25

20

15

10

0

5

HR: 0.61(95% CI: 0.53, 0.70)

P<0.0001

6 12 18 24 30 36 42 480

4124

2061

3994

1946

3848

1836

3669

1703

3171

1433

2279

1016

Empagliflozin

Placebo

Patients1887

833

1219

521

290

106

Months

Placebo

Empagliflozin



Empagliflozin Placebo

no. with event/analysed (%)

rate/1000pt-yr

no. with event/analysed (%)

rate/1000pt-yr

HR (95% CI) P value

Incident or worsening nephropathy or CV death 675/4170(16.2) 60.7 497/2102

(23.6) 95.9 0.61 (0.55–0.69) <0.001

Incident or worsening nephropathy 525/4124(12.7) 47.8 388/2061

(18.8) 76.0 0.61 (0.53–0.70) <0.001

Progression to macroalbuminuria 459/4091(11.2) 41.8 330/2033

(16.2) 64.9 0.62 (0.54–0.72) <0.001

Doubling of serum creatinine 70/4645(1.5) 5.5 60/2323

(2.6) 9.7 0.56 (0.39–0.79) <0.001

Initiation of renal replacement therapy 13/4687(0.3) 1.0 14/2333

(0.6) 2.1 0.45 (0.21–0.97) 0.04

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

81/4645(1.7) 6.3 71/2323

(3.1) 11.5 0.54 (0.40–0.75) <0.001

Incident albuminuria in patients with normoalbuminuria at baseline

1430/2779(51.5) 252.5 703/1374

(51.2) 266.0 0.95 (0.87–1.04) 0.25

0,125 0,25 0,5 1,0 2,0 4,0

Favours placeboFavours empagliflozin

EMPA-REG: Renal outcomes

CI, confidence interval; CV, cardiovascular; HR, hazard ratioWanner C, et al. N Engl J Med 2016;375:323–334

HR(95% CI)



Patie

nts

with

eve

nt (%

)

7

6

5

3

2

0

1

6 12 18 24 30 36 42 480

4

HR: 0.54(95% CI: 0.40, 0.75)

P=0.0002

Placebo

Empagliflozin

Months

4645

2323

4500

2229

4377

2146

4241

2047

3729

1771

2715

1289

Empagliflozin

Placebo

No. of patients2280

1079

1496

680

360

144

EMPA-REG: Composite of doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease

CI, confidence interval; HR, hazard ratioWanner C, et al. N Engl J Med 2016;375:323–334

Individual relative risk reductions for empagliflozin vs placebo:• Doubling of serum creatinine: –44%• Initiation of renal replacement therapy: –55%• Three deaths from renal disease with empagliflozin (0.1%) vs none with placebo



66

Adju

sted

mea

n (S

E) e

GFR

(mL/

min

/1.7

3m2 )

70

72

74

76

78

68

0 4 12 28 52 66 80 94 108 122 136 150 164 178 192 206

Empagliflozin 10 mg

Empagliflozin 25 mg

Placebo

Weeks

PlaceboEMPA 10 mg

232323222322

229522902288

226722642269

220522352216

212121612156

206421142111

192720122006

198120642067

176318391871

147915401563

126213141340

112311801207

97710241063

731785838

448513524

171193216EMPA 25 mg

After initial decrease, long term weekly changes of:• EMPA (10 mg): +0.48±0.04 mL/min• EMPA (25 mg): +0.55 ±0.04 mL/min• PBO: –0.04 ±0.04

P<0.001 for both EMPA groups vs placebo

EMPA-REG: Change in eGFR over time

eGFR, estimated glomerular filtration rate; EMPA, empagliflozin; PBO, placebo; SE, standard errorWanner C, et al. N Engl J Med 2016;375:323–334

No. of patients



CANVAS: cardiovascular and renal endpoints

Neal B et al, NEJM 12 june 2017



CANVAS: composite of 40% reduction in eGFR, ESRD, deathfrom renal causes




CANVAS: progression of albuminuria




Cardiovascular outcome trials with SGLT2 Inhibitors that will generate data on renal endpoints

CHF, congestive heart failure; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; MACE, major adverse cardiovascular event; MI, myocardial infarction; SGLT2, sodium–glucose co-transporter 2; UACR, urine albumin:creatinine ratio1. NCT01989754. Available at https://clinicaltrials.gov/ct2/show/NCT01989754; 2. NCT01032629. Available at https://clinicaltrials.gov/ct2/show/NCT01032629; 3. NCT01730534. Available at https://clinicaltrials.gov/ct2/show/NCT01730534; 4. NCT02065791. Available at https://clinicaltrials.gov/ct2/show/NCT02065791

Trial Patient cohorts N EndpointsCANVAS-R1 Canagliflozin / placebo 1:1 5813 Primary: Progression of albuminuria

Secondary: Regression of albuminuria, eGFR, UACR

CANVAS2 Canagliflozin / placebo 2:1 4331 Primary: MACE (CV death, non-fatal MI or non-fatal stroke)Secondary: Fasting insulin secretion, progression of albuminuria, blood glucose reduction

DECLARE3 Dapagliflozin / placebo 1:1 17,150 Primary: MACE non-inferiority and then superiority of co-primary endpoints of MACE and hospitalisation for heart failure or CV deathSecondary: all-cause mortality; renal composite endpoint (sustained ≥40% decrease in eGFR to eGFR <60 mL/min/1.73m2 and/or ESRD and/or renal or CV death)

CREDENCE4 Canagliflozin / placebo 1:1 4200 Primary: Composite renal and CV endpoint (ESRD, doubling of serum creatinine, renal or CV death)Secondary: 5P-MACE (CV death, non-fatal MI or non-fatal stroke, hospitalisation for CHF, hospitalisation for unstable angina), renal composite endpoint (ESRD, doubling of serum creatinine, renal death), all-cause mortality

2015 20212016 2017 2018 2019 2020

CANVAS and CANVAS-R DECLARE CREDENCE



https://clinicaltrials.gov/ct2/show/NCT01989754




Summary

• Intensive glycaemic control is associated with improved CKD outcomes; however, multifactorial intervention is necessary to prevent its progression

• Newer anthyperglycaemic classes have been demonstrated to nephroprotective effects:

• SGLT2i: ↓ intraglomerular hypertension– Reduce eGFR loss and albuminuria in Type 2 diabetes

• Incretin therapies – no apparent TGFB effect

– Reduce albuminuria in Type 2 diabetes

• Results of several cardiovascular outcomes and dedicated renal endpoint studies to further investigate the potential of newer agents in diabetes and CKD are eagerly anticipated



NEFROPROTEZIONE NEL PAZIENTE DIABETICO › diapositive › guest › 2017 - Fioretto Paola...De...

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