ottimizzazione della terapia nel paziente complesso€¦ · ottimizzazione della terapia nel...

Andrea [email protected]

ottimizzazione della terapianel paziente complesso

category HbA1c target statin

1. healthy < 7.5 yes

2. complex / intermediate healthy < 8.0 yes

3. very complex / poor health < 8.5 consider

0.4

75 80 85 90 95

0.6

0.8

1.0

1.2

1.4

0.4

75 80 85 90 95

0.6

0.8

1.0

1.2

1.4

0.4

75 80 85 90 95

0.6

0.8

1.0

1.2

1.4

Statins for primary prevention in old adults

0.4

75 80 85 90 95

0.6

0.8

1.0

1.2

1.4

no diabetes type 2 diabetes

age age

Ramos R. et al.: BMJ 362:k3359, 2018 doi: 10.1136/bmj.k3359.

all

cause m

ort

ality

Hazard

Ratio

CV d

isease

Hazard

Ratio

ADA/EASD

Step 1: assess cardiovascular diseasePresence of cardiovascular disease is compelling indication

ASCVD PREDOMINATES HEART FAILURE (HF) PREDOMINATES

GLP-1 RAwith provenCVD benefit1

SGLT2-iwith proven

CVD benefit1-2

if eGFR adequate

orGLP-1 RAwith provenCVD benefit1

SGLT2-iwith proven

CVD benefit2-3

if eGFR adequate

or

if further intensification is required or patient is unable to tolerate GLP-1 RA and/or SGLT2-i, choose agents demonstrating CV safety:• consider adding the other class with proven CVD benefit• DPP4i if not on GLP-1 RA• basal insulin4

• TZD5

• SU6

• Avoid TZD

• consider adding the other class with proven CVD benefit1

• DPP4i (not saxagliptin) if not on GLP-1 RA• basal insulin4

• SU6

Choose agents demonstrating CV safety:

1. SGLT2-i = empagliflozin preferred, GLP-1 RA = liraglutide preferred. Proven CVD benefit means it has label indication of reducing CVD events. 2. Be aware that SGLT2-i vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use. 3. Both empagliflozin and canagliflozin have shown reduction in HF in CVOT trial. 4. Degludec or U100 glargine have demonstrated CVD safety. 5. Low dose may be better though less well studied for CVD effect. 6. Choose later generation SU with lower risk of hypoglycaemia.

if HbA1c above target if HbA1c above target

ADA/EASD

Terapia farmacologica nell’anziano:Principali fattori da considerare:

• rischio di ipoglicemia

• insufficienza renale

• pregresso ictus/IMA

• storia di scompenso cardiaco

• profilo glicemico

• riserva funzionale beta cellula

• stato nutrizionale

• facilità di somministrazione

SIGG-SID per la terapia del diabete

obiettivi e terapia del diabete

obiettivodi glicata

farmaco peril diabete

obiettivi e terapia del diabete

farmaco peril diabete

obiettivodi glicata

a rischiodi ipoglicemia

NON a rischiodi ipoglicemia

• SUs• repaglinide• insulina

• metformina• SGLT-2i• DPP-4i• GLP-1 RA• pioglitazone• acarbosio

HbA1c < 7% HbA1c 7.0 – 7.5 %

HbA1c 7.5 – 8.0 %

2a scelta1a scelta

se fragile

Terapia farmacologica nell’anziano

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facilitàsomm. fragile

Metformina

SU e glinidi

pioglitazone

Gliptine

GLP-1 RA

Gliflozine

Insulina bas

Management of Diabetes in Older AdultsSesti G. et al.: NMCD 28:206, 2018 doi: 10.1016/j.numecd.2017.11.007


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Metformina NO no<30 SI NO digiuno XR

SU e glinidi

pioglitazone

Gliptine

GLP-1 RA

Gliflozine

Insulina bas



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SU e glinidi SIsolo

gliclaziderischio neutro vari SI no

pioglitazone

Gliptine

GLP-1 RA

Gliflozine

Insulina bas


events

%

0

5

10

25

30

0 12 18 366

pioglitazoneplacebo

months

PROACTIVE: primary outcome

24

20

15

HR 95% CI p value

pioglitazone vs placebo

0.904 0.802, 1.018 0.0951

Dormandy JA et al.: Lancet 366:1279, 2005

events

%

0

5

15

0 12 18 366

pioglitazone

months

PROACTIVE: MACEMI, stroke and CV mortality

24

10

pio vs. placeboHR 0.82

(0.70-0.97)p=0.02

Wilcox R. et al AHJ 155:712, 2008

placebo

PROACTIVE: Heart failure risk

Erdmann E et al.: Diabetes Care 30:2773, 2007

events

%

0

2

4

6

0 12 18 30 366

pioglitazone

placebo

months

24

Heart Failure CV diseaseAll cause mortality

No treat. 1.00 1.00 1.00

Metformin0.68 *

(0.65 to 0.71)

0.76 *

(0.74 to 0.79

0.64 *

(0.63 to 0.66

SUs1.00

(0.94 to 1.07)

1.00

(0.95 to 1.05)

1.24 †

(1.20 to 1.28)

Insulin1.26 †

(1.10 to 1.44)

1.22 †

(1.08 to 1.37)

1.64 †

(1.55 to 1.74)

Glitazones0.50 *

(0.26 to 0.97)

0.79

(0.53 to 1.18)

0.89

(0.67 to 1.18)

Gliptins0.87

(0.58 to 1.31)

1.14

(0.85 to 1.54)

1.20

(1.00 to 1.44)

Hippisley-Cox J et al.: BMJ 354:i3477, 2016

diabetes treatments and CV riska cohort (469,688) study in primary care in UK

months

IRIS primary endpoint(stroke or MI, fatal or non-fatal)

Insulin Resistance Intervention after Stroke

Kernan WN et al. NEJM 374:1321, 2016

years 50 1 2 3 4

0

3

6

9

12

15

18

pioglitazone

placebo

patients

with e

vents

(%)

pio vs. placeboHR 0.76

(0.62-0.93)p=0.007

insulin-resistant, non-diabetic subjects


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SU e glinidi SIsolo


pioglitazone NO no<15 SI SI digiuno si

Gliptine

GLP-1 RA

Gliflozine

Insulina bas


gliptin vs. glipizideadd-on to metformin

%

6.0

7.5

8.0

7.0

6.5

weeks

glipizide + met

6 5230 380 12 18 24 46

Nauck MA Diab Ob Metab 9:194, 2007

sitagliptin 100 mg + met

0

10

20

30

40

n episodes

hypos

titrated glipizide + met

gliptins: efficacy according to basal HbA1cthe higher is HbA1c, the higher is efficacy

Reductions are placebo-subtractedNauck MA Diab Ob Metab 9:194, 2007

-2.0

-1.5

-1.0

-0.5

0

<8 8-9 >9

Δ%

HbA1c

sitagliptin 100 mg + met

TECOS: Primary CV Outcome PP Analysis for Non-inferiority

events

%

0

5

10

15

0 2 3 41

sitagliptinplacebo

years

Green JB et al. NEJM 2015* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina

SAVOR: Hospitalization for HF

0%

1%

2%

3%

4%

5%

0 180 360 540 720 900Ho

sp

ita

liza

tio

n f

or

HF

Days

Saxagliptin Placebo

Scirica BM, et al. November 2013. HR: hazard ratio

TECOS: First hospitalization for HF

TECOS, McGuire DK et al.: JAMA Cardiol 1:126, 2016years

410 2 3

patients

with e

vents

(%)

5

4

3

2

1

0

placebo

sitagliptin

CARMELINA hHF

Linagliptin event rate 2.77/100 PY Placebo event rate 3.04/100 PY Treated set, Kaplan-Meier estimate. Hazard ratio and 95% CI based on Cox regression model with terms for treatment group (p=0.2635), region (p=0.0012), history of heart failure (p≤0.0001); *Two-sidedhHF, hospitalization for heart failureRosenstock J et al. JAMA 2018; doi: 10.1001/jama.2018.18269

HR 0.90

(95% CI 0.74, 1.08)

Years

Pa

tie

nts

wit

h e

ve

nt

(%)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.50

5

10

15

Placebo

Linagliptin

gliptins: time to insulin initiation

0%

10%

20%

30%

40%

0 1 2 3 4 5 6 7

patients

requirin

g insulin

initia

tion

years

N=7,728 sulphonylureas

sitagliptin

Valensi P et al. for The Odyssee Observational Study: Diabetes Metab 41:231, 2015


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SU e glinidi SIsolo



Gliptine NO SI NO dig/pra SI si

GLP-1 RA

Gliflozine

Insulina bas


farmacidiversi

short and long-acting GLP-1R agonistsShort-acting GLP-1

RALong-acting GLP-1 RA

FPG reduction + +++

PPG reduction +++ ++

HbA1c reduction ++ +++

Body weight reduction ++ ++

Gastric empting rate +++ +

fasting glucagon secr. +/Neutral ++

GI effects ++ +

Compliance + ++

LEADER: primary composite CV outcome

MACE 3: CV death, non-fatal MI or stroke

years

50 1 2 3 4

0

3

6

9

12

15

18

liraglutide

placebo

Marso SP et al.: NEJM 375:311, 2016

HR: 0.8795% CI: 0.78.097p<0.001 for non-inferiorityp=0.01 for superiority

patients

with e

vents

(%)

months2460

placebo

semaglutide

12 18patients

with e

vent

(%)

SUSTAIN6: MACE (primary outcome)CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke

Marso SP et al.: NEJM 375:1834, 2016

Hazard ratio, 0.74 (95% CI, 0.58–0.95) P<0.001 for noninferiorityP=0.02 for superiority

10

8

6

4

1

0

HARMONY OUTCOMESMACE CV death

MI stroke

Hernandez AF et al.: Lancet. 2018 Oct 1. doi: 10.1016/S0140-6736(18)32261-X

REWIND press release


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SU e glinidi SIsolo




GLP-1 RA NO NO NO vario SI

Gliflozine

Insulina bas


farmacidiversi

farmacidiversi

farmacidiversi

CANVAS & EMPAREGMACE 3: CV death, non-fatal MI or stroke

EMPAREG, Zinman B et al.: NEJM 373:2117, 2015CANVAS, Neal B et al.: NEJM Jun 12, 2017

years

5 610 2 3 4

patients

with e

vents

(%)

20

16

12

8

4

0

EMPAREG:99 % with previous CV event

CANVAS:65 % with previous CV event

placebo

canagliflozin

empaglifllozin

Zinman B et al.: NEJM 373:2117, 2015

9

8

7

6

5

4

3

2

1

0

empagliflozin

placebo

1 2 3 40

HR 0.62(95% CI 0.49, 0.77)

p<0.0001risk reduced by 38%

patients

with e

vent

(%)

years

EMPAREG: CV mortality

FINALLY!happy doctors

DECLARE has the broadest representation of the T2D patients with CV risk among the of the SGLT2i CV outcomes studies

CV, cardiovascular; SGLT2, sodium glucose co-transporter 2; T2D, type 2 diabetes; eCVD, established CV disease.

1. Zinman B, et al. N Engl J Med 2015;373:2117–2128;; 2. Neal B, et al. N Engl J Med 2017; DOI: 10.1056/NEJMoa1611925;3. SattarDiabetologia (2013) 56:686–695 4. Raz I, et al. Diabetes Obes Metab 2018. http://dx.doi.org/10.1111/dom.13217

.

34%of patients did not have eCVD

~60%of patientsdid not have eCVD

1%of patients

did not have eCVD

The proportion of patients with and without established CV disease varied across the three SGLT2 CV outcome studies

EMPAREG(N=7,020)

CANVAS(N=10,142)

DECLARE(N=17,160)

In this low CV risk population, dapagliflozin patients had a significant reduction of hHF/CV death and fewer MACE events compared to placebo

N at risk is the number of subjects at risk at the beginning of the period. 2-sided p-value is displayed; HR, CI, and p-value are from cox proportional hazard model.

CV, cardiovascular; Dapa, dapagliflozin; hHF, hospitalization for heart failure; MACE, major adverse cardiac event

Wiviott SD et al. Online ahead of print. N Engl J Med. 2018

hHF/CVD

HR 95% CI P value

0.83 (0.73, 0.95) 0.005Patients

with e

vent

(%)

6

0 1 2 3 4 5

4

2

0

Placebo (496 Events)

DAPA 10 mg (417 Events)

yearsPatients

with e

vent

(%)

10.0

0 1 2 3 4 5

7.5

5.0

2.5

0.0

Placebo (803 Events)

DAPA 10 mg (756 Events)

MACE

HR 95% CI P value

0.93 (0.84, 1.03) 0.172

years

hHF per CV history

Dapagliflozin prevents hHF consistently across a broad range of T2D patients regardless of history of eCVD or HF

Overall population

CV, cardiovascular; eCVD, established CV disease; HF, heart failure; hHF, hospitalized heart failure; SGLT-2i, SGLT co-transporter 2 inhibitor; T2D, type 2 diabetes


0.78 (0.63, 0.97)

Hazard ratio (95% CI)

Favors Dapagliflozin

Favors Placebo

0.64 (0.46, 0.88)

0 0,5 1 1,5

Established CV Disease (eCVD)

Multiple Risk Factors (No eCVD)

CV history

0.73 (0.61, 0.88) Overall population

0 0,5 1 1,5

0.73 (0.55, 0.96)



Favors Placebo

Prior HF*

0.73 (0.58, 0.92)No prior HF

*10% of patients in DECLARE had prior HF

hHF per HF history

0.73 (0.61, 0.88)

HF history

The renal protective effects of dapagliflozin were similar across baseline CV risk subgroup

CV, cardiovascular; eCVD, established CV disease; HF, heart failure; hHF, hospitalized heart failure; SGLT-2i, SGLT co-transporter 2 inhibitor; T2D, type 2 diabetes


0.79 (0.66, 0.94)



Favors Placebo

0.74 (0.60, 0.91)

0 0,5 1 1,5 0 0,5 1 1,5

0.55 (0.41, 0.75)



Favors Placebo

0.51 (0.37, 0.69)

composite Renal & CV death composite Renal

Overall population



CV history

0.76 (0.67, 0.87) 0.53 (0.43, 0.66)Overall population



CV history

composite Renal: composite of ≥40% decrease in eGFRa to <60 mL/min/1.73 m2, ESRD, or renal death

add on tomonotherapy

efficacy of gliflozins in various settingscompared vs. placebo at 24 weeks

-0,23-0,3

-0,04-0,13

-0,42-0,3

-0,89 -0,84

-0,45

-0,82

-0,97-0,9

-1,2

-1

-0,8

-0,6

-0,4

-0,2

0

1Ferrannini E, et al. Diabetes Care 2010;33:2217-24. 2Bailey CJ, et al. Lancet 2010;375:2223-33. 3Jabbour et al., Diabetes Care, pub online 15Jan2014 ; 4Strojek K, et al. Diabetes Obes Metab 2011;13:928-38. 5Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 0986-P. 6Wilding J, et al. Diabetes. 2010;59 (Suppl 1):A21-A22. Abstract 0078-OR.

HbA1c (

%)

met gliptin SU pio insulin


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Gliflozine NO NO SIpreviene

!dig/pra si

Insulina bas

farmacidiversi


farmacidiversi

farmacidiversi


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Gliflozine NO NO SIpreviene

!dig/pra si

Insulina bas SI SI NO NO dig prandiale no obbligato?

farmacidiversi


farmacidiversi

farmacidiversi

Migliorare qualità della VITA

Evitare ipoglicemieEvitare i sintomi della iperglicemia

Evitare reazioni avverse

Prevenire rischio cardiovascolare

Prevenire il calo ponderale eccessivo

Prevenire complicanze vascolari

Valutazione comprensiva BIOLOGICA-PSICOLOGICA-SOCIALE

Scelta del miglior rapporto rischio beneficiopossibile

conoscere il PAZIENTE conoscere i FARMACI

obiettivi della personalizzazione della terapia nell’ anziano diabetico

take home messages

team diabete

Gian Pio

Francesca

Flavia

Ilaria Teresa Simona

RacheleChiara

Serena

ottimizzazione della terapia nel paziente complesso€¦ · ottimizzazione della terapia nel...

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