Sara BelcastroSCDU Endocrinologia, Diabetologia e Metabolismo

Università di Torino

sara.belcastro@unito.it

Congresso Congiunto AMD-SID-SIEDP-ANIED-OSDIGenova 26 ottobre 2019

Sistema nervoso centrale: effetti sulle patologie cerebrovascolari e sulle malattie degenerative del sistema nervoso

Terapie del diabete: certezze consolidate e nuove prospettive

Dr. Sara Belcastro declares to have received in the last two yearscompensation or financing from the following pharmaceutical and/or

diagnostic companies: Merck, Novartis, Boehringer, Lilly, Mundipharma, Novo Nordisk and Bruno.

Disclosure

Ischaemic heart disease is the leading cause of mortality in patients with T2D

35%

15%10%

40%

Low Wang CC et al. Circulation 2016;133:2459–502

Non-cardiovascular causes

Ischaemic heartdisease

Other heart disease(predominantly congestive)

Stroke

Despite management of modifiable risk, placebo-treated patients were still at risk of CV and renal events

aEvent rate ranges are taken from values reported for the placebo groups in the CANVAS Program, EMPA-REG OUTCOME and DECLARE-TIMI 58 CV outcome trials; bComponents of the renal composite endpoint differed slightly across trials. CANVAS: 40% reduction in eGFR, renal replacement therapy or renal death; EMPA-REG Outcome: 40% reduction in eGFR (to < 60 ml/min/1.73 m2), end stage renal disease or renal death; DECLARE-TIMI 58: Doubling of serum creatinine accompanied by eGFR of ≤ 45 ml/min/1.73 m2, initiation renal replacement therapy or renal death. CV, cardiovascular; HF, heart failure, MI, myocardial infarction. 1. Zinman B et al. N Engl J Med 2015;373:2117–28; 2. Neal B et al.N Engl J Med 2017;377:644–57; 3. Wiviott SD et al. N Engl J Med 2019;380:347–57; 4. Wanner C et al. N Engl J Med 2016;375:1801–2

CV event rates in placebo-treated patients in CV outcome trials

CV deatha

7–20patients per

1000 patient-years1-3

Non-fatal strokea

7–9patients per

1000 patient-years1-3

Non-fatal MIa

12–19patients per

1000 patient-years1-3

Hospitalizationfor HFa

9–15patients per

1000 patient-years1-3

Renal compositea,b

7–12patients per

1000 patient-years2–4

Modifiable risk factors were addressed in patients with T2D in CV outcomes trials

aAverage of placebo-group populations from CANVAS Program, DECLARE-TIMI 58, EMPA-REG OUTCOME and overall population for VERTIS CV, CV outcomes trials bAverage of placebo-group populations from CANVAS Program, EMPA-REG Outcome and overall population for DECLARE-TIMI 58 and VERTIS CV. BMI; BMI, body mass index; CV, cardiovascular, RAS, renin–angiotensin system1. Zinman B et al. N Engl J Med 2015;373:2117–28; 2. Neal B et al. N Engl J Med 2017;377:644–57; 3.

4. Cannon CP et al. Am Heart J 2018;206:11–23; 5. Raz I et al. Diabetes Obes Metab 2018;20:1102–10.Wiviott SD et al. N Engl J Med

2019;380:347–57;

Total cholesterol1,2,4,5,b Blood pressure1–4,a Obesity (BMI)1–4,a HbA1c1–4,a

Range: 4.2–4.4 mmol/L Systolic range: 133–137Diastolic range: 77–78

30.7–32.0 kg/m2 8.1–8.3% (65–67 mmol/mol)

Management of modifiable risk factors in CV outcomes trial populations1–5

Statin use ranged from 75–81% of patients across

CVOTs1–4a

Anti-thrombotic use ranged from 61–90%

of patients across CVOTs1–4a

RAS-inhibitor use ranged from 80–81%

of patients across CVOTs1–4a

β-blocker use ranged from 53–69% of patients across

CVOTs1–4a

Diuretic use ranged from 41–45% of patients across

CVOTs1–4a

Hyperglycaemia is a strong predictor of stroke or acute MI among patients with T2D

Patients with T2D: n = 271 174GFR, glomerular filtration rate; LDL, low-density lipoprotein; MI, myocardial infarction

1. Rawshani A et al. N Engl J Med 2018;379:633-44

Stroke MIHbA1c

Systolic blood pressureDuration of diabetes

Physical activityAtrial fibrillation

IncomeMarital status

SmokingEstimated GFR

Lipid-lowering medicationBlood pressure medication

LDL cholesterolDiastolic blood pressure

Body mass indexHeart failureAlbuminuria

EducationImmigrant

0.000 0.005

Increasing importance

0.010 0.015R2

0.000 0.005

Increasing importance

0.010 0.020R2

0.015

HbA1cSystolic blood pressure

LDL cholesterolPhysical activity

SmokingDuration of diabetes

Estimated GFRIncome

Diastolic blood pressureHeart failure

Blood pressure medicationMarital status

EducationAlbuminuria

Lipid-lowering medicationImmigrant

Atrial fibrillationBody mass index

Elevated risk of mortality and cardiovascular morbidity in patients with T2D

1. Rawshani A et al. N Engl J Med 2018;379:633–44

0.8

1.0

2.0

Haza

rd ra

tio

0.0

LDL cholesterol (mmol/L)

1.2

1.6

2.5 5.0 7.5

Systolic blood pressure (mmHg)Glycated haemoglobin (mmol/mol)

100 150 200

50 75 100

Death from any cause

0.8

1.0

2.5

Haza

rd ra

tio

0.0

1.5

2.0

2.5 5.0 7.5

100 150 200

50 100 150

Acute myocardial infarction

3.0

0.8

1.0

2.0

0.0

1.2

1.6

2.5 5.0 7.5

100 150 200

50 100 150

Stroke

1.0

4.0

0.0

2.0

3.0

2.5 5.0 7.5

100 150 200

50 100 150

Heart failure

Haza

rd ra

tio

Haza

rd ra

tio

DPP4 is do not increase or decrease the overall risk of CV events

Study SAVOR-TIMI 531,4

(N = 16 492)EXAMINE2,4

(N = 5380)TECOS3,4

(N = 14 671)

DPP4i Saxagliptin Alogliptin Sitagliptin

Study population History of established CV disease or multiple CV risk factors

Acute MI or unstable angina requiring hospitalization

Pre-existing CV disease

3-P MACE 1.00a,b (0.89–1.12) 0.96a,b (upper ≤ 1.16) 0.99a,b (0.89–1.10)

CV death 1.03 (0.87–1.22) 0.79 (0.60–1.04) 1.03 (0.89–1.19)

Fatal or non-fatal MI 0.95 (0.80–1.12) 1.08 (0.88–1.33)c 0.95 (0.81–1.11)

Fatal or non-fatal stroke 1.11 (0.88–1.39) 0.91 (0.55–1.50)c 0.97 (0.79–1.19)

Hospitalization for HF 1.27a (1.07–1.51) – 1.00 (0.83–1.20)

All-cause death 1.11 (0.96–1.27) 0.88 (0.71–1.09) 1.01 (0.90–1.14)

1. Scirica BM et al. N Engl J Med 2013;369:1317–26; 2. White WB et al. N Engl J Med 2013;369:1327–35;3. Green JB et al. N Engl J Med 2015;373:232–42; 4. Son JW, Kim S. Diabetes Metab J 2015;39:373–83

HRs (95% CI) for DPP4i CV outcomes trial endpoints

GLP1RAs have variable effects on CV outcomes

Study ELIXA1

(N = 6068)LEADER2

(N = 9340)SUSTAIN-63

(N = 3297)EXSCEL4

(N = 14 752)HARMONY5

(N = 9463)

GLPIRA Lixisenatide Liraglutide Semaglutide sc Exenatide Albiglutide

Study population T2D and acute coronary syndrome

T2D and high CV risk

T2D T2D with or without previous CV disease

T2D and CV disease

Primary endpointa 1.02 (0.89–1.17)b 0.87b,c (0.78–0.97) 0.74b,c (0.58–0.95) 0.91b,c (0.83–1.00) 0.78b,c (0.68–0.90)

CV death 0.98 (0.78–1.22) 0.78b (0.66–0.93) 0.98 (0.65–1.48) 0.88 (0.76–1.02) 0.93 (0.73–1.19)

Non-fatal MI 1.03 (0.87–1.22) 0.88 (0.75–1.03) 0.74 (0.51–1.08) 0.97d (0.85–1.10) 0.75b,d (0.61–0.90)

Non-fatal stroke 1.12 (0.79–1.58) 0.89 (0.72–1.11) 0.61b (0.38–0.99) 0.85d (0.70–1.03) 0.86d (0.66–1.14)

Hospitalization for HF 0.96 (0.75–1.23) 0.87 (0.73–1.05) 1.11 (0.77–1.61) 0.94 (0.78–1.13) –

All-cause death 0.94 (0.78–1.13) 0.85b (0.74–0.97) 1.05 (0.74–1.50) 0.86 (0.77–0.97) 0.95 (0.79–1.16)

1. Pfeffer MA et al. N Engl J Med 2015;373:2247–57; 2. Marso SP et al. N Engl J Med 2016;375:311–22; 3. Marso SP et al. N Engl J Med 2016;375:1834–44; 4. Holman RR et al. N Engl J Med 2017;377:1228–39; 5. Hernandez AF et al. Lancet 2018;392:1519 –29

HRs (95% CI) for GLP1RA CV outcomes trial endpoints

J. Lovshin and David Cherney Diabetes 2015

SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: A systematic review and meta-analysis

Diabetes, Obesity and Metabolism, Volume: 20, Issue: 8

Inzucchi SE Endocrinol Metab Clin N Am 2018

Proposed glucose-lowering strategy in T2DM with CVD favoring agents demostrated to improve CV outcomes

Il passaporto di un farmaco antidiabetico Ottimizzazione del compenso glico-metabolico

Riduzione di peso

No ipoglicemia

Sicurezza CV o superiorità!

Manegevolezza

Effetti extraglicemici …capacità di modificare la storia naturale della malattia

Y. Seino, D.Yabe Journal of Diabetes Investigation 2013

GLP-1 RA Neuroprotection

Adapted from: Kim DS. et al.,Cell. Transplantation, 2017, Vol 26(9) 1560-1571

Y. Seino, D.Yabe Journal of Diabetes Investigation 2013

Exenatide had positive effects onpratically defined off-medicationmotor scores in Parkinson’s disease,which were sustained beyond theperiod of exposure. Exenatiderepresents a major new avenue forinvestigation in Parkinson’s disease,and effects on everyday symptomsshould be examined in longer-termtrials.

D. Athauda et al. The Lancet Vol 390. 2017

IY Simsir et al . Diabetes & Metabolic Syndrome Review 2018

Study ongoing…

«Sapere che sappiamo quel che sappiamo, e sapere che nonsappiamo quel che non sappiamo; questa è la vera conoscenza».