Terapia con agonisti GLP1 e outcome cardiovascolare. Edoardo Mannucci

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1 Terapia con agonisti GLP e outcome cardiovascolare Edoardo Mannucci

2 Conflitti di interessi Negli ultimi due anni, E. Mannucci ha ricevuto compensi per relazioni e/o consulenze da: Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, and Takeda. La struttura diretta da E. Mannucci ha ricevuto donazioni, finanziamenti per ricerca o compensi per trial clinici da: AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, and Novo Nordisk. 2

3 FDA Guidance for CV safety of new drugs for diabetes 3

4 CV safety studies for diabetes drugs Methodological issues Designed for non-inferiority (event-driven, target 6 events) Enrolment of very high-risk patients Relatively short duration of follow-up Attempt at minimizing between-group differences in glucose control Mannucci E, Mosenzon O, Avogaro A. Diabetes Care. 39 Suppl 42:S96-204, 206.

5 Lixisenatide: effect on major cardiovascular events Results of the ELIXA trial Principal endpoint: 4-point MACE (nonfatal MI, nonfatal stroke, and cardiovascular death, hospitalization for unstable angina) 6068 T2DM patients with recent acute coronary syndrome, lixisenatide vs placebo :. Follow-up: 2. y Pfeffer MA et al. N Engl J Med 373: , 205

6 Liraglutide: effect on major cardiovascular events Results of the LEADER trial Principal endpoint: 3-point MACE (nonfatal MI, nonfatal stroke, and cardiovascular death) 9,340 T2DM patients with prior cardiovascular disease and/or high CV risk, Liraglutide vs placebo :. Follow-up: 4 y Marso SP et al. N Engl J Med 375: 3-22, 206 6

7 Liraglutide: effect on all-cause mortality Results of the LEADER trial Secondary endpoint: All-cause mortality 9,340 T2DM patients with prior cardiovascular disease and/or high CV risk, Liraglutide vs placebo :. Follow-up: 4 y Marso SP et al. N Engl J Med 375: 3-22, 206 7

8 Semaglutide: effect on major cardiovascular events Results of the SUSTAIN-6 trial Principal endpoint: 3-point MACE (nonfatal MI, nonfatal stroke, and cardiovascular death) 3,297 T2DM patients with prior cardiovascular disease and/or high CV risk, Semaglutide vs placebo :. Follow-up: 2 y Marso SP et al. N Engl J Med 375: , 206 8

9 Liraglutide: characteristics of the enrolled sample Characteristic (%) Yes No Women Age<60 y BMI<30 kg/m Ac<8.3% 5 49 Duration of DM<0 y Prior CVD 8 9 Insulin treatment egfr<60 ml/min Principal endpoint: 3-point MACE (nonfatal MI, nonfatal stroke, and cardiovascular death) 9,340 T2DM patients with prior cardiovascular disease and/or high CV risk, Liraglutide vs placebo :. Follow-up: 4 y Marso SP et al. N Engl J Med 375: 3-22, 206 9

10 GLP receptor agonists kinetics Liraglutide vs lixisenatide Lixisenatide Liraglutide Time (hours) 0 Cantini G, Mannucci E, Luconi M. Trends Endocrinol Metab 27: ,

11 Exenatide LAR vs bid: glucose profiles Results of the DURATION- trial Drucker DJ et al. Lancet, 372:240-50, 2008

12 CV risk factors in CV safety trials in diabetes Mean differences between active treatment and placebo Study Drug Ac (%) BW (kg) sbp (mmhg) MACE (%) TECOS Sitagliptin EXAMINE Alogliptin SAVOR Saxagliptin ELIXA Lixisenatide LEADER Liraglutide SUSTAIN-6 Semaglutide EMPAREG Empagliflozin

13 Glycemic control and risk of MI in T2DM Meta-analysis of RCTs on intensification of therapy Mannucci E et al. Nutr Metab Cardiovasc Dis 9: 604-2,

14 Glycemic control and cardiovascular risk in type 2 DM Summary of CVOTs and RCTs on intensification of therapy Mannucci E, Monami M, Ceriello A, Rotella CM. Nutr Metab Cardiovsc Dis, 207 4

15 GLP receptor agonists: cardiovascular actions Mannucci E & Dicembrini I, Curr Med Res Opin 28:75-2, 202 5

16 Myocardial effects of GLP- (9-36) Recovery after ischemia-reperfusion in rats Ban et al. Circulation 7: ,

17 Biological effects of liraglutide Human pre-adipocites from primary cultures, visceral adipose tissue Cantini G, Di Franco A, Samavat J, Forti G, Mannucci E, Luconi M. Mol Cell Endocrinol. 402: 43-50,

18 Biological effects of GLP- (9-36) Human pre-adipocites from primary cultures, visceral adipose tissue Cantini G, Di Franco A, Mannucci E, Luconi M. Mol Cell Endocrinol. 439:0-5,

19 GLPRA: effect on major cardiovascular events Pooled analyses of phase 2-3 trials Mannucci E, Monami M. Adv Ther 34:-40, 207 9

20 Exenatide: results of CV outcome trials The FREEDOM-CVO trial was designed to test CV safety in a preapproval setting, and we are pleased that it has achieved all of its clinical endpoints and was completed on time. Intarcia Press release on ITCA-650 exenatide, May 6th, 206 The EXSCEL trial met its primary safety objective of non-inferiority for MACE. These results address the US Food and Drug Administration (FDA) requirement that medicines to treat T2D are not associated with an increase in CV risk. Fewer CV events were observed in the Bydureon arm of the trial, however, the efficacy objective of a superior reduction in MACE did not reach statistical significance. AstraZeneca Press release on exenatide LAR, May 23th,