Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes

TLDR

Cardiovascular effects of once‑weekly exenatide in type 2 diabetes are unknown. The study aimed to determine whether once‑weekly exenatide was noninferior to placebo for safety and superior for efficacy. A randomized, double‑blind, placebo‑controlled trial of 14,752 patients compared once‑weekly 2 mg exenatide to placebo, with the primary composite outcome of cardiovascular death, non‑fatal myocardial infarction, or non‑fatal stroke. Exenatide met the noninferiority safety endpoint (hazard ratio 0.91, 95 % CI 0.83–1.00) but did not achieve superiority for efficacy, with no significant difference in major adverse cardiovascular events versus placebo. Funded by Amylin Pharmaceuticals, trial registered at ClinicalTrials.

Abstract

The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 . ).