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To satisfy regulatory requirements about showing cardiovascular (CV) safety of new diabetes medications, industry-sponsored researchers have conducted this randomized trial of once-weekly injected exenatide (Bydureon), a glucagon-like peptide-1 (GLP-1)-receptor agonist. Nearly 15,000 patients (mean age, 62) with longstanding type 2 diabetes received exenatide or placebo. During the trial, patients were permitted to use other diabetes drugs (oral agents and insulin). At baseline, about 70% of patients had experienced previous adverse CV events, and glycosylated hemoglobin (HbA1c) level averaged 8%.
During average follow-up of about 3 years, mean HbA1c levels changed little in the placebo group and dropped by roughly 0.5% in the exenatide group. The incidence of the primary CV outcome (CV-related death, myocardial infarction, or stroke) was 11.4% in the exenatide group and 12.2% in the placebo group. This difference met statistical criteria for exenatide's noninferiority (for safety) but not superiority (for efficacy).
Holman RR et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017 Sep 28; 377:1228. (http://dx.doi.org/10.1056/NEJMoa1612917)
Comment
In this study, exenatide did not demonstrate CV harm, but it fell short of showing a statistically significant CV benefit. In contrast, another FDA-approved GLP-1 analogue (liraglutide) was associated with a significant 2 percentage-point reduction in adverse CV events during 4 years (NEJM JW Gen Med Jul 15 2016 and N Engl J Med 2016; 375:311). This apparent inconsistency might reflect intrinsically different CV effects of the two drugs or just differences in various aspects of the two trials.