Exenatide fails to beat placebo on major cardiovascular events in 14,752-patient EXSCEL trial

Researchers reported in 2017 that adding once-weekly extended-release exenatide to usual care did not significantly reduce major cardiovascular events in adults with type 2 diabetes ^[1]. In the trial, called EXSCEL, the gap between the drug and placebo fell short of the statistical bar the investigators had set for superiority ^[1].

Participants were randomly assigned to subcutaneous injections of 2 mg extended-release exenatide or a matching placebo once a week ^[1]. Everyone continued usual care ^[1]. People could enroll whether or not they already had cardiovascular disease, and most did: 10,782 of the 14,752 participants, or 73.1%, had previous cardiovascular disease ^[1]. Median follow-up was 3.2 years, with an interquartile range of 2.2 to 4.4 years ^[1].

The primary endpoint combined three outcomes, counted as the first of any of them to occur: death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke ^[1]. It occurred in 839 of 7,356 patients taking exenatide, or 11.4%, for a rate of 3.7 events per 100 person-years ^[1]. In the placebo group, 905 of 7,396 patients had such an event, or 12.2%, for 4.0 events per 100 person-years ^[1]. The hazard ratio was 0.91, with a 95% confidence interval of 0.83 to 1.00 ^[1].

That interval produces the trial's split verdict. Exenatide was noninferior to placebo on safety, with P<0.001 for noninferiority, but it was not superior for efficacy, with P=0.06 ^[1]. Because the confidence interval reaches 1.00, the data are compatible both with a small reduction in risk and with no effect at all ^[1].

Individual components pointed the same inconclusive way. Rates of cardiovascular death, fatal or nonfatal heart attack, fatal or nonfatal stroke, hospitalization for heart failure and hospitalization for acute coronary syndrome showed no significant difference between groups ^[1]. Neither did the rates of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma or serious adverse events overall ^[1]. The authors wrote that the incidence of major adverse cardiovascular events did not differ significantly between the exenatide and placebo groups ^[1]. Amylin Pharmaceuticals funded the study, registered as NCT01144338 ^[1].

Why it matters for patients

A cardiovascular outcomes trial is the test used to show whether a diabetes drug protects the heart and blood vessels, and this one did not clear that bar for exenatide ^[1]. Even in a group where nearly three-quarters of participants already had cardiovascular disease, the trial did not demonstrate a statistically significant drop in heart attacks, strokes or cardiovascular deaths ^[1].

The result reads as a near miss rather than a sign of harm. The confidence interval of 0.83 to 1.00 spans everything from a meaningful benefit to no difference, and the safety comparison against placebo was met ^[1]. So people taking exenatide get no evidence here that the drug raises cardiovascular risk, and no evidence that it lowers it ^[1].

Exenatide is a separate molecule from semaglutide (Ozempic, Wegovy, Rybelsus) and tirzepatide (Mounjaro, Zepbound). Cardiovascular benefit is established one drug at a time in its own trial, so findings for exenatide do not carry over to other GLP-1 medicines or to tirzepatide ^[1].

What has not been reported

The trial report does not describe any regulatory action, labeling change or effect on prescribing or sales that followed the result ^[1]. It also does not say whether exenatide later received a cardiovascular indication ^[1]. Outcomes beyond the median follow-up of 3.2 years were not reported ^[1], and the report does not compare exenatide with other GLP-1 medicines for cardiovascular risk ^[1]. The noninferiority margin the researchers used is not stated in the abstract ^[1].