Patients with type 2 diabetes who took once-daily exenatide did not appear to have an increase in their overall cardiovascular risk, compared with those who took placebo, a large randomized trial demonstrated.

“We did not observe any specific safety issues during our trial; there was no adverse signal with respect to heart failure, despite the higher mean heart rate in the exenatide group than in the placebo group, and events of acute pancreatitis and pancreatic cancer were rare, with similar rates in the two groups,” according to researchers led by Rury R. Holman, F.Med.Sci. Their study was published online Sept. 14 in the New England Journal of Medicine, and was presented at the annual meeting of the European Association for the Study of Diabetes.

For the trial, which was funded by Amylin Pharmaceuticals and known as the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), the researchers randomly assigned 14,752 patients with type 2 diabetes at 687 sites in 35 countries to receive subcutaneous injections of extended-released exenatide at a dose of 2 mg, or matching placebo once per week, from June 18, 2010, through Sept. 16, 2015. The patients were followed for a median of 3.2 years and the main outcome of interest was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or stroke.

Dr. Holman, professor of diabetic medicine at Oxford (England) University and director of the University of Oxford Diabetes Trials Unit of the Oxford Center for Diabetes, England, and his associates reported that 10,782 of the 14,752 patients (73.1%) had previous cardiovascular disease. A primary composite outcome event occurred in 11.4% of patients in the exenatide group, compared with 12.2% of those in the placebo group, which translated into a hazard ratio of 0.91.

In the meantime, the intention-to-treat analysis revealed that exenatide was noninferior to placebo with respect to safety (P less than .001) but was not superior to placebo with respect to safety (P = .06). The researchers observed no significant differences between the two groups in the rates of death from cardiovascular causes, fatal or nonfatal MI, or stroke, hospitalization for heart failure or for acute coronary syndrome, or in the incidence of cute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events.

“The pragmatic design of the trial included integration with usual care and wide-ranging eligibility criteria,” the researchers wrote. “For example, patients with any degree of cardiovascular risk who were at least 18 years of age (with no upper age limit) were eligible. To further augment the potential generalizability of any findings, we evaluated the cardiovascular effect of once-weekly extended-release exenatide in the usual-care setting by maintaining the focus of management of diabetes and cardiovascular risk with the usual-care provider.”

The researchers acknowledged certain limitations of the study, including the rate of premature discontinuation of the trial regimen, “which was driven by patient decision. We speculate that probable factors for discontinuation were the complexity of the first-generation injection device that was used and the fact that our trial had no run-in period.”

The trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trial Unit, in collaboration with Amylin Pharmaceuticals. Dr. Holman and his coauthors reported having numerous financial ties to the pharmaceutical industry.

PRIMARY SOURCE: N Engl J Med 2017 Sept. 14. doi: 10.1056/NEJMoa1612917


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