Once-weekly therapy with the glucagonlike peptide-1 (GLP-1) receptor agonist exenatide in patients with type 2 diabetes mellitus (T2DM) does not appear to cause an increase in their overall cardiovascular risk, according to results of a large cardiovascular safety outcomes trial.
Trials that have assessed cardiovascular outcomes associated with the use of newer glucose-lowering agents have shown mixed results, noted researchers led by Rury R. Holman, director of the University of Oxford Diabetes Trials Unit, United Kingdom.
A once-weekly, injectable, extended-release formulation of exenatide, a GLP-1 receptor agonist approved for the treatment of T2DM in 2012, has been shown to lower blood glucose and induce modest decreases in body weight, blood pressure, and lipid levels. But the drug has also been shown to increase heart rate.
The multinational Exenatide Study of Cardiovascular Event Lowering (EXSCEL) assessed the long-term cardiovascular safety and efficacy of exenatide, administered once weekly, in 14,752 patients, median age 62 years, with T2DM who had a wide range of cardiovascular risk; 7356 patients were assigned to receive exenatide 2 mg subcutaneously and 7396 to receive placebo once weekly.
The researchers published their results in the September 14, 2017 New England Journal of Medicine.
Baseline characteristics were well-balanced between the two groups. About three-quarters of the patients had previous cardiovascular disease. Most were obese (mean body mass index of 32 kg/m2) and median duration of T2DM was 12 years.
Open-label medications for diabetes were permitted, except for GLP-1 receptor agonists. About three-quarters of patients were using metformin, about one-third were taking sulfonylureas, 45% were also using insulin, 12% dipeptidyl peptidase-4 inhibitors, and a small number were using sodium glucose cotransporter-2 (SGLT2) inhibitors.
The trial met its primary safety hypothesis. There was no cardiovascular risk with exenatide, and no risk of hospitalization for heart failure, pancreatic cancer, or pancreatitis. The findings for secondary outcomes, including rates of death from cardiovascular causes, fatal or nonfatal MI, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, did not differ significantly between the two groups.
However, exenatide was not superior to placebo with respect to efficacy. The risk of death from any cause was 6.9% in the exenatide group and 7.9% in the placebo group (hazard ratio, 0.86). The primary composite end point was first occurrence of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. This occurred in 11.4% of patients taking exenatide over a median of 3.2 years compared with 12.2% of those taking placebo. There was a reduction in all-cause mortality and a hint of cardiovascular benefit in a subgroup of patients aged 65 years and older.
The authors state that the lack of cardiovascular efficacy in the current trial may be related to multiple factors, including:
- Short median follow-up and duration of drug exposure;
- A lower level of baseline glycated hemoglobin;
- A large number of placebo patients receiving therapies known to reduce cardiovascular risk, such as SGLT-2 inhibitors and GLP-1 receptor agonists.
Also, there was no “run-in” period in contrast to most of the other GLP-1 agonist cardiovascular-outcomes trials, the researchers noted.