Adding a weekly injection of exenatide, a glucagon-like peptide-1 (GLP-1) analogue, to usual care did not affect the rate of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2DM). Seventy-three percent of patients in the industry-funded trial had pre-existing cardiovascular (CV) disease. Over 3.2 years of follow-up, a MACE occurred in 11.4% of the exenatide group compared to 12.2% of the placebo group, an insignificant difference.
The study was published in the Sept. 28, 2017, New England Journal of Medicine and summarized in the October 2017 ACP Diabetes Monthly. The following commentary by Lorraine L. Lipscombe, MD, MSc, was published in the ACP Journal Club section of the Dec. 19, 2017, Annals of Internal Medicine.
GLP-1 analogues lower serum glucose by suppressing glucagon and enhancing insulin secretion in response to hyperglycemia; exenatide is one of six GLP-1 analogues approved for treatment of T2DM. EXSCEL is the fourth placebo-controlled trial to report CV outcome results for GLP-1 analogues. Like lixisenatide, liraglutide, and semaglutide, exenatide was noninferior to placebo for MACE outcomes in patients with T2DM and high CV risk. However, whereas liraglutide and semaglutide also reduced major CV events compared with usual care, no CV benefit was shown for lixisenatide or exenatide.
The lack of CV benefit for lixisenatide may be explained by differences in the study population, shorter follow-up, and a smaller reduction in HbA1c levels compared with other GLP-1 analogue trials. However, these factors were comparable between EXSCEL and trials of liraglutide and semaglutide. Why exenatide failed to reduce CV outcomes is unclear. One reason may be that almost half of patients (43%) discontinued the drug prematurely, which is substantially higher than in other trials and may have attenuated potential benefits. The efficacy of exenatide may also be lower than for liraglutide and semaglutide. Head-to-head comparisons of GLP-1 analogues for CV outcomes are lacking; however, liraglutide is associated with a greater reduction in HbA1c levels and body weight than exenatide.
Exenatide can be considered a second-line option for patients with T2DM because safety is similar to that of other GLP-1 analogues. Patients may also prefer the convenience of once-weekly dosing. However, for T2DM patients at high CV risk, agents with demonstrated CV benefit should be selected.