Cardiovascular Events and Mortality With GLP-1 Receptor Agonists

woman taking blood sugar test, finger, diabetes
woman taking blood sugar test, finger, diabetes
Glucagon-like peptide-1 receptor agonists can reduce major adverse cardiovascular events in patients with type 2 diabetes.

Lixisenatide, liraglutide, semaglutide, and extended-release exenatide represent safe glucagon-like peptide-1 (GLP-1) receptor agonist drugs that can lower 3-point major adverse cardiovascular events (MACE), cardiovascular mortality, and all-cause mortality effectively in patients with type 2 diabetes, according to findings from a meta-analysis published in Lancet Diabetes & Endocrinology.1

For this systematic review and meta-analysis, investigators collected data from 4 randomized controlled trials that reported efficacy and safety outcomes associated with GLP-1 receptor agonists vs placebo in adult patients with type 2 diabetes. Each trial assessed a different GLP-1 receptor agonist: ELIXA (lixisenatide; identifier: NCT01147250), LEADER (liraglutide; identifier: NCT01179048), SUSTAIN 6 (semaglutide; identifier: NCT01720446), and EXSCEL (extended-release exenatide; identifier: NCT01144338). Studies included patients who had a 3-point MACE primary outcome (cardiovascular mortality, nonfatal myocardial infarction [MI], and nonfatal stroke).

Following an analysis of the available data, treatment with GLP-1 receptor agonists was associated with a 10% relative risk reduction in the 3-point MACE primary outcome (hazard ratio [HR], 0.90; 95% CI, 0.82-0.99; P =.033) as well as a 13% relative risk reduction in cardiovascular mortality (HR, 0.87; 0.79-0.96; P =.007) and 12% relative risk reduction in all-cause mortality (HR, 0.88; 0.81-0.95; P =.002). There were no significant differences between GLP-1 receptor agonists and placebo on fatal and nonfatal MI, hospital admission for unstable angina, hospital admission for heart failure, or fatal and nonfatal stroke.

Additionally, there was no difference between GLP-1 receptor agonist therapy or placebo with regard to the incidence of pancreatitis, pancreatic cancer, medullary thyroid cancer, or hypoglycemia.

Aggregate data were used in this analysis, limiting the ability to understand the effect of GLP-1 receptor agonist therapy on different patient subgroups or to determine the cumulative follow-up time for safety outcomes. In addition, many of the studies included in this analysis had a follow-up period of only 2 to 4 years, restricting the ability to determine long-term use of GLP-1 receptor agonists in the treatment of diabetes.

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Because various GLP-1 receptor agonist therapies appear to be safe for patients with diabetes, the investigators suggested treatment should be, “based on factors important to patients, including convenience, potency, ease of delivery, tolerability, and price, as well as their effect on cardiovascular risk.”

Disclosures: This study was funded by Amylin Pharmaceuticals (AstraZeneca). In addition, several authors have received funding from various pharmaceutical companies.


Bethel MA, Patel RA, Merrill P, et al; for the EXSCEL Study Group. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis [published online December 5, 2017]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(17)30412-6