Assessment of Cardiovascular Risk With Glucagon-Like Peptide 1 Receptor Agonists in Patients With Type 2 Diabetes Using an Alternative Measure to the Hazard Ratio

Abstract

Background: Randomized clinical trials with the aim of evaluating the cardiovascular risks associated with glucagon-like peptide 1 (GLP-1) receptor agonists, lixisenatide, liraglutide, semaglutide, and exenatide, have been conducted. They showed different results among the agents, but the reason has not been explained. Objective: To evaluate the cardiovascular risks associated with GLP-1 receptor agonists by using an alternative measure to the hazard ratio. Methods: We used the difference in restricted mean survival time (RMST) as a measure of cardiovascular risks. Four randomized clinical trials with cardiovascular events as a primary endpoint, ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide), were reevaluated by estimating the RMSTs for each of the agents and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. Results: The differences of RMSTs (GLP-1 receptor agonist minus placebo: point estimate and 95% CI) for primary composite endpoint of cardiovascular events were 0 days [−14, 14] in ELIXA (1080 days follow-up), 20 days [6, 34] in LEADER (1620 days follow-up), 8 days [1, 15] in SUSTAIN-6 (672 days follow-up), and 11 days [−3, 26] in EXSCEL (1825 days follow-up). As for the risk of other cardiovascular outcomes, there were no substantial differences between GLP-1 receptor agonists and placebo. Conclusions: Liraglutide and semaglutide decrease the risk of major adverse cardiovascular events compared with placebo when using the difference in RMST. The previously reported result that GLP-1 receptor agonists do not increase the risk of cardiovascular outcomes compared with placebo is also confirmed.