Update in Cardiovascular Safety of Glucagon-Like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes—A Mixed Treatment Comparison Meta-analysis of Randomized Controlled Trials

Background: The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) was recently published. Thus, we here present a mixed treatment comparison meta-analysis (MTC) of major randomized clinical trials to determine Glucagon like peptide 1 (GLP-1) receptor agonists’ effects on CV outcomes in patients with T2DM. Methods: A comprehensive, systematic review was conducted using Embase and MEDLINE databases. Studies were included in the MTC meta-analysis if they were (1) RCTs and (2) evaluated the effects of one of the GLP-1 agonists vs. placebo on CV outcomes as their primary endpoint. The primary outcomes were CV death, nonfatal MI, and nonfatal stroke. Hospitalization for HF was evaluated as a secondary endpoint. Results: A total of 202 publications were identified and reviewed, of which 198 were excluded based on study design or relevance to the research question. A total of 4 trials, including 33,457 patients, met the eligibility criteria and were retained analysis. The pairwise meta-analysis showed a 13% reduction in death from cardiovascular causes in patients who received GLP-1 agonists vs. those who received placebo (RR 0.87, 95% CI: 0.78-0.96, I2=0%, P=0.592). The NMA showed no differences among all the interventions, with liraglutide the preferred agent (53%) followed by semaglutide (18%). The pairwise meta-analysis showed no significant reduction in non-fatal MI events between the two groups (RR 0.95, 95% CI: 0.86-1.04, I2=19.5%, P=0.293). Like the pairwise meta-analysis, the NMA results showed no reduction in non-fatal MI events with semaglutide as the preferred agent (66%), followed by liraglutide (19%). Conclusion: GLP-1 therapy was associated with a significant reduction in CV death. However, GLP-1 agonists seem to have a safety profile comparable to placebo in terms of reducing non-fatal MI, non-fatal stroke events, and rates of HF hospitalization. Disclosure O. Alfayez: None. M.S. Al Yami: None. R. Alsheikh: None.