Comparative Cardiovascular Outcomes and Safety Profiles of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Trials

Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been assessed in several large cardiovascular outcome trials (CVOTs); however, the individual agents differ in molecular structure, pharmacology, and the populations studied, and their reported effects range from neutral to clearly beneficial. This review compares the cardiovascular efficacy and safety of GLP-1 RAs across all eligible randomized, placebo-controlled CVOTs in T2DM and quantitatively pools the primary outcome. Following the PRISMA 2020 statement, ClinicalTrials.gov, MEDLINE, Embase, and the Cochrane CENTRAL were searched from inception to 15 December 2025 for randomized, double-blind, placebo-controlled CVOTs comparing a GLP-1 RA with placebo in adults with T2DM and reporting adjudicated major adverse cardiovascular events (MACE) as a primary or co-primary endpoint. The protocol was not prospectively registered. Two reviewers independently performed screening, data extraction, and risk-of-bias assessment (Cochrane RoB 2), and certainty of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Findings were synthesized narratively and, for the primary MACE outcome, pooled using a DerSimonian-Laird random-effects model on the log-hazard-ratio scale, with heterogeneity quantified by I² and Cochran's Q, leave-one-out sensitivity analysis, and small-study assessment by funnel plot and Egger's test. Nine trials enrolling 69,730 participants met the eligibility criteria. The primary MACE hazard ratio favored the GLP-1 RA in eight of nine trials (range = 0.73-1.02) and reached statistical superiority in five. Random-effects meta-analysis yielded a pooled MACE hazard ratio of 0.86 (95% CI: 0.82-0.92; P < 0.001), corresponding to a 14% relative risk reduction, with moderate heterogeneity (I² = 37%; Cochran's Q = 12.7, P = 0.12) and a 95% prediction interval of 0.75-1.00. The pooled estimate was robust to leave-one-out analysis (0.85-0.88), and no small-study asymmetry was detected (Egger's P = 0.13). The composite benefit was driven by reductions in myocardial infarction and stroke, with a neutral effect on hospitalization for heart failure. Gastrointestinal adverse events were the most common class effect; a class-level excess of gallbladder and biliary disease was also evident, and a diabetic retinopathy signal was observed with subcutaneous semaglutide. Eight trials were judged to be at low risk of bias, and the certainty of evidence was moderate for the principal cardiovascular outcomes. In adults with T2DM, GLP-1 RAs as a class reduce the risk of MACE by approximately 14% with an acceptable safety profile, supporting their role as a cornerstone of cardiovascular risk reduction. Between-agent and between-trial heterogeneity preclude a definitive ranking of individual agents.