Preferred GLP-1 Receptor Agonists in Type 2 Diabetes With Established Cardiovascular Disease or High Cardiovascular Risk: A Network Meta-Analysis of Randomized Trials.

BACKGROUND: The comparative cardiovascular (CV) efficacy and safety of GLP-1 receptor agonists (GLP-1RAs) in patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or high CV risk remain uncertain. METHODS: PubMed, Embase, Web of Science, Scopus, and CENTRAL were searched from inception to 20 December 2025 for randomized controlled trials. We conducted a frequentist random-effects network meta-analysis and reported risk ratios (RRs) with 95% confidence intervals (CIs). Treatments were ranked using P-scores. Regimens were analyzed as individual agents, including albiglutide, dulaglutide, efpeglenatide, exenatide ER, ITCA 650, liraglutide, lixisenatide, subcutaneous semaglutide, oral semaglutide, tirzepatide, and placebo. RESULTS: Eleven trials (n=83,215) were included. In the three-point major adverse CV event (MACE) network (11 trials; 11 regimens), heterogeneity and inconsistency were absent (I2=0%; τ2=0). MACE was reduced with subcutaneous semaglutide (RR 0.74, 95% CI 0.58-0.94), efpeglenatide (0.76, 0.61-0.94), and albiglutide (0.79, 0.69-0.91); tirzepatide, oral semaglutide, liraglutide, and dulaglutide were also significant compared with placebo. Top ranks were semaglutide SC (P-score 0.87), efpeglenatide (0.84), and albiglutide (0.80). No regimen significantly reduced all-cause or CV death compared with placebo. Stroke was reduced with tirzepatide (RR 0.71, 0.54-0.93) and dulaglutide (0.77, 0.63-0.95) compared with placebo. Discontinuation and gastrointestinal discontinuation were higher with subcutaneous semaglutide, oral semaglutide, lixisenatide, and ITCA 650. CONCLUSION: Several GLP-1-based therapies reduced MACE versus placebo, with 3-point MACE emerging as the most consistent efficacy signal. Overall, these findings support guideline-based use of GLP-1 RAs in high-risk T2DM while highlighting the need for individualized treatment selection.