Preferred Glucagon-like Peptide-1 Receptor Agonists in Adults With Type 2 Diabetes and Established Cardiovascular Disease or High Cardiovascular Risk: A Network Meta-analysis of Randomized Trials.

The comparative cardiovascular (CV) efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or high CV risk remain uncertain. PubMed, Embase, Web of Science, Scopus, and CENTRAL were searched from inception to December 20, 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 extended release, ITCA 650, liraglutide, lixisenatide, subcutaneous semaglutide, oral semaglutide, tirzepatide, and placebo. Eleven trials (n=83,215) were included. In the 3-point major adverse CV event (MACE) network (11 trials, 11 regimens), heterogeneity and inconsistency were absent (I=0%, τ=0). MACE rate was reduced with subcutaneous semaglutide (RR 0.74, 95% CI 0.58 to 0.94), efpeglenatide (0.76, 0.61 to 0.94), and albiglutide (0.79, 0.69 to 0.91); tirzepatide, oral semaglutide, liraglutide, and dulaglutide were also significantly reduced compared with placebo. Top ranked 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 to 0.93) and dulaglutide (0.77, 0.63 to 0.95) vs placebo. Discontinuation and gastrointestinal discontinuation were higher with subcutaneous semaglutide, oral semaglutide, lixisenatide, and ITCA 650. Several GLP-1-based therapies reduced MACE vs 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 T2D while highlighting the need for individualized treatment selection.