Preferred GLP-1 Receptor Agonists in Type 2 Diabetes With Established Cardiovascular Disease or High Cardiovascular Risk: A Network Meta-Analysis of Randomized Trials.
This network meta-analysis pooled data from 11 randomized controlled trials (n = 83,215) to compare the cardiovascular (CV) efficacy and safety of GLP-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes and established cardiovascular disease or high CV risk. Trials were identified through a systematic search of five major databases up to December 2025. Using a frequentist random-effects framework, the authors found that several GLP-1RAs — including subcutaneous semaglutide, efpeglenatide, albiglutide, tirzepatide, oral semaglutide, liraglutide, and dulaglutide — significantly reduced three-point major adverse cardiovascular events (MACE) compared with placebo, with no detected heterogeneity or inconsistency. Subcutaneous semaglutide, efpeglenatide, and albiglutide ranked highest by P-score. No agent significantly reduced all-cause or CV mortality versus placebo. Tirzepatide and dulaglutide were associated with reduced stroke risk. Tolerability signals showed higher rates of discontinuation due to gastrointestinal adverse events with subcutaneous semaglutide, oral semaglutide, lixisenatide, and ITCA 650. The authors concluded that MACE reduction is the most consistent efficacy signal across GLP-1RAs in this population. Limitations include the indirect nature of network comparisons and differing trial designs and populations across included studies.
Why this grade: This is a large, pre-registered network meta-analysis of 11 RCTs with over 83,000 participants, providing high-quality, direct and indirect comparative evidence in humans, though indirect comparisons introduce inherent uncertainty.
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.
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