Abstract
Type 2 diabetes mellitus (T2DM) markedly increases the risk of cardiovascular and renal complications, emphasizing the need for therapies that extend benefits beyond glycemic control. Injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated both cardioprotective and renoprotective potential, but the comparative efficacy of individual agents remains uncertain. This network meta-analysis (NMA) evaluated and ranked the effects of GLP-1 RAs on major adverse cardiovascular events (MACE) and renal composite outcomes, both prespecified as co-primary endpoints. A systematic search of PubMed, Scopus, ScienceDirect, Web of Science, and the Cochrane Library was conducted from inception to January 2024. Eligible randomized controlled trials enrolled adults with T2DM, including those with or without established cardiovascular disease or chronic kidney disease. Renal composite outcomes were defined as a decline in estimated glomerular filtration rate (eGFR) and/or onset of macroalbuminuria. Direct and indirect evidence were synthesized using a frequentist NMA framework to generate odds ratios (ORs) with 95% confidence intervals (CIs), while treatment hierarchy was assessed with Surface Under the Cumulative Ranking Curve (SUCRA) values. Transitivity and consistency assumptions were tested and satisfied, and the risk of bias was assessed with the Cochrane RoB2 tool. Fifteen randomized trials involving a pooled sample of more than 90,000 participants were included. Efpeglenatide ranked highest for both MACE (OR: 0.74; 95% CI: 0.62-0.87; SUCRA: 81.5%) and renal outcomes (OR: 0.68; 95% CI: 0.57-0.81; SUCRA: 81.33%), underscoring its clinical significance over other effective agents such as albiglutide and semaglutide. Albiglutide, semaglutide, dulaglutide, and liraglutide also provided significant benefits, albeit with lower rankings. No major inconsistency or publication bias was detected. In conclusion, this NMA reinforces the class-wide cardiorenal benefits of GLP-1 receptor agonists while emphasizing variations in efficacy among individual agents, the limited evidence base for certain drugs, and the need for future head-to-head trials specifically designed to evaluate cardiovascular and renal endpoints.