Relative Efficacy of Next-Generation Incretin Therapies for Cardio-Renal Protection in Type 2 Diabetes: Evidence From a Network Meta-Analysis.

BACKGROUND: Type 2 diabetes (T2D) management has shifted towards integrated cardiometabolic and renal risk reduction. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and newer dual agonists show promising benefits, comparative evidence across agents and outcomes remains limited. OBJECTIVES: To compare the cardiovascular and renal effects of modern GLP-1RAs (dulaglutide, semaglutide, lixisenatide), tirzepatide and cotadutide in high-risk T2D populations, and to explore multivariate relationships among clinical outcomes. METHODS: A systematic review and network meta-analysis was conducted following PRISMA and Cochrane guidance (PROSPERO: CRD42024592825). Randomised controlled trials published between 2014 and 2025 with ≥ 6 months follow-up were included. Outcomes were cardiovascular death, myocardial infarction (MI), stroke, total major adverse cardiovascular events (MACE), eGFR and UACR. Random- and common-effects models were applied using netmeta (R). Treatment rankings were estimated using p-scores. Inconsistency, heterogeneity and small-study effects were evaluated. Correlation networks and principal component analysis (PCA) were performed to characterise interrelationships among clinical variables. RESULTS: Thirty-four trials were included, predominantly multinational CVOTs and CKD-focused studies. Semaglutide regimens showed the most consistent reduction in MACE and MI versus placebo, with the strongest effect observed for semaglutide combined with SGLT2 inhibition. Dulaglutide 1.5 mg and tirzepatide 15 mg significantly reduced stroke risk. Cardiovascular death estimates were largely imprecise with evidence of small-study effects. Renal effects differed by endpoint: eGFR changes were generally modest, whereas UACR showed marked reductions, particularly with dulaglutide plus dapagliflozin, DPP-4 inhibitors and semaglutide 1 mg. PCA confirmed strong cardiometabolic-renal interdependence. CONCLUSIONS: Cardiovascular and renal benefits of GLP-1-based therapies are outcome-specific. Semaglutide favoured MACE/MI reduction, dulaglutide and tirzepatide supported stroke prevention, and albuminuria outcomes were more responsive than eGFR. Further long-term head-to-head trials are needed.