Cardiovascular and kidney outcomes may vary across glucagon-like peptide-1–based therapies used in type 2 diabetes mellitus (T2DM). A systematic review and network meta-analysis published in Diabetes, Obesity and Metabolism evaluated the comparative cardiovascular and renal effects of several glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual agonists in high-risk T2DM populations.
The analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane guidance and included 34 randomized controlled trials (RCTs) published between 2014 and 2025 with at least 6 months of follow-up. Evaluated therapies included dulaglutide, semaglutide, lixisenatide, tirzepatide, and cotadutide. Outcomes assessed were cardiovascular death, myocardial infarction (MI), stroke, major adverse cardiovascular events (MACE), estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR). Random- and common-effects models were applied using the netmeta package in R, with treatment ranking estimated using p-scores.
Across the trials, semaglutide regimens showed the most consistent reductions in MACE and MI compared with placebo, with the strongest effect observed when combined with sodium-glucose cotransporter-2 (SGLT2) inhibition. Dulaglutide 1.5 mg and tirzepatide 15 mg significantly reduced stroke risk, while estimates for cardiovascular death remained imprecise with evidence of small-study effects. Renal outcomes differed by endpoint. Changes in eGFR were modest, whereas reductions in UACR were more pronounced, particularly with dulaglutide combined with dapagliflozin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and semaglutide 1 mg. Principal component analysis (PCA) indicated strong cardiometabolic–renal interdependence.
Overall, cardiovascular and renal benefits varied by outcome. Semaglutide favored MACE and MI reduction, while dulaglutide and tirzepatide supported stroke risk reduction, and albuminuria outcomes appeared more responsive than eGFR changes. Further long-term head-to-head trials are needed.
