Comparative cardiovascular efficacy of antidiabetic therapies in type 2 diabetes: a systematic review and network meta-analysis of randomized trials

BACKGROUND: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus (T2DM), imposing a substantial burden on healthcare systems. This systematic review and network meta-analysis evaluated the comparative efficacy of antidiabetic medications and combination therapies in reducing cardiovascular outcomes in patients with T2DM. METHODS: PubMed (Medline), Embase, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to December 30, 2024, for randomized controlled trials (RCTs) assessing cardiovascular outcomes in adults with T2DM treated with metformin, sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase‑4 (DPP‑4) inhibitors, glucagon‑like peptide‑1 (GLP‑1) receptor agonists, sodium-glucose cotransporter‑2 (SGLT2) inhibitors, or insulin. Outcomes included cardiovascular mortality, myocardial infarction (MI), stroke, heart failure, hospitalization for cardiovascular events, and unstable angina. Risk of bias was assessed using the Cochrane RoB 2.0 tool, and analyses were conducted with a random-effects model in Stata (version 18). RESULTS: From 10,514 records, 133 RCTs involving 289,558 participants (mean age: 64.7 years) were included. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduced cardiovascular mortality (RR = 0.85, 95% CI: 0.75-0.98; high-certainty evidence) and stroke (RR = 0.83, 95% CI: 0.74-0.93; high-certainty evidence). SGLT2 inhibitors significantly reduced heart failure (RR = 0.64, 95% CI: 0.53-0.77; high-certainty evidence) and hospitalization for cardiovascular events (RR = 0.72, 95% CI: 0.68-0.77; high-certainty evidence). An indirect comparison suggested lower cardiovascular mortality with DPP-4 inhibitors versus GLP-1 receptor agonists, although this finding should be interpreted cautiously due to network imbalance. CONCLUSIONS: GLP-1 RAs and SGLT2 inhibitors are associated with significant reductions in specific cardiovascular outcomes in patients with T2DM, particularly in reducing cardiovascular mortality, stroke, heart failure, and hospitalization. Treatment decisions should integrate patient-specific risk profiles and cost-effectiveness to optimize outcomes.