Comparative Effectiveness of SGLT2 Inhibitors Versus GLP-1 Receptor Agonists in Reducing Cardiovascular Events in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is a global health burden affecting over 500 million people, with cardiovascular disease (CVD) being the predominant cause of death among these patients. Traditionally, antidiabetic therapies focused solely on glycemic control, but recent evidence emphasizes the importance of cardiovascular risk reduction. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are two novel classes of antidiabetic agents that have shown cardiovascular benefits beyond glucose lowering in large cardiovascular outcome trials. Despite widespread use, their comparative effectiveness in preventing major cardiovascular events remains uncertain, warranting a direct evaluation to guide personalized therapy. To systematically compare the cardiovascular outcomes of SGLT2 inhibitors versus GLP-1 receptor agonists in patients with T2DM, focusing on major adverse cardiovascular events (MACE), cardiovascular mortality, heart failure hospitalization, and all-cause mortality. A systematic search was conducted across PubMed, EMBASE, Cochrane Library, and Scopus databases for studies published up to June 2025. Eligible studies included randomized controlled trials (RCTs) and high-quality observational cohorts that reported direct or indirect comparisons of SGLT2 inhibitors and GLP-1 RAs in adults with T2DM. Study selection and data extraction were performed independently by two reviewers. The primary outcomes were MACE (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) and cardiovascular mortality. Secondary outcomes included hospitalization for heart failure (HHF) and all-cause mortality. Risk of bias was assessed using the Cochrane RoB 2 and ROBINS-I tools. Results: A total of 21 studies (12 RCTs and 9 observational studies) comprising over 180,000 patients were included. Both drug classes significantly reduced MACE compared to placebo. SGLT2 inhibitors demonstrated superior reduction in heart failure hospitalization (HR: 0.75; 95% CI: 0.68–0.84) and showed favorable outcomes in patients with pre-existing heart failure or chronic kidney disease. GLP-1 receptor agonists showed a slightly greater effect in reducing nonfatal stroke (HR: 0.87; 95% CI: 0.78–0.96) and had comparable effects on cardiovascular and all-cause mortality to SGLT2 inhibitors. Conclusions: SGLT2 inhibitors and GLP-1 receptor agonists both significantly reduce cardiovascular risk in patients with T2DM, though with differing strengths. SGLT2 inhibitors appear more effective in preventing heart failure-related outcomes, while GLP-1 receptor agonists offer marginally better protection against cerebrovascular events. These findings support a patient-centered approach in choosing glucose-lowering therapies based on individual cardiovascular profiles.