SGLT2 inhibitors versus GLP-1 receptor agonists for major adverse cardiovascular events in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials

Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to reduce cardiovascular risk, but direct comparison is limited. Objective: Compare the effects of SGLT2 inhibitors and GLP-1 receptor agonist on major adverse cardiovascular events (MACE) in adults with T2DM using randomized controlled trials and indirect comparisons. A systematic search of PubMed, Scopus, CENTRAL, and Google Scholar was conducted through October 20, 2025, following PRISMA 2020 guidelines. The protocol was registered with PROSPERO (CRD420251168485). We included randomized controlled trials (RCTs) of SGLT2i or GLP-1RA versus placebo in adults with T2DM that reported cardiovascular or renal outcomes. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using the generic inverse variance method with a random-effects model. An indirect treatment comparison was performed using the Bucher method. Risk of bias was assessed with the Cochrane RoB 1 tool. We reviewed twelve trials involving 99,261 individuals (5 SGLT2i, 7 GLP-1RA). Compared to placebo, SGLT2i significantly reduced MACE (HR 0.89, 95% CI 0.84–0.95; p = 0.0003), as did GLP-1RA (HR 0.82, 95% CI 0.78–0.87; p < 0.00001). The indirect comparison indicated a nominally greater MACE reduction with GLP-1RA (HR 1.09, 95% CI 1.00–1.18; p = 0.0497). SGLT2i demonstrated pronounced benefits for heart failure hospitalization (HR 0.68) and composite renal outcomes (HR 0.69), while GLP-1RA showed significant but more modest effects on these endpoints and greater benefits for atherosclerotic events and weight loss. Both SGLT2i and GLP-1RA are highly effective in reducing MACE in high-risk T2DM. Their markedly different secondary outcome profiles for heart failure, renal protection, atherosclerotic events, and weight loss underscore that they are complementary rather than interchangeable. The optimal choice should be individualized based on the patient's predominant comorbidities, treatment goals, and local access.