Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular and renal risks in type 2 diabetes mellitus (T2DM), but their relative efficacy remains uncertain due to the absence of direct comparative trials. This systematic review and network meta-analysis aimed to evaluate the efficacy and safety of interventions concerning major adverse cardiovascular events (MACE), heart failure, and renal outcomes. A systematic review and network meta-analysis of large-scale, placebo-controlled cardiovascular outcome trials was conducted. PubMed, Embase, and CENTRAL were searched for trials published up to December 2025. The primary outcome was MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). The secondary outcomes included hospitalization for heart failure (HHF), composite renal outcomes, and all-cause mortality. The evaluated safety outcomes included severe hypoglycemia, diabetic ketoacidosis, amputation, fracture, and genital infections. Data were pooled using a frequentist random-effects model. In total, 14 trials involving 117,633 participants were included. Both drug classes reduced the risk of MACE compared with placebo (SGLT2i: hazard ratio (HR) = 0.89, 95% confidence interval (CI) = 0.84-0.94; GLP-1RA: HR = 0.86, 95% CI = 0.80-0.93), with no statistically significant difference observed between the two (HR = 1.03, 95% CI = 0.94-1.13). SGLT2 inhibitors had a greater efficacy than GLP-1 receptor agonists in reducing HHF (HR = 0.75, 95% CI = 0.66-0.85) and composite renal outcomes (HR = 0.76, 95% CI = 0.66-0.87). Similarly, both classes lowered all-cause mortality. SGLT2 inhibitors exhibited an elevated risk of genital infections (relative risk (RR) = 3.49, 95% CI = 2.63-4.55) and diabetic ketoacidosis (RR = 2.36, 95% CI = 1.33-4.17) compared to GLP-1 receptor agonists. SGLT2 inhibitors and GLP-1 receptor agonists are equally effective in preventing MACE. However, SGLT2 inhibitors offer enhanced protection against heart failure and renal disease progression, whereas GLP-1 receptor agonists exhibit a more favorable safety profile for genital infections and ketoacidosis. These findings support a phenotype-specific treatment approach for patients with T2DM.
GLP-1 Therapies