Type 2 diabetes (T2DM) management increasingly focuses on cardiometabolic protection. Sodium-glucose co-transporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have complementary mechanisms, making their combination a promising strategy. This systematic review evaluates the cardiometabolic benefits and risks of SGLT2i and GLP-1 RA combination therapy in T2DM. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search of PubMed, Scopus, Embase, and Web of Science was conducted for randomised controlled trials (RCTs) published between 2020 and 2025. Nine RCTs, including cardiovascular outcome trials and mechanistic studies, were included. Data on cardiovascular, renal, glycaemic, and safety outcomes were extracted. The Cochrane RoB 2 tool was used for quality assessment. Combination therapy demonstrated additive cardioprotective effects. Post-hoc analyses showed GLP-1 RAs reduced major adverse cardiovascular events (MACE) and heart failure hospitalisation regardless of background SGLT2i use, and SGLT2i benefits were maintained with concomitant GLP-1 RAs. The combination provided superior glycaemic control (HbA1c reduction), weight loss, and systolic blood pressure reduction compared to monotherapy. The safety profile was consistent with the known effects of each drug class, with no new or unexpected safety signals and manageable gastrointestinal and genital infection risks. The combination of SGLT2is and GLP-1 RAs in T2DM provides synergistic benefits for cardiovascular risk reduction, glycaemic control, weight, and blood pressure, without a significant increase in adverse events. This supports its use as a potent therapeutic strategy for high-risk patients, though definitive evidence from prospective trials designed specifically for combination therapy is still needed.
