Type 2 diabetes mellitus (T2DM) is associated with substantial cardiovascular and renal morbidity and premature mortality. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiorenal events beyond their glucose-lowering effects. This systematic review compared cardiovascular, heart failure, kidney, mortality, metabolic, and safety outcomes of the two classes of medications and evaluated evidence for complementary use. Randomized controlled trials, systematic reviews and meta-analyses, and large comparative observational studies of adults with type 2 diabetes reporting relevant cardiovascular, renal, mortality, metabolic, or safety outcomes were eligible. Glycemia-only studies without relevant clinical outcomes, pediatric and preclinical studies, case reports, editorials, and noninformative reports were excluded. PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched from January 2010 through August 30, 2026, supplemented by Google Scholar and backward and forward citation searching. Risk of bias was assessed using RoB 2 for randomized trials, ROBINS-I for nonrandomized comparative studies, and AMSTAR 2 for systematic reviews and meta-analyses. Certainty of evidence was assessed at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Because of heterogeneity across populations, interventions, outcomes, and study designs, results were evaluated using a structured narrative synthesis rather than a de novo meta-analysis. Thirty-eight studies were included, comprising 14 randomized controlled trials, 12 nonrandomized comparative studies, and 12 systematic reviews or meta-analyses. SGLT2 inhibitors showed particularly consistent benefit for heart failure and kidney outcomes, whereas GLP-1 receptor agonists showed strong atherosclerotic cardiovascular benefit and greater weight reduction. Certainty was moderate for the principal comparative cardiovascular and kidney outcomes and lower for real-world comparative effectiveness and combination therapy. Evidence supported potentially complementary cardiorenal effects with combined use, although superiority of combination therapy over appropriately selected monotherapy was not established. Safety profiles differed, with genital infections, volume depletion, and rare diabetic ketoacidosis more closely associated with SGLT2 inhibitors and gastrointestinal adverse effects more common with GLP-1 receptor agonists. Interpretation was limited by heterogeneity in study populations, interventions, outcome definitions, follow-up periods, and study designs, residual confounding in observational evidence, and the possibility of publication and selective-reporting bias. Overall, the findings support individualized treatment selection according to cardiovascular and renal risk, heart failure, weight goals, safety, tolerability, and access, with combined use considered when complementary benefits are clinically appropriate.
