| Sumario: | Introduction: While glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are established for cardiorenal benefits in type 2 diabetes mellitus (T2DM), prior meta-analyses have not fully integrated cross-class comparisons or net benefit analyses with updated cardiovascular outcome trials (CVOTs). Methods: We conducted a systematic review and meta-analysis of 17 CVOTs (N = 132,038; GLP-1RA: N = 73,263; SGLT-2i: N = 58,775) using PubMed and Cochrane CENTRAL. We uniquely synthesized major adverse cardiovascular events (MACE), hospitalization for heart failure (hHF), renal composites, and safety outcomes (e.g., retinopathy, genitourinary infections) with random-effects models for hazard ratios (HRs) and relative risks (RRs). Innovative graphical syntheses (tornado/scatter plots, risk curves) and net benefit calculations (absolute risk reductions [ARRs] minus absolute excess risks [AERs]) were employed. Risk of bias (RoB 2) and GRADE certainty were assessed. Results: Both classes reduced MACE (HR 0.87, 95% CI 0.84–0.90; p = 0.73 for class difference). SGLT-2is were superior for hHF (HR 0.69 vs. 0.88, p < 0.0001) and renal outcomes (HR 0.68 vs. 0.79, p = 0.026). GLP-1RAs increased retinopathy (RR 1.18, AER + 6.5/1000); SGLT-2is increased genitourinary infections (RR 3.34, AER + 19.9/1000) and DKA (RR 2.67, AER + 1.2/1000). Amputation signals attenuated post-sensitivity analysis. Net benefits favored GLP-1RAs for MACE (+ 2.5/1000). For SGLT-2is, base-case estimates using genital-mycotic infections as the sentinel harm were marginal (hHF: − 4.9/1000; renal: − 1.9/1000), whereas sensitivity scenarios with alternative harms (e.g., volume depletion, amputation, DKA) yielded positive net benefits. GRADE certainty was high for efficacy, moderate for harms. Conclusions: Our innovative integration of updated CVOTs, cross-class comparisons, and graphical risk–benefit tools refines therapeutic decision-making, highlighting tailored T2DM management based on patient-specific cardiorenal risks. Trial Registration: PROSPERO (CRD420251146788).
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