Effect of Combination Therapy with SGLT2 Inhibitors and GLP-1 Receptor Agonists on Myocardial Infarction and Stroke in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

INTRODUCTION: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer cardioprotection in type 2 diabetes mellitus (T2DM). We evaluated their monotherapy versus their combined use for prevention of myocardial infarction (MI) and stroke. METHODS: Conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines, five databases were systematically searched through November 2025 for studies evaluating use of SGLT2i and GLP-1RA in combination versus their monotherapy in adults with T2DM. Hazard ratios (HRs) for MI and stroke were pooled utilizing random-effects models. Subgroup interaction testing and grading of recommendations assessment, development, and evaluation (GRADE) certainty assessments were performed. RESULTS: Of the studies, eight comprising ten comparisons were included. Combination therapy was associated with a lower overall risk of MI (HR 0.79, 95% CI 0.70-0.88; I2 = 72.8%) and stroke (HR 0.85, 95% CI 0.77-0.93; I2 = 63.5%) compared with their monotherapy. For MI, combination therapy significantly outperformed SGLT2i monotherapy (HR 0.74, 95% CI 0.60-0.90) but not GLP-1RA monotherapy (HR 0.80, 95% CI 0.55-1.16). For stroke reduction, combination therapy outperformed both SGLT2i (HR 0.73, 95% CI 0.54-0.99) and GLP-1RA (HR 0.92, 95% CI 0.88-0.96) monotherapy. Cerebrovascular benefit appeared stronger in adults > 65 years (HR 0.50, 95% CI 0.37-0.68). Overall certainty of evidence was very low. CONCLUSIONS: In adults with T2DM, SGLT2i and GLP-1RA combination therapy may be associated with lower risks of MI and stroke compared with their monotherapy. While the MI benefit appears primarily to be driven by GLP-1RA, combination therapy yields an additive reduction in stroke risk, particularly in older adults. Given the very low certainty of evidence, these hypothesis-generating findings require confirmation through dedicated prospective trials. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261320374 .