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.

IntroductionSodium-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.MethodsConducted 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.ResultsOf 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.ConclusionsIn 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 registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420261320374 .