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Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are associated with significant cardiovascular benefit in type 2 diabetes (T2D). However, GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities., Aim: To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D., Methods: The systematic review was conducted according to PRISMA recommendations. The protocol was registered on PROSPERO (ID: 42022385007). A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment. Effect modification of prior myocardial infarction (MI) and heart failure (HF) was also explored to provide clinical insight as to when the combination treatment should be considered., Results: The estimated hazard ratios (HR) GLP-1RA/SGLT-2I vs Placebo (0.75-0.98) and HR Combination vs GLP-1RA/SGLT-2I (0.26-0.86) for primary and secondary cardiovascular outcomes suggested that the combination treatment may achieve additional cardiovascular benefit compared with GLP-1RA or SGLT-2I alone. In patients with prior MI or HF, the mono-therapies may not improve the overall cardiovascular outcomes, as the estimated HR MI+/HF+ (0.57-1.52) suggested that GLP-1RA or SGLT-2I alone may be associated with lower risks of hospitalization for HF but not cardiovascular death., Conclusion: Considering its greater cardiovascular benefit in T2D, the combination treatment of GLP-1RA and SGLT-2I might be prioritized in patients with prior MI or HF, where the monotherapies may not provide sufficient cardiovascular protection., Competing Interests: Conflict-of-interest statement: Zhu JJ and Gu XS have no conflict of interest or financial disclosures that are relevant to the content of this research report. Wilding JPH reports consultancy/advisory board work for the pharmaceutical industry contracted via the University of Liverpool (no personal payment) for Altimmune, AstraZeneca, Boehringer Ingelheim, Cytoki, Lilly, Napp, Novo Nordisk, Menarini, Pfizer, Rhythm Pharmaceuticals, Sanofi, Saniona, Tern, and Shionogi & Ysopia; research grants for clinical trials from AstraZeneca and Novo Nordisk and personal honoraria/lecture fees from AstraZeneca, Boehringer Ingelheim, Medscape, Napp, Novo Nordisk, and Rhythm. Wilding JPH is past president of the World Obesity Federation, a member of the Association for the Study of Obesity, Diabetes UK, EASD, ADA, Society for Endocrinology, and the Rank Prize Funds Nutrition Committee. Wilding JPH is national lead for the Metabolic and Endocrine Speciality Group of the UK NIHR Clinical Research Network., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)