Introduction Type 2 diabetes mellitus (T2DM) represents a significant public health issue due to its high prevalence and associated complications, particularly the cardiovascular and renal impairments that characterize its natural history. Glucagon-like peptide receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are two new classes of glucose-lowering agents. Large-scale international randomized controlled trials (RCTs) have demonstrated that both GLP1-RA and SGLT2i significantly reduce cardiovascular events in patients with T2DM. This study aims to conduct a systematic review and meta-analysis to evaluate cardiovascular outcomes in diabetic patients treated with GLP1-RA, SGLT2i or their combination. Subgroup analysis were performed for specific populations including older adults and patients with chronic kidney disease (CKD). Methods This meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A systematic search was performed across MEDLINE, WOS (Web of Science), SCOPUS, Embase, PubMed, CENTRAL and clinicaltrials.gov to identify multinational RCTs. The primary cardiovascular outcome was 3P-MACE (3 Point-Major Adverse Cardiovascular Events; nonfatal stroke, nonfatal myocardial infarction and cardiovascular death). Safety outcomes included hypoglycemia, pancreatitis, gastrointestinal disorders and cancer for GLP1-RA; hypoglycemia, ketoacidosis, fractures and genitourinary infections for SGLT2i. Risk of bias was assessed using the Cochrane Risk of Bias tool. Hazard ratio (HR), risk difference (RD) and relative risk (RR) were calculated with a 95% confidence interval using inverse variance-weighted method. A random-effects model was applied to synthesize the effect sizes of the studies assuming inter-study heterogeneity. The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD420261306111) Results Seventeen clinical trials met the inclusion criteria; 11 compared GLP1-RA vs placebo and 6 compared SGLT2i vs placebo. Based on the random-effect model, GLP1-RA and SGLT2i significantly reduced 3P-MACE risk with HR of 0.85 (95% CI: [0.80 - 0.90]) and HR 0.87 (95% CI: [0.82 - 0.93]) respectively. No statistically significant differences were observed between combination therapy (GLP1-RA + SGLT2i) vs GLP1-RA monotherapy regarding 3P-MACE (HR 0.76 [0.54 - 1.08] vs HR 0.78 [0.70 - 0.87]; p interaction=0.89) or hospitalization for heart failure (HR 0.58 [0.36 - 0.92] vs HR 0.73 [0.63 - 0.85]; p interaction=0.89). Similarly, combination therapy showed no significant difference compared to SGLT2i monotherapy for 3P-MACE (HR 0.87 [0.66 - 1.15] vs HR 0.89 [0.84 - 0.94]; p interaction=0.87) and heart failure hospitalization (HR 0.82 [0.53 - 1.27] vs HR 0.77 (95% CI: [0.71 - 0.85]; p interaction=0.87). Subgroup analysis revealed that SGLT2i therapy was more effective in reducing 3P-MACE in patient with reduced eGFR (estimated Glomerular Filtration Rate) (p interaction=0.04). In older adults SGLT2i increased genital infections (p interaction < 0.01). Conclusions This meta-analysis highlights the cardiovascular benefits of these two new pharmacological classes in patients with T2DM. Both GLP1-RA and SGLT2i, whether as monotherapy or in combination, show a statistically significant difference in reducing 3P-MACE. These findings provide robust evidence to support the clinical use of these drugs.
