Comparison of three types of drugs for cardiovascular and renal benefits in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM), one of the most common chronic metabolic diseases, is also one of the most significant risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). AIM: To conduct a systematic review and network meta-analysis of cardiovascular (CV) and renal benefits of glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and nonsteroidal mineralocorticoid receptor antagonists (nsMRA) in T2DM patients. METHODS: We searched four databases-PubMed, EMBASE, Cochrane Library, and Web of Science- for publications from inception to March 6, 2025. Total 500 participants were enrolled and had an intervention period of at least one year (or 52 weeks). Eligible studies included adult patients with T2DM and interventions with a placebo or another GLP-1RA, SGLT2i, or nsMRA. Data were standardized using Stata 17.0 software. The quality of evidence was assessed using the CINeMA and GRADE approaches. RESULTS: Total 14970 articles were retrieved, of which 25 high-quality studies were included for the systematic review and network meta-analysis, covering 189797 patients and three drug classes (14 drugs). Network meta-analysis revealed low heterogeneity, thus ensuring reliable results. Meta-regression analysis indicated that baseline factors, such as comorbidities and blood glucose levels, did not affect our results. Overall, all included drugs demonstrated significant CV and renal benefits compared with the placebo. nsMRA showed the best efficacy in reducing the incidence of major adverse CV events and myocardial infarction. SGLT2i were most effective in reducing all-cause mortality, CV mortality, and the incidence of renal outcomes. GLP-1RA showed the greatest benefits in reducing the incidence of stroke. SC-semaglutide had the most significant effect on reducing major adverse CV events, oral semaglutide was most effective in reducing all-cause mortality and CV mortality, empagliflozin had the strongest effect in reducing composite renal outcomes and renal replacement therapy, canagliflozin was most effective in slowing the progression of proteinuria, and dapagliflozin showed the most significant reduction in end-stage renal disease. CONCLUSION: T2DM, as one of the most common chronic metabolic diseases, is also one of the most significant risk factors for CVD and CKD. GLP-1RA, SGLT2i, and nsMRAs have emerged as novel therapeutic agents to comprehensively manage T2DM-related CVD and CKD. We conducted a network meta-analysis to compare the efficacy and safety of GLP-1RAs, SGLT2i, and nsMRA in patients with T2DM.