Efficacy and safety of drugs for people with type 2 diabetes mellitus and chronic kidney disease on kidney and cardiovascular outcomes: A systematic review and network meta-analysis of randomized controlled trials

Aim: To evaluate the comparative efficacy and safety of promising kidney protection drugs, including sodium -glucose cotransporter-2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl-peptidase IV Inhibitors (DPP-4Is), aldosterone receptor agonists (MRAs), endothelin receptor antag-onist (ERAs), pentoxifylline (PTF), and pirfenidone (PFD), on cardiovascular and kidney outcomes in type 2 diabetes (T2DM) and chronic kidney disease (CKD) population. Methods: PubMed, Embase, and Cochrane Library were searched from inception to August 12, 2022. We used the Bayesian model for network meta-analyses, registered in the PROSPERO (CRD42022343601). Results: This network meta-analysis identified 2589 citations, and included 27 eligible trials, enrolling 50,237 patients. All results presented below were moderate to high quality. For kidney outcomes, SGLT-2Is were optimal in terms of reducing composite kidney events (RR 0.69, 95%CI 0.61-0.79), and slowing eGFR slope (MD1.34, 95%CI 1.06-1.62). Then MRAs (RR 0.77, 95%CI 0.68-0.88; MD 1.31, 95%CI 0.89-1.74), GLP-1RAs (RR 0.78, 95%CI 0.62-0.97; MD 0.75, 95%CI 0.46-1.05), and ERAs (RR 0.75, 95%CI 0.57-0.99; MD 0.7, 95%CI 0.3-1.1) were followed in parallel. For cardiovascular outcomes, SGLT-2 inhibitors were also among the best for lowing the risk of heart failure hospitalization (RR 0.67, 95%CI 0.57-0.78), followed by GLP-1RAs (RR 0.73, 95%CI 0.55-0.97) and MRAs (RR 0.79, 95%CI 0.67-0.92). SGLT-2Is (RR 0.8, 95%CI 0.71-0.89) and GLP-1RAs (RR 0.72, 95%CI 0.6-0.86) had comparable effects to reduce the risk of major adverse cardiovascular events. MRAs were possibly associated with increased drug discontinuation due to adverse events (RR 1.21, 95%CI 1.05-1.38). For the hyperkalemia outcome, MRAs (RR 2.08, 95%CI 1.86-2.33) were linked to the risk of hyperkalemia, whereas SGLT-2Is (RR 0.78, 95%CI 0.65-0.93) were in contrast. Conclusions: SGLT-2Is significantly reduced kidney and cardiovascular risk in T2DM and CKD, subsequently GLP-1RAs and MRAs. SGLT-2Is-MRAs combination might be a recommended treatment regimen for maximizing kidney and cardiovascular protection but with a low risk of hyperkalemia in T2DM and CKD.