Abstract
AIMS: To investigate the renal outcomes of dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose transport protein-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus (T2DM) with chronic renal disease (CKD). MATERIALS AND METHODS: PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were searched through July 2025 for randomized controlled trials with ≥24 weeks of follow-up in patients with T2DM and CKD. Outcomes included composite renal outcome, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR). A network meta-analysis was conducted, and the certainty of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation used to evaluate evidence certainty (GRADE). RESULTS: Twenty RCTs enrolling 80,670 participants were included. Compared with placebo, several agents significantly reduced composite renal outcomes, with dapagliflozin 10 mg showing the greatest efficacy (OR 0.55, 95% CI 0.42-0.72; high-certainty evidence), followed by canagliflozin, empagliflozin, efpeglenatide, sotagliflozin 400 mg, semaglutide, and dulaglutide 1.5 mg. Canagliflozin 100-300 mg significantly reduced UACR, whereas dapagliflozin had no effect. None of the novel antidiabetic agents significantly altered eGFR. Certainty of evidence ranged from high for placebo-controlled comparisons to low or very low for indirect estimates. CONCLUSIONS: In patients with T2DM and CKD, SGLT2 inhibitors provide the most consistent renal protection, while GLP-1 receptor agonists offer additional but variable benefits. Dapagliflozin showed the greatest efficacy, and canagliflozin most strongly reduced albuminuria, highlighting meaningful heterogeneity across agents. DPP-4 inhibitors conferred no renal benefit. Overall, evidence from placebo-controlled trials was robust, whereas certainty was lower for indirect estimates, highlighting the need for drug-specific evaluation in clinical practice.