Comparison of the renal outcomes of novel antidiabetic agents in patients with type 2 diabetes with chronic kidney disease: A systematic review and network meta-analysis of randomized controlled trials.
This systematic review and network meta-analysis examined the renal effects of three classes of novel antidiabetic agents—DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors—in adults with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Researchers searched four major databases through July 2025 and identified 20 randomized controlled trials enrolling 80,670 participants, with a minimum follow-up of 24 weeks. Key outcomes assessed were composite renal outcomes, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR). The study found that several agents significantly reduced composite renal outcomes compared with placebo; dapagliflozin demonstrated the largest effect (high-certainty evidence), followed by canagliflozin, empagliflozin, and select GLP-1 agonists (efpeglenatide, sotagliflozin, semaglutide, dulaglutide). Canagliflozin most strongly reduced UACR, while dapagliflozin showed no significant effect on this measure. No agent significantly altered eGFR. DPP-4 inhibitors showed no renal benefit. Certainty of evidence, assessed via GRADE, was high for direct placebo-controlled comparisons but fell to low or very low for indirect network estimates. A key limitation is that conclusions about head-to-head drug comparisons rely on indirect evidence, which carries greater uncertainty.
Why this grade: The study synthesizes 20 RCTs with over 80,000 participants using GRADE-assessed network meta-analysis, providing high-certainty direct evidence for placebo-controlled comparisons in humans, though indirect head-to-head estimates are of lower certainty.
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.
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