Beyond Monotherapy: The Superior Efficacy of Combined GLP-1 Receptor Agonist and SGLT2 Inhibitors on Renal Biomarkers: A Systematic Review and Meta-Analysis.

Abstract

Diabetic kidney disease (DKD) is a leading cause of chronic and end-stage renal diseases. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) confer renoprotection; however, emerging evidence suggests that combination therapy has synergistic benefits. This meta-analysis evaluated dual versus monotherapy, focusing on the urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. PubMed, Scopus, Embase, CINAHL, Medline, and Web of Science were searched until August 2025 for RCTs comparing GLP-1RA plus SGLT2i versus monotherapy or placebo in adults with T2D. The primary outcome was the change in UACR, and the secondary outcome was eGFR. Pooled standardized mean differences (SMD) were estimated using random-effects models, including subgroup and sensitivity analyses. Eight RCTs (n = 1974; sample size, 41-4000; follow-up, 16 weeks-3.4 years) were included. Combination therapy was well tolerated and significantly reduced UACR compared with monotherapy (SMD -0.25, 95% confidence interval (CI) -0.38, -0.13; I² = 0%). The benefits remained significant against SGLT2i alone (SMD, -0.28) but not for GLP-1RA alone. For eGFR, dual therapy provided a modest benefit versus SGLT2i (SMD 0.12, 95% CI 0.00-0.23) but not for GLP-1RA. The effects were consistent in patients with DKD and in larger trials. Early SGLT2is and GLP-1RA combination therapy is safe and provides superior renoprotection compared to monotherapy in patients with type 2 diabetes, albuminuria, and high cardiorenal risk. Broader adoption of combination therapy could improve outcomes, although cost and access barriers remain an issue.