Divergent renal benefits of SGLT2 inhibitors and mineralocorticoid receptor antagonists in non-diabetic kidney disease

Introduction: Non-diabetic kidney disease (NDKD) is a major contributor to chronic kidney disease (CKD) worldwide. Although renin–angiotensin system inhibitors (RASi) remain standard therapy, sodium-glucose cotransporter-2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (non-steroidal MRA), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are now recommended in clinical guidelines. However, direct comparative evidence to guide their prioritization in NDKD is limited. Methods: We performed a systematic review and Bayesian network meta-analysis of randomized controlled trials enrolling adults with NDKD. The primary endpoint was the annualized change in estimated glomerular filtration rate (eGFR) slope; secondary endpoints included urine protein-to-creatinine ratio (UPCR), blood pressure, and biochemical safety parameters. Results: Eighteen trials were included. SGLT2i, as add-on to RASi, produced the greatest preservation of kidney function compared with RASi alone (mean difference [MD] 12.1 mL/min/1.73 m²/year; 95% credible interval [CrI] 3.9 to 20.4). non-steroidal MRA achieved the largest reduction in proteinuria versus RASi (UPCR MD -0.4 g/g; 95% CrI -1.0 to -0.2). SGLT2i also yielded the greatest systolic blood pressure reduction versus RASi (MD -9.1 mmHg vs RASi; 95% CrI -11.7 to -6.5). Surface under the cumulative ranking (SUCRA) probabilities identified SGLT2i as most effective for eGFR slope preservation (99.8%) and non-steroidal MRA as most effective for proteinuria reduction (98.8%). Safety analyses showed a mild, expected hemoglobin decrease with SGLT2i and a non-significant creatinine rise with non-steroidal MRA. Conclusions: SGLT2i and non-steroidal MRA confer distinct renal benefits in NDKD—SGLT2i primarily preserve kidney function, whereas non-steroidal MRA most effectively reduce proteinuria. These results support a phenotype-driven therapeutic framework and highlight the need for head-to-head trials to validate precision-guided treatment strategies in NDKD.