Efficacy and safety of novel non-steroidal mineralocorticoid receptor antagonists in diabetic kidney disease: an updated systematic review and meta-analysis of randomized controlled trials

Aims To evaluate the efficacy and safety of novel non-steroidal mineralocorticoid receptor antagonists (nsMRAs) in diabetic kidney disease (DKD). Methods Following PRISMA 2020, we searched four databases to 31 July 2026, for randomized controlled trials (RCTs) comparing nsMRAs with placebo in adults with DKD. Pooled estimates used random-effects models, with mean differences (MDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes, each with 95% confidence intervals (CIs). Risk of bias was assessed with Cochrane RoB 2, and certainty of evidence with GRADE. Results Eight RCTs (15,143 patients) were included. nsMRAs reduced log-transformed UACR (MD -0.36 log mg/g, 95% CI -0.44 to −0.28; n = 14,512 from 8 trials, predominantly driven by finerenone (5 of 8 trials), with significant drug-type interaction; P < 0.00001) and systolic BP (MD -4.72 mmHg, 95% CI -8.64 to −0.80; n = 7,538 from 3 trials (6 trials reported systolic BP; only 3 were poolable); predominantly driven by FIGARO-DKD; P = 0.02), but increased serum potassium (MD 0.22 mmol/L, 95% CI 0.16 to 0.29; n = 1,468 from 4 trials (6 trials reported serum potassium; FIDELIO-DKD and FIGARO-DKD excluded); P < 0.00001) and induced early eGFR decline (MD -3.01 mL/min/1.73 m 2 , 95% CI -4.46 to −1.56; n = 1,218 from 3 trials; P < 0.0001). Hyperkalemia risk was higher (OR 2.24, 95% CI 1.99 to 2.52; n = 14,734 from 6 trials; P < 0.00001), whereas overall adverse events, eGFR decline, and acute kidney injury did not differ. GRADE certainty was low for UACR, systolic BP, serum potassium, and early eGFR decline, and moderate for hyperkalemia. Conclusion In DKD, nsMRAs may reduce UACR and systolic BP. However, UACR was driven by finerenone with significant drug-type interaction, requiring agent-specific interpretation. Systolic BP was driven by FIGARO-DKD. Furthermore, nsMRAs may increase serum potassium and hyperkalemia risk, although the serum potassium analysis excluded two large trials. nsMRAs may also cause early hemodynamic eGFR decline. Notably, this review assessed only surrogate endpoints and safety outcomes. Several outcomes were supported by only 3–4 trials. Given these limitations and low-to-moderate certainty, findings warrant cautious interpretation and risk-benefit assessment. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251072300 , identifier CRD420251072300.