Combination therapy with mineralocorticoid receptor antagonists and SGLT2 inhibitors versus SGLT2 inhibitor monotherapy in chronic kidney disease: an updated meta-analysis of randomized controlled trials

Abstract Background Chronic kidney disease (CKD) affects millions worldwide and poses a major healthcare challenge. While both sodium-glucose co-transporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs) or aldosterone synthase inhibitors (ASIs) have shown individual benefits in CKD, data on their combined use remain limited. This study examined the safety and efficacy of combining an SGLT2 inhibitor with an MRA or ASI compared to SGLT2 inhibitor monotherapy. Methods A comprehensive search was conducted on PubMed, Cochrane (CENTRAL), ScienceDirect, and Embase for randomized controlled trials (RCTs) comparing combination therapy with an MRA or ASI and an SGLT2 inhibitor with SGLT2 inhibitor monotherapy in patients with CKD. Continuous and dichotomous outcomes were pooled as Mean Difference (MD) or Risk Ratio (RR), respectively, with 95% Confidence Intervals (CIs) using Review Manager (v5.4.1.), and heterogeneity was assessed using the I² statistic. Results Five RCTs (n = 808 patients) were included. Combination therapy significantly reduced albuminuria (MD: -32.82% [95% CI: -39.16, -26.48] %; p < 0.001), systolic blood pressure (MD: -5.02 mm Hg [95% CI: -6.95, -3.08] mm Hg; p < 0.001), and estimated glomerular filtration rate (MD: -2.59 mL/min/1.73 m2 [95% CI: −3.78, − 1.40] mL/min/1.73 m2; p < 0.001). While the risk of hyperkalemia was higher (RR: 1.91 [95% CI: 1.10,3.33]; p = 0.02) with combination therapy, no significant differences were found in serious adverse events (RR: 0.95 [95% CI: 0.57,1.59]; p = 0.86). Conclusion The combination therapy provides added renal and cardiovascular benefits in CKD without increasing serious adverse effects. These findings support its superior therapeutic potential and highlight the need for large-scale, prospective studies to assess long-term effects on hard renal and cardiovascular outcomes. Prospero registration CRD420251106173.