Comparative Efficacy and Safety of Finerenone versus Spironolactone in the Management of Diabetic Kidney Disease with Proteinuria

Background: Diabetic kidney disease (DKD) with persistent proteinuria remains a leading cause of end-stage renal disease (ESRD) and cardiovascular mortality worldwide, despite optimal use of renin–angiotensin system (RAS) inhibitors and sodium–glucose cotransporter-2 (SGLT2) inhibitors. Mineralocorticoid receptor antagonists (MRAs) provide additional renoprotective effects by reducing inflammation and fibrosis. Spironolactone, a first-generation steroidal MRA, has demonstrated reductions in albuminuria but is often limited by adverse events such as hyperkalemia and gynecomastia. Finerenone, a novel non-steroidal MRA with higher receptor selectivity and lower lipophilicity, has shown significant renal and cardiovascular benefits with a reduced risk of hyperkalemia in large phase III trials. However, a direct comparative evaluation of these agents in DKD with proteinuria is lacking. Objective: To systematically compare the efficacy and safety of finerenone versus spironolactone in the management of DKD with proteinuria, highlighting their impact on renal outcomes, cardiovascular endpoints, and adverse event profiles. Methods: A comprehensive literature search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted through September 2025. Randomized controlled trials (RCTs), observational studies, and meta-analyses evaluating finerenone or spironolactone in adults with DKD and proteinuria were included. Primary efficacy outcomes were reduction in urinary albumin-to-creatinine ratio (UACR) and preservation of estimated glomerular filtration rate (eGFR). Secondary outcomes included composite kidney failure endpoints and major adverse cardiovascular events (MACE). Safety outcomes assessed were hyperkalemia incidence, endocrine-related adverse effects, and treatment discontinuation rates. Results: Evidence from the FIDELIO-DKD (n=5,734) and FIGARO-DKD (n=7,437) trials demonstrated that finerenone significantly reduced progression to kidney failure (hazard ratio [HR]: 0.82) and lowered risk of cardiovascular events (HR: 0.87) compared to placebo, with a moderate increase in hyperkalemia (18% vs 9% in placebo) but low discontinuation rates (~2%). Spironolactone trials in DKD populations reported reductions in proteinuria ranging from 30–40%, often comparable or slightly greater than finerenone; however, rates of hyperkalemia were substantially higher (up to 20–25%), with 8–10% of patients requiring discontinuation. Additionally, spironolactone was associated with gynecomastia and menstrual irregularities due to its non-selective steroidal activity, adverse effects not observed with finerenone. Indirect comparisons suggest that finerenone provides more durable renal and cardiovascular benefits while maintaining a superior safety and tolerability profile. Conclusion: Both spironolactone and finerenone effectively reduce proteinuria in DKD, yet finerenone offers a more favorable balance of efficacy and safety. Spironolactone remains effective in lowering albuminuria but carries a higher risk of hyperkalemia and endocrine-related adverse effects, limiting its long-term use. Finerenone, supported by robust large-scale RCTs, emerges as the preferred therapeutic option for DKD with proteinuria, particularly in patients at high risk of adverse events. Nevertheless, the absence of direct head-to-head trials underscores the need for future comparative studies to refine individualized treatment strategies.