Pharmacovigilance profiles of three generations of mineralocorticoid receptor antagonists and network toxicology analysis.

INTRODUCTION

Mineralocorticoid receptor antagonists, spironolactone, eplerenone, and finerenone, are cornerstone therapies in cardiovascular and renal diseases. While their efficacy is established, a systematic, head-to-head comparison of their post-marketing safety profiles based on large-scale real-world data is lacking.

METHODS

This study comprehensively compared the post-marketing safety profiles of spironolactone, eplerenone, and finerenone using 11,556 primary suspect reports from the FAERS database (Q1 2004-Q3 2025).

RESULTS

Disproportionality analyses revealed distinct adverse event (AE) signatures. Spironolactone exhibited the broadest safety profile, with disproportionate reporting indicating congenital malformations, acute pulmonary edema, serious cutaneous reactions, and antiandrogenic effects including rare signals such as endometriosis in males. Eplerenone showed a more focused yet severe profile, with signals for serious cardiac events and renal/hepatic failure. Finerenone demonstrated the most targeted profile, with signals predominantly confined to renal and metabolic domains. Hyperkalemia was a consistent moderate-priority signal across all three drugs, and several high-signal, unlabeled AEs were identified. Network toxicology analysis further supported these findings by linking shared and drug-specific molecular targets to key pathways (e.g., aldosterone-regulated sodium reabsorption, MAPK signaling).

DISCUSSION: These hypothesis-generating findings underscore the need for personalized safety monitoring, potential label updates, and independent validation in other pharmacovigilance databases before clinical or regulatory conclusions can be drawn.