The Emerging Role of Aldosterone Synthase Inhibitors in Overcoming Renin-Angiotensin-Aldosterone System Therapy Limitations: A Narrative Review.

Abstract

The renin-angiotensin-aldosterone system is integral to cardiorenal health, with aldosterone controlling fluid balance, blood pressure and cardiac remodelling. Despite the widespread use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists, 'aldosterone escape' persists, contributing to treatment failure and adverse outcomes. Steroidal mineralocorticoid receptor antagonists also cause hyperkalaemia and anti-androgenic effects, limiting their use. Aldosterone synthase inhibitors (ASIs) selectively block cytochrome P450 11B2, reducing pathological aldosterone levels while preserving basal mineralocorticoid receptor activity, thus potentially lowering hyperkalaemia risk. This narrative review identified 41 relevant publications from a PubMed/MEDLINE search of "aldosterone synthase inhibitor" through 11 January 2025. Early clinical trials of ASIs (baxdrostat, lorundrostat, vicadrostat, dexfadrostat phosphate, JX09) report significant reductions in aldosterone, blood pressure and albuminuria, with promising safety. Challenges include ensuring high selectivity, mitigating hyperkalaemia and establishing long-term benefits. Ongoing Phase III trials will clarify their efficacy, safety and synergy with additional therapies - including sodium-glucose cotransporter 2 inhibitors - and clinical outcomes, positioning ASIs as an important advance in renin-angiotensin-aldosterone system modulation.