Aldosterone synthase inhibition: a novel bullet to fight cardiovascular–kidney–metabolic syndrome

Aldosterone is synthesized by the CYP11B2 enzyme, primarily in the zona glomerulosa of the adrenal gland. It exerts its classical effects on sodium and water balance in the renal distal nephron through binding to the mineralocorticoid receptor (MR). Excess aldosterone production or overactivation of the MR outside the distal nephron leads to cardiac, renal, and vascular injury by increasing oxidative stress and activating the inflammatory and fibrotic pathways. MR antagonists (MRAs) have proved effective at decreasing organ damage and the deleterious effects of excess aldosterone/MR activation. However, MRAs do not fully block the non-genomic effects of aldosterone, which may contribute to residual risks. CYP11B2 inhibition has emerged as an additional therapeutic approach to decreasing the deleterious genomic and non-genomic effects of aldosterone. The development of specific aldosterone synthase inhibitors (ASi) has proved challenging due to the considerable similarity between aldosterone synthase and 11β-hydroxylase, an enzyme encoded by the CYP11B1 gene that catalyzes cortisol synthesis. In this review, we summarize the latest developments on preclinical evidence and clinical trials for ASi and explore the potential clinical advantages of ASi.