Aldosterone Synthase Inhibitors: A Revival for Treatment of Renal and Cardiovascular Diseases

Abstract Inappropriate aldosterone excess plays a key role in the pathophysiology of various cardiovascular, endocrine, and renal diseases. Mineralocorticoid receptor antagonists (MRAs) such as spironolactone block of the harmful effects of aldosterone and are recommended treatment in these various conditions. However, the sexual adverse effects of spironolactone from its lack of specificity for the mineralocorticoid receptor and the risk of hyperkalemia in patients with decreased renal function, limit its use. While eplerenone is a more selective MRA, it is less potent than spironolactone. Newer nonsteroidal MRAs, though promising, are either unavailable globally or still under development. Moreover, aldosterone exerts both genomic and nongenomic effects, the latter not fully blocked by MRAs. Aldosterone synthase inhibitors (ASIs) have thus emerged as potential alternatives to MRAs, though the development of selective ASIs has been challenging. This is due to the close homology between the final step of aldosterone synthesis, mediated by CYP11B2 in the zona glomerulosa of the adrenal cortex, and cortisol synthesis, mediated by CYP11B1 in the zona fasciculata. Despite these challenges, new ASIs have demonstrated high in vitro as well as in vivo selectivity for CYP11B2, effectively reducing aldosterone production without affecting cortisol synthesis in humans across large dose ranges. Early phase II trials demonstrated that these ASIs decrease (1) blood pressure in uncontrolled hypertension and (2) urinary albumin excretion in proteinuric chronic kidney disease. Further longer term trials will evaluate their efficacy in lowering blood pressure as well as in reducing kidney disease progression and cardiovascular outcomes in heart failure when given alone or in combination with SGLT2 inhibitors.