Aldosterone synthase inhibitors in cardio-renal diseases: a state-of-the-art review

Aldosterone plays a pivotal role in the progression of cardio-renal diseases by driving myocardial fibrosis, vascular dysfunction, and renal injury through both genomic and non-genomic mechanisms. While mineralocorticoid receptor antagonists have long served as the cornerstone of pharmacologic intervention, their use is limited by adverse effects such as hyperkalemia, gynecomastia, and incomplete suppression of aldosterone-mediated pathology. Aldosterone synthase inhibitors, a novel class of therapeutics, offer a promising alternative by targeting the enzymatic production of aldosterone at its source, thereby circumventing receptor-level limitations. This narrative review comprehensively explores the physiological role of aldosterone, critiques existing RAAS-targeted therapies, and provides an in-depth evaluation of the pharmacology, efficacy, and safety of emerging ASIs including baxdrostat, lorundrostat, and osilodrostat. Evidence from recent clinical trials such as BrigHTN, HALO, Target-HTN, and FIONE is synthesized to assess their clinical potential. In addition, the review highlights novel mechanistic frontiers including the role of ASIs in overcoming aldosterone escape, attenuating cardio-renal fibrosis, modulating neurohormonal dysregulation, and enabling precision therapy through pharmacogenomic stratification. Future directions emphasize drug design innovations such as adrenal-specific prodrugs and nanoparticle-based formulations. Overall, ASIs represent a mechanistically robust and clinically promising advancement in the treatment of heart failure, chronic kidney disease, and primary aldosteronism. Their integration into multidrug regimens and personalized treatment frameworks may redefine the therapeutic landscape of cardio-renal-metabolic disease.