Aldosterone Synthase Inhibitors: Emerging Therapeutic Strategies in Resistant Hypertension

Resistant hypertension (RH) is a high-risk phenotype associated with increased cardiovascular and renal morbidity despite multidrug therapy. Dysregulation of the renin-angiotensin-aldosterone system (RAAS), particularly excess aldosterone activity, plays a central role in the pathophysiology of RH. Although conventional RAAS-targeted therapies including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists improve outcomes, their effectiveness is limited by aldosterone breakthrough, persistent non-genomic aldosterone effects, hyperkalaemia, and off-target adverse effects. Aldosterone synthase inhibitors (ASIs) have emerged as a novel therapeutic strategy targeting CYP11B2, the terminal enzyme responsible for aldosterone biosynthesis. This review summarises the physiological basis of aldosterone synthesis, the pathological consequences of aldosterone excess, and the pharmacological evolution of ASIs. Early-generation agents were limited by inadequate selectivity between CYP11B2 and the closely related CYP11B1 enzyme, resulting in cortisol suppression and deoxycorticosterone accumulation. Advances in structural biology and medicinal chemistry enabled the development of second-generation ASIs with markedly improved selectivity and preserved cortisol biosynthesis. Recent clinical trials of baxdrostat, lorundrostat, vicadrostat, and dexfadrostat have demonstrated clinically meaningful reductions in blood pressure and albuminuria with acceptable safety profiles. Based on the positive trial data, baxdrostat has become the first in class ASI to be approved by regulatory authorities for management of uncontrolled hypertension.