Vicadrostat

Resistant and uncontrolled hypertension remain major unmet needs, with aldosterone dysregulation or frank excess increasingly recognized as a central driver. To this end, aldosterone synthase inhibitors (ASIs) represent a novel therapeutic approach targeting CYP11B2, the key enzyme responsible for aldosterone biosynthesis. By reducing aldosterone production at its source, ASIs may overcome limitations associated with conventional renin-angiotensin-aldosterone system (RAAS) blockade and attenuate both genomic and non-genomic effects of aldosterone. Advances in drug development have led to second-generation ASIs, including baxdrostat, lorundrostat, dexfadrostat, and vicadrostat, characterized by high selectivity for CYP11B2 over CYP11B1, thereby preserving cortisol synthesis. Clinical trials across phases I-III demonstrate that second-generation ASIs, including baxdrostat, lorundrostat, dexfadrostat, and vicadrostat, effectively lower aldosterone levels and produce substantial blood pressure reductions, particularly in resistant or uncontrolled hypertension. ASIs are generally well tolerated. Hyperkalemia is the most common adverse event, particularly in patients with chronic kidney disease, but is typically manageable and appears less frequent than with mineralocorticoid receptor antagonists in comparable populations. No clinically significant suppression of the hypothalamic-pituitary-adrenal axis has been observed with second-generation compounds. These findings support ASIs as a promising addition to the therapeutic armamentarium for hypertension. The recent FDA approval of baxdrostat, the first second-generation ASI, represents an important milestone for this therapeutic class. However, further studies are required to establish long-term safety, optimal patient selection, and their role in combination therapies and cardiovascular risk reduction.

Hypertension and organ damage caused by an inappropriate balance between aldosterone and salt are deeply involved in pathologies such as chronic heart failure, chronic kidney disease, and vascular disorders. Mineralocorticoid receptor antagonists are effective not only as antihypertensives, but also as organ-protective drugs, blocking direct aldosterone-induced organ damage independent of blood pressure. In recent years, research into selective aldosterone synthase inhibitors has progressed, resulting in the development of drugs such as baxdrostat, lorundrostat, and vicadrostat. These drugs are highly selective for aldosterone synthase with little inhibition of 11β-hydroxylase, making them promising antihypertensive and organ-protecting drugs. This article summarizes the basic and clinical research on aldosterone synthase inhibitors to date and reviews their characteristics. Aldosterone synthase inhibitors are drugs with the unprecedented characteristic of reducing blood aldosterone levels. Many studies have shown that low serum aldosterone levels are associated with a reduced risk of cardiovascular events. In fact, clinical trials of aldosterone synthase inhibitors have shown that lowering serum aldosterone levels by 50–70% results in lower blood pressure and organ protection. Even a small reduction in serum or local aldosterone levels is highly likely to improve hypertension and organ damage. Clinically, lowering blood aldosterone levels is very important.　Compared to the clinical evidence for mineralocorticoid receptor antagonists, clinical evidence for aldosterone synthase inhibitors remains insufficient. How these two drug types should be used given their differences thus remains unresolved. Discussing the differences in clinical effects in the future is thus important.