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. 2025 Nov;85(11):1429-1453.
doi: 10.1007/s40265-025-02229-2. Epub 2025 Aug 30.

Aldosterone Synthase Inhibitors for Resistant Hypertension: Pharmacological Insights - A Systematic Review

Arrigo F G Cicero #  1   2 , Giuliano Tocci #  3 , Ashot Avagimyan  4 , Peter Penson  5   6 , Giulia Nardoianni  3 , Francesco Perone  7 , Claudio Borghi  1   2 , Federica Fogacci  8
Affiliations

Aldosterone Synthase Inhibitors for Resistant Hypertension: Pharmacological Insights - A Systematic Review

Arrigo F G Cicero et al. Drugs. 2025 Nov.

Abstract

Background: Resistant hypertension (RHT) is a challenging clinical condition characterized by persistently elevated blood pressure despite adherence to lifestyle modifications and the use of at least three antihypertensive agents, including a high-dose diuretic. RHT is a heterogeneous condition, influenced by multiple pathophysiological mechanisms such as sodium retention, sympathetic overactivity, and vascular dysfunction. Among these, hyperaldosteronism plays a pivotal role in a subset of patients.

Methods: This systematic review examines in depth the pharmacokinetic properties of aldosterone synthase inhibitors (ASIs), with a focus on their therapeutic potential in patients with RHT. A comprehensive literature search was conducted to identify clinical trials and pharmacological studies investigating ASIs, including baxdrostat, dexfadrostat, lorundrostat, LY3045697, and osilodrostat (LCI699).

Results: ASIs have shown compelling efficacy in lowering both office-based and 24-h ambulatory blood pressure, particularly in patients with elevated aldosterone levels. These findings underscore the critical role of aldosterone-mediated mechanisms in the pathophysiology of RHT. The inhibitors differ substantially in their metabolic pathways, selectivity profiles, and pharmacokinetic characteristics.

Conclusions: Emerging data support the potential of ASIs as a therapeutic option for RHT, particularly when treatment is individualized based on renal function, dietary sodium intake, and comorbidities. Personalized treatment strategies may enhance efficacy, improve tolerability, and support durable blood pressure control in this difficult-to-treat population.

Registration: PROSPERO identifier number CRD42024522918 [Graphical abstract available].

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Conflict of interest statement

Declarations. Funding: Open access funding provided by Alma Mater Studiorum - Università di Bologna within the CRUI-CARE Agreement. Author Contributions: Conceptualization: AFGC and FF. Data curation: AFGC, GT, AA, PP, GN, FP, CB, and FF. Investigation: AFGC, GT, AA, PP, and FF. Methodology: AFGC, GT, AA, PP, GN, FP, CB, and FF. Project administration: AFGC, GT, and FF. Supervision: AFGC and FF. Visualization: AA, FP, and FF. Writing: AFGC, GT, AA, PP, and FF. Reviewing and editing: GN, FP, and CB Data Availability Statement: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Conflicts of Interest: Claudio Borghi has received personal fees from Servier Pharma, EGIS Pharma, the Menarini Group, and Mineralys Therapeutics. Arrigo FG Cicero, Giuliano Tocci, Ashot Avagimyan, Peter Penson, Giulia Nardoianni, Francesco Perone, and Federica Fogacci have no potential conflicts of interest that might be relevant to the contents of this manuscript. Ethics Approval: Not applicable. Code Availability: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable.

Figures

Fig. 1
Fig. 1
Overview of the adrenal steroidogenesis pathway affected by aldosterone synthase inhibitors (ASIs). ASIs block the activity of cytochrome P450 (CYP)-11B2, the enzyme responsible for the conversion of 11-deoxycorticosterone to corticosterone, corticosterone to 18-hydroxycorticosterone, and ultimately to aldosterone. By inhibiting CYP11B2, ASIs reduce the biosynthesis of aldosterone and its precursors
Fig. 2
Fig. 2
Flow chart of the number of studies identified and included in the systematic review
Fig. 3
Fig. 3
Molecular formulas of the main aldosterone synthase inhibitors in development for the treatment of resistant hypertension
See this image and copyright information in PMC

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