Dose–Response Relationships and Comparative Efficacy of Aldosterone Synthase Inhibitors in Resistant Hypertension: A Comprehensive Network Meta-Analysis and Meta-Regression

Abstract

Background: Resistant hypertension represents a significant clinical challenge, often driven by dysregulated aldosterone production. Aldosterone synthase inhibitors (ASIs) are a novel therapeutic class designed to directly suppress aldosterone biosynthesis. This study aimed to synthesize evidence regarding the comparative efficacy, optimal dosing, and dose–response relationships of three ASIs—baxdrostat, lorundrostat, and osilodrostat—for the treatment of resistant hypertension. Methods: A systematic review and network meta-analysis (NMA) were conducted following PRISMA 2020 guidelines. We searched PubMed, Web of Science, and CENTRAL for randomized controlled trials (RCTs) published up to 31 October 2025. The primary outcome was the mean change in systolic blood pressure (SBP) compared to placebo. We utilized a frequentist random-effects model, characterized dose–response relationships via meta-regression, and ranked treatments using the Surface Under the Cumulative Ranking Curve (SUCRA). Results: The analysis included 8 RCTs comprising 3253 participants. Baxdrostat 2 mg once daily demonstrated the greatest antihypertensive efficacy with a mean SBP reduction of −13.8 mmHg (95% CI: −17.5 to −10.1) versus placebo, followed by Lorundrostat 100 mg (−12.5 mmHg) and Baxdrostat 1 mg (−11.5 mmHg). SUCRA analysis identified Baxdrostat as the highest-ranked treatment (83.0%), followed by Lorundrostat (67.8%) and Osilodrostat (55.5%). Dose–response meta-regression revealed strong linear correlations for Baxdrostat (R2 = 0.91), Osilodrostat (R2 = 0.81), and Lorundrostat (R2 = 0.80). Conclusions: ASIs, particularly Baxdrostat and Lorundrostat, offer robust blood pressure reductions in patients with resistant hypertension. The strong linear dose–response relationships suggest these agents have a favorable therapeutic window for titration. While effective, clinical implementation requires careful monitoring for adverse events.