Lorundrostat for Patients With Uncontrolled Hypertension: A Systematic Review With Meta-Analysis and Trial Sequential Analysis.

Abstract

Background: The efficacy and safety of lorundrostat, a selective aldosterone synthase inhibitor, in patients with uncontrolled hypertension remain unclear. This meta-analysis aimed to evaluate its effects on blood pressure and risk of hyperkalemia.

Methods: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were systematically searched through July 2025 for randomized controlled trials comparing lorundrostat with placebo. Pooled mean differences (MD) and risk ratios (RR) with 95% CIs were estimated using a random-effects model with the Restricted Maximum Likelihood estimator. Trial sequential analysis (TSA) was conducted to assess the conclusiveness of safety evidence.

Results: Three RCTs including 1060 patients were identified. Lorundrostat significantly reduced systolic blood pressure at 50 mg (MD, -9.08 mmHg; 95% CI, -13.14 to -5.03) and 100 mg (MD, -11.41 mmHg; 95% CI, -15.97 to -6.85), and diastolic blood pressure at 50 mg (MD, -3.48 mmHg; 95% CI, -5.98 to -0.98). However, lorundrostat increased the risk of hyperkalemia at 50 mg (RR, 6.56; 95% CI, 1.53-28.12; NNH = 71) and 100 mg (RR, 10.37; 95% CI, 2.44-44.03; NNH = 42). TSA confirmed hyperkalemia at 100 mg as the only conclusive harm signal, while other safety outcomes remained inconclusive.

Conclusions: Lorundrostat effectively lowered blood pressure but increased dose-dependent risk of hyperkalemia. These findings support its potential as a novel therapy for uncontrolled hypertension, while emphasizing the need for longer-term cardiovascular outcome trials and direct comparisons with mineralocorticoid receptor antagonists concerning efficacy and safety.