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% confidence intervals (CI) 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 1,060 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.