Lorundrostat efficacy and safety in patients with uncontrolled hypertension: a systematic review and meta-analysis of randomized controlled trials

Abstract Background/Introduction Aldosterone synthase inhibition has emerged as a potential approach for lowering blood pressure in uncontrolled hypertension. A novel selective inhibitor targeting this pathway has demonstrated promising early results, but its overall efficacy and safety profile have not been comprehensively evaluated. Purpose To systematically assess the efficacy and safety of selective aldosterone synthase inhibition compared with placebo in adults with uncontrolled hypertension. Methods A systematic review and meta-analysis was conducted according to established methodological standards. Randomised controlled trials enrolling adults with uncontrolled hypertension and comparing a selective aldosterone synthase inhibitor with placebo were identified through searches of major biomedical databases to the latest update. Outcomes included blood pressure control, changes in systolic blood pressure, and adverse events. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were calculated using random-effects models. Heterogeneity was assessed with the I² statistic, and predefined subgroup analyses explored effects across baseline characteristics. Results Three randomised controlled trials were included (n = 1,568). Treatment increased the proportion of participants achieving systolic blood pressure ≤130 mmHg compared with placebo (RR 1.88; 95% CI 1.55–2.28). Office systolic blood pressure decreased significantly (MD –9.60 mmHg; 95% CI –14.27 to –4.93). Adverse events occurred more frequently with active treatment (RR 1.46; 95% CI 1.28–1.66), including higher rates of hyperkalaemia (RR 6.69; 95% CI 2.62–17.10) and symptomatic hypotension (RR 2.59; 95% CI 1.02–6.59). A modest reduction in estimated glomerular filtration rate was observed (MD –6.21 mL/min/1.73 m²; 95% CI –7.97 to –4.44). There was no difference in all-cause mortality. Subgroup analyses showed consistent effects across BMI categories, dose ranges and racial groups. Conclusion(s) Selective aldosterone synthase inhibition improves blood pressure control in uncontrolled hypertension but is associated with higher rates of adverse events, particularly hyperkalaemia and symptomatic hypotension. These findings highlight the therapeutic potential of this mechanism while underscoring the need for careful monitoring and further studies to clarify long-term safety.Overview of study analysisFor image description, please refer to the figure legend and surrounding text.