Efficacy and Safety of Aldosterone Synthase Inhibitors in Resistant Hypertension

Background: Hypertension is a major global health burden and a leading preventable risk factor for cardiovascular morbidity and mortality, affecting approximately 1.28 billion people globally, many of whom remain inadequately controlled. Aldosterone, a key hormone involved in the pathogenesis of hypertension, has led to increasing interest in aldosterone synthase inhibitors (ASls), which may represent a promising therapeutic option for patients with treatment-resistant hypertension. Methods: A systematic review and meta-analysis was done in accordance with PRISMA 2020 guidelines. A comprehensive search of PubMed, Embase, MEDLINE, and Cochrane Central was conducted from inception through May 9, 2026, to identify randomized controlled trials (RCTs) comparing ASls with placebo in patients with treatment-resistant hypertension. Our search strategy identified 2,200 articles, of which only 12 RCTs met our eligibility criteria and were included in this meta-analysis. Baseline characteristics and outcomes were extracted using an online Excel sheet. The Cochrane Risk of Bias Tool was used to assess the quality of included trials across five domains: selection, reporting, performance, detection, and attrition bias. Certainty of evidence was assessed using the GRADE approach. Statistical analyses were done using ReMan version 5.4, applying random-effects models for forest plots with a significance level set at p<0.05. Continuous outcome data were expressed as mean differences (MDs) with 95% confidence intervals (Cls) and dichotomous outcome data as risk ratios (RRs) with 95% Cls. Results: Twelve RCTs involving 4,367 patients showed that ASIs significantly reduced systolic blood pressure (SP) by -8.24 mmHg [95% Cl, -10.09 to -6.04; p<0.00001] and diastolic blood pressure (DBP) by -3.82 mmHg [95% Cl, -5.13 to -2.51; p<0.00001]. There was no significant difference in the risk of serious adverse events between patients receiving ASIs and placebo (risk ratio, 1.12 [95% Cl, 0.72 to 1.74]; p=0.63). Overall adverse events were more frequent in patients receiving ASIs (risk ratio, 1.18 [95% Cl, 1.08 to 1.29]; p=0.0004).No treatment-related deaths occurred. Additionally, the risks of hyperkalemia (risk ratio, 4.73[95% CI, 2.73 to 8.18]; p<0.00001), hypotension (risk ratio, 2.38 [95% Cl, 1.17 to 4.86)];p=0.02), and hyponatremia (risk ratio, 1.82 [95% CI, 1.14 to 2.90]; p=0.01) were increased in patients receiving ASls. Conclusion: ASIs significantly reduce SBP and DBP in patients with treatment-resistant hypertension and demonstrate a tolerable safety profile. However, adverse events including hyperkalemia, hypotension, and hyponatremia warrant careful monitoring. These findings support the use of ASIs as a promising therapeutic option for treatment-resistant hypertension; however, further large-scale studies are required to determine their role in hypertension management.