Efficacy of Aldosterone synthase inhibitors in uncontrolled and resistant hypertension: A systematic review and updated meta-analysis with grade assessment

BACKGROUND: The current therapy for resistant hypertension is often limited by hyperkalemia, renal decline, and a failure to prevent compensatory increases in circulating aldosterone. The aldosterone synthase inhibitors (ASIs) address these limitations by directly suppressing aldosterone biosynthesis sparing other steroid pathways. AIM: To evaluate the safety and efficacy of ASIs in resistant hypertension. METHODS: Databases searched through March 2026 to find relevant studies, following PRISMA guidelines. Data analysis was performed using R-Software. Primary outcome analyzed was reduction in systolic and diastolic blood pressures. RESULTS: A total of 8 RCTs were analyzed which showed that Aldosterone Synthase Inhibitors (ASI) significantly reduced systolic blood pressure (MD:8.0; 95% CI:10.53, -5.47, p < 0.01) and diastolic blood pressure (MD:3.44; 95% CI:5.03, -1.86, p < 0.01) and with double the likelihood of achieving target SBP < 130 mmHg (RR: 2.26; 95% CI: 1.73, 2.95, p = 0.002). ASI were associated with significant risk of any adverse events (RR: 1.23; 95% CI: 1.08, 1.41, p = 0.02), hyponatremia (RR: 2.04; 95% CI: 1.10, 3.80, p = 0.024), hypotension (RR: 2.47; 95% CI: 1.14,5.33, p = 0.02), and notably seven-fold increase risk of hyperkalemia (RR: 7.18; 95% CI: 3.20, 16.12, p < 0.001). Despite these risks, there was no statistically significant increase in serious adverse events (RR: 1.26; 95% CI: 0.68, 2.34, p = 0.47) and drug discontinuation rate (RR: 1.84; 95% CI: 0.41, 8.12, p = 0.28) with ASIs compared to placebo. Mechanistically, ASI was associated with a significant reduction in aldosterone (SMD:1.12; 95% CI:1.25, -1.0; p < 0.01), reduction in eGFR (MD:6.48; 95% CI:9.02, -3.94, p < 0.01) and an increase in plasma renin activity (SMD: 0.53; 95% CI: 0.37, 0.68, p < 0.01) associated with significant increase in serum potassium level(MD:0.47; 95% CI:0.34, 0.61; p < 0.01). CONCLUSION: Aldosterone synthase inhibitors (ASI) provide clinically meaningful reductions in systolic and diastolic blood pressure in uncontrolled or resistant hypertension, doubling the likelihood of achieving target blood pressure levels, with treatable safety concerns which is evidenced by non-significant trend in serious adverse events and drug discontinuation rate.