Aldosterone Synthase Inhibitors for Uncontrolled and Resistant Hypertension

Introduction: Uncontrolled/Resistant hypertension affects 10-20% of hypertensive patients and carries elevated cardiovascular risk. Aldosterone Synthase Inhibitors (ASIs) selectively inhibit CYP11B2, offering targeted aldosterone suppression without glucocorticoid interference. We conducted a meta-analysis of randomized controlled trials (RCTs) evaluating their efficacy and safety. Methods: We did an extensive literature search of PubMed, Embase, and Cochrane databases for RCTs comparing Aldosterone Synthase Inhibitors (ASIs) with placebo in adults with uncontrolled or resistant hypertension. We measured in-office seated systolic blood pressure (SBP) from baseline (primary outcome), diastolic blood pressure (DBP), 24-hour ambulatory SBP, and blood pressure control defined as SBP < 130 mmHg. Safety endpoints included serious adverse events, treatment discontinuation due to adverse events, hyperkalemia, and hypotension. Prespecified subgroup analyses included resistant hypertension status, treatment duration (6-8 vs 12 weeks), and individual ASI agents. Pooled analyses were performed using random-effects models. Mean differences (MDs) were used for continuous outcomes and risk ratios (RRs) or odds ratios (ORs) for dichotomous outcomes. Heterogeneity was assessed using the I 2 statistic. Results: Seven RCTs, including 2,315 participants (ASI n=1,426; placebo n=889), were included. ASIs significantly reduced SBP compared with placebo (MD –8.79 mmHg, 95% CI –11.06 to –6.51; p < 0.00001; I 2 = 34%). Subgroup analyses showed numerically greater SBP reductions at 12 weeks (MD –10.17 mmHg) compared with 6-8 weeks (MD –6.94 mmHg), with no significant interaction between subgroups. Effects were consistent across agents, with similar reductions for Baxdrostat (MD –8.60 mmHg) and Lorundrostat (MD –9.15 mmHg). ASIs also reduced diastolic BP (MD –3.45 mmHg, 95% CI –5.18 to –1.71) and 24-hour ambulatory SBP (MD –11.27 mmHg, 95% CI –17.13 to –5.42). The likelihood of achieving SBP <130 mmHg was increased (RR 1.62, 95% CI 1.06-2.48), although with substantial heterogeneity (I 2 = 86%). Safety analyses showed that ASIs were associated with increased overall adverse events (OR 1.31, 95% CI 1.01-1.71), treatment discontinuation due to adverse events (OR 2.94, 95% CI 1.09-7.93), hyperkalemia (OR 4.93, 95% CI 1.99-12.20), and hypotension (OR 3.32, 95% CI 1.36-8.08). Serious adverse events were not significantly increased (OR 1.32, 95% CI 0.76-2.32). Conclusion: ASIs produced consistent, statistically significant SBP reductions. However, ASIs significantly increased hyperkalemia, hypotension, and treatment discontinuation without increasing serious adverse events. These findings support ASIs as an efficacious add-on therapy for uncontrolled/resistant hypertension, with regular monitoring essential for safe clinical implementation.