Efficacy and Safety of Selective Aldosterone Synthase Inhibitors in Uncontrolled Hypertension: A Systematic Review and Dose-Specific Network Meta-Analysis of Randomized Controlled Trials

Abstract

Selective aldosterone synthase inhibitors (ASIs), including baxdrostat and lorundrostat, target CYP11B2 while sparing cortisol synthesis, offering a novel strategy for resistant and uncontrolled hypertension. Yet existing meta-analyses have included nonselective agents or omitted the latest phase 3 data. We searched PubMed, Scopus, Cochrane, and Web of Science from inception to March 7, 2026, for randomized controlled trials of selective ASIs versus placebo. Random-effects dose-level network meta-analyses were performed for 16 efficacy and safety outcomes. Trial sequential analysis assessed evidence firmness, and certainty was rated using the GRADE CINeMA framework. Six randomized controlled trials (2856 patients across 30 countries) were included. ASIs reduced office systolic blood pressure versus placebo [mean difference (MD) -8.22 mm Hg; 95% CI, -9.43 to -7.00; I2 = 0%]. Baxdrostat 2 mg achieved the greatest reductions in office systolic blood pressure (-10.24 mm Hg), office diastolic blood pressure (-4.40 mm Hg), and ambulatory systolic blood pressure (-14.53 mm Hg). ASIs lowered serum aldosterone and raised plasma renin activity. Safety signals included reduced eGFR (MD -6.91 mL/min/1.73 m2), hyperkalemia [risk ratio (RR) 5.04], hyponatremia (RR 2.11), and symptomatic hypotension (RR 3.17), with dose-dependent risks most pronounced for lorundrostat 100 mg.