Aldosterone Synthase Inhibitors Lorundrostat and Baxdrostat in Uncontrolled Hypertension

Background: Despite the availability of antihypertensive therapies, uncontrolled and resistant hypertension remains common, possibly driven by inappropriate aldosterone activity. Novel aldosterone synthase inhibitors (ASIs) such as Lorundrostat and Baxdrostat selectively inhibit CYP11B2, offering to reduce aldosterone production without effects of MRAs (mineralocorticoid receptor antagonists). This systematic review and meta-analysis evaluated the efficacy and safety of ASIs in patients with uncontrolled hypertension. Methods: We systematically searched Pubmed, Google scholar Cochrane library and clinicaltrials.gov from inception to February 2026 for RCTs evaluating Lorundrostat or Baxdrostat versus placebo in adults with uncontrolled or resistant hypertension. The primary outcome was the change in SBP (systolic blood pressure) from baseline to study endpoint. Secondary outcomes included mean change in diastolic blood pressure (DBP) and safety events such as adverse effects and discontinuations. Random effect model was employed and RevMan software version 5.4 was used. Risk of Bias was assessed using the Cochrane RoB-2 tool. Results: Five RCTS with 2439 patients were included. Compared to placebo high dose ASIs (Lorundrostat 100mg or Baxdrostat 1-2mg) significantly reduced SBP at 6-8 weeks by -7.93mm Hg, 95% CI: -930 to -6.56; I2= 0%, Figure 1 and at 10-12 weeks by -9.49 mm Hg, 95% CI -11.96 to -7.03; I2= 0%) Low dose ASIs (Lorundrostat 50mg or Baxdrostat 0.5 mg) also reduced SBP at 10-12 weeks by -7.23 mmHg, 95% CI: -9.98 to -4.48; I2=0%) Figure 2. The overall pooled SBP reduction was -8.57mm Hg, 95% CI -9.74, -7.21). DBP reduction was -4.36mm Hg. Regarding safety, ASIs significantly increased hyperkalemia (RR 8.97) similarly hypotension (RR=2.27) and hyponatremia (RR= 2.24) too. Treatment of emergent adverse events showed an increase of RR: 1.4. A dose dependent decline in eGFR was also observed with both drugs. All studies demonstrated low risk of bias using RoB-2. Conclusions: ASIs represent a promising adjunctive therapy for resistant hypertension but requires careful monitoring of electrolytes and renal function because these benefits are accompanied by increased risks of hyperkalemia, hypotension and hyponatremia as well as eGFR decline. Trials with long term cardiovascular outcomes are warranted.