Lorundrostat in Participants With Uncontrolled Hypertension and Treatment-Resistant Hypertension

Uncontrolled hypertension remains a global health concern and dysregulated aldosterone production is a central mechanism. Lorundrostat, a novel aldosterone synthase inhibitor that reduces aldosterone production, demonstrated efficacy in participants with uncontrolled hypertension, including those with treatment-resistant hypertension.

To evaluate the efficacy and safety of lorundrostat for lowering blood pressure (BP) when added to a prescribed regimen of 2 to 5 antihypertensive medications in adults with uncontrolled hypertension and treatment-resistant hypertension. Design, Setting, and Participants: In this phase 3, randomized clinical trial, adults with uncontrolled hypertension, including those with treatment-resistant hypertension, were enrolled between November 2023 and September 2024 at 159 clinic sites across 13 countries. The last date of follow-up was January 24, 2025. Intervention: Randomization ratio of 1:2:1 to 50 mg/d of lorundrostat for 6 weeks followed by 100 mg/d of lorundrostat for 6 weeks (n = 270) if they met prespecified criteria, 50 mg/d of lorundrostat for 12 weeks (n = 541), or daily placebo for 12 weeks (n = 272). The prespecified criteria included systolic BP of 130 mm Hg or greater, potassium level of 4.8 mmol/L or less, sodium level of 135 mmol/L or greater, an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2, and less than a 25% reduction in eGFR. Main Outcome and Measures: The primary outcome was change in automated office systolic BP at week 6 for participants randomized to 50 mg of lorundrostat vs placebo. Adverse events of special interest included dose reduction, interruption, or discontinuation due to events such as hyperkalemia, hyponatremia, and reduction in kidney function.