A new randomized, double-blind, placebo-controlled trial found that lorundrostat, an aldosterone synthase inhibitor, could reduce blood pressure in patients with uncontrolled, treatment-resistant hypertension.
In the Advance-HTN trial, researchers demonstrated that a 50-mg daily dose of lorundrostat achieved a placebo-adjusted reduction of 7.9 mmHg in 24-hour average systolic blood pressure (BP) after 12 weeks. A dose-adjustment strategy starting at 50 mg with a potential increase to 100 mg showed a placebo-adjusted reduction of 6.5 mmHg.
"Aldosterone dysregulation contributes to hypertension," the study authors stated, noting that lorundrostat's mechanism of directly targeting aldosterone biosynthesis may offer advantages over existing therapies that target the renin-angiotensin-aldosterone system.
Study Design and Patient Population
The phase IIb multicenter trial enrolled 285 participants who were randomly assigned to one of three groups:
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Stable 50 mg daily dose of lorundrostat (n = 94)
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Lorundrostat with potential dose adjustment (50 mg initially, with increase to 100 mg if systolic BP remained ≥ 130 mm Hg after 4 weeks) (n = 96)
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Placebo (n = 95).
All of the participants had uncontrolled hypertension despite taking two to five antihypertensive medications and underwent a standardized antihypertensive regimen for 3 weeks prior to randomization. Notably, 53% of the participants were Black, a population disproportionately affected by treatment-resistant hypertension.
The trial utilized 24-hour ambulatory BP monitoring to assess outcomes, eliminating potential confounders like inadequate medication dosing and white coat hypertension.
Key Findings
After 12 weeks, the mean changes in 24-hour average systolic BP were:
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–15.4 mmHg in the stable-dose group
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–13.9 mmHg in the dose-adjustment group
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–7.4 mmHg in the placebo group.
The researchers also demonstrated efficacy at 4 weeks, with a placebo-adjusted reduction of 5.3 mmHg across both lorundrostat groups. Interestingly, the 50-mg dose provide maximal BP reduction, as increasing to 100 mg didn't enhance efficacy.
Safety Outcomes and Concerns
The safety profile revealed expected effects of renin-angiotensin-aldosterone system inhibition. Hyperkalemia (potassium > 6.0 mmol/L) occurred in 5% of the stable-dose group and 7% of the dose-adjustment group, with 0% in the placebo group. Participants with hyperkalemia had a mean baseline estimated glomerular filtration rate (eGFR) of 58.3 ± 22.4 mL/min/1.73m².
After 12 weeks, mean eGFR calculated with cystatin C decreased by 13% in the stable-dose group and 15% in the dose-adjustment group compared with 3% in the placebo group. Importantly, eGFR recovered after a 4-week washout period in the participants who received lorundrostat, suggesting hemodynamic rather than structural changes to kidney function.
"By inhibiting aldosterone production while sparing other adrenal steroid pathways, lorundrostat may offer better efficacy and have fewer adverse effects than existing approved therapies," the study authors noted.
Implications for Clinical Practice
This trial added to growing evidence supporting aldosterone's role in treatment-resistant hypertension, particularly relevant for Black patients who comprised more than half the study population.
The study authors noted: "Among patients with uncontrolled, treatment-resistant hypertension, aldosterone dysregulation is increasingly recognized as a driver of persistent [BP] elevation."
The findings demonstrated a potential new therapeutic option for the challenging population of patients with resistant hypertension, though longer-term studies are needed. An open-label extension trial of lorundrostat (NCT05968430) and the phase III Launch-HTN trial (NCT06153693) are ongoing to further evaluate its efficacy and safety.
Author disclosure forms are available in the original study.