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Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial.

Author(s): Calhoun DA, White WB, Krum H, Guo W, Bermann G, Trapani A, Lefkowitz MP, Menard J

Affiliation(s): Vascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, AL 35294, USA. dcalhoun@uab.edu

Publication date & source: 2011-11-01, Circulation., 124(18):1945-55. Epub 2011 Oct 10.

Publication type: Research Support, Non-U.S. Gov't

BACKGROUND: LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension. METHODS AND RESULTS: We performed the first double-blind, randomized trial with LCI699 in patients with primary hypertension. We randomized 524 patients to LCI699 0.25 mg once daily (n=92), 0.5 mg once daily (n=88), 1.0 mg once daily (n=86), and 0.5 mg twice daily (n=97); eplerenone 50 mg twice daily (n=84); or placebo (n=77) for 8 weeks. Adrenocorticotropic hormone (250 mug IV) stimulation testing was performed in a subset of patients to quantify the selectivity of LCI699 for aldosterone synthase compared with 11-beta-hydroxylase. Reductions in clinic diastolic blood pressure were significant for LCI699 1.0 mg (-7.1 mm Hg; P=0.0012) and eplerenone 50 mg twice daily (-7.9 mm Hg; P<0.0001) compared with placebo (-2.6 mm Hg) but not other doses of LCI699. Significant reductions in clinic systolic blood pressure were observed with all doses of LCI699 (P<0.005 or better) and eplerenone (P<0.0001). All doses of LCI699 significantly reduced 24-hour ambulatory blood pressure compared with placebo (P<0.01). Adrenocorticotropic hormone stimulation of cortisol was suppressed in approximately 20% of subjects receiving LCI699 at a total daily dose of 1.0 mg. Safety and tolerability were similar among LCI699, placebo, and eplerenone. CONCLUSIONS: Aldosterone synthase inhibition with LCI699 significantly lowered clinic and ambulatory blood pressure. A minority of subjects developed blunted adrenocorticotropic hormone-stimulated release of cortisol. These results support additional research to evaluate use of aldosterone synthase inhibition in primary hypertension and/or patients characterized by aldosterone excess. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00758524.

Page last updated: 2011-12-09

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