Effects of a Novel Aldosterone Synthase Inhibitor for Treatment of Primary Hypertension

Abstract

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 μg IV) stimulation testing was performed in a subset of patients to quantify the selectivity of LCI699 for aldosterone synthase compared with 11-β-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 ≈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.