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
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.
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In patients with primary hypertension, treatment with the aldosterone synthase inhibitor LCI699 reduced serum aldosterone levels and blood pressure.
“A randomized controlled trial in patients with primary hypertension showed that treatment with the aldosterone synthase inhibitor LCI699 reduced serum aldosterone levels and BP79.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [79]
The blood-pressure-lowering effect of LCI699 was less than that observed with MR antagonism, and LCI699 therapy was associated with reduced cortisol synthesis.
“The BP-lowering effect of LC1699 was not as impressive, however, as that observed with MR antagonism, and LC1699 therapy was associated with an important adverse effect of reduced cortisol synthesis.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [79]
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- Authors
- Calhoun, D. A., White, W. B., Krum, H., Guo, W., Bermann, G., Trapani, A., Lefkowitz, M. P., & Ménard, J.
- Affiliations
- Novartis (Switzerland) (CH)
- Venue
- Circulation
- Published
- 2011-11
- Volume
- 124
- Issue
- 18
- Pages
- 1945-1955
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2014029753
- Cited by
- 227
- References
- 35
- Citations by year
- 2026: 22 · 2025: 15 · 2024: 18 · 2023: 11 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 10 · 2018: 9 · 2017: 10 · 2016: 16 · 2015: 23 · 2014: 29 · 2013: 26 · 2012: 24
- FWCI
- 20.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- aldosterone synthase inhibitors, essential hypertension, eplerenone, blood pressure reduction, ambulatory blood pressure, adrenocorticotropic hormone stimulation, cortisol suppression, aldosterone excess
- MeSH terms
- Adrenocorticotropic Hormone, Adult, Aged, Aged, 80 and over, Aldosterone, Blood Pressure, Double-Blind Method, Enzyme Inhibitors, Female, Hormones, Humans, Hydrocortisone, Hypertension, Male, Middle Aged, Placebos, Renin, Cytochrome P-450 CYP11B2
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