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Published on: October 12, 2015
Aldosterone synthase inhibition in humans
Michel Azizi1, Laurence Amar, Joël Menard
1Faculté de Médecine, The Université Paris Descartes, Paris F-75006, France. michel.azizi@egp.aphp.fr
Summary
The first aldosterone synthase inhibitor, LCI699, effectively lowers aldosterone levels and blood pressure in hypertensive patients. However, its impact on the glucocorticoid axis limits higher doses, necessitating further development of more selective inhibitors.
Area of Science:
- Endocrinology
- Cardiovascular Medicine
- Pharmacology
Background:
- Aldosterone synthase (CYP11B2) inhibition offers a novel therapeutic strategy for hypertension, heart failure, and renal disorders.
- This approach aims to reduce aldosterone levels, mitigating its effects on target organs.
- Mineralocorticoid receptor (MR) blockade is a current standard, but CYP11B2 inhibition presents a complementary or alternative pathway.
Purpose of the Study:
- To evaluate the efficacy and safety of LCI699, the first orally active aldosterone synthase inhibitor.
- To assess the impact of LCI699 on aldosterone concentrations, blood pressure, and hormonal axes.
- To explore the potential of CYP11B2 inhibition as a treatment for aldosterone-related conditions.
Main Methods:
- Dose-dependent administration of LCI699 in healthy subjects and patients with primary aldosteronism and essential hypertension.
- Measurement of plasma and urine aldosterone, renin activity, cortisol, ACTH, and 11-deoxycortisol.
- Placebo-controlled, dose-response study in patients with essential hypertension, comparing LCI699 with eplerenone.
Main Results:
- LCI699 dose-dependently decreased plasma and urine aldosterone by 70-80% and increased plasma renin activity.
- In primary aldosteronism, LCI699 corrected hypokalemia and modestly decreased blood pressure, with significant deoxycorticosterone accumulation.
- In essential hypertension, LCI699 (1 mg q.d.) lowered blood pressure comparably to eplerenone, with some patients showing blunted cortisol response to ACTH.
Conclusions:
- LCI699 demonstrates proof-of-concept for aldosterone synthase inhibition, reducing aldosterone and blood pressure.
- Inhibition of the glucocorticoid axis at higher doses limits LCI699's utility and selectivity for CYP11B2.
- Development of next-generation inhibitors with improved selectivity is crucial for advancing this therapeutic approach.
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