The Effects of Aldosterone Synthase Inhibition on Aldosterone and Cortisol in Patients With Hypertension: A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study
Article first published online: 7 JUN 2012
© 2012 Wiley Periodicals, Inc.
The Journal of Clinical Hypertension
Volume 14, Issue 9, pages 580–587, September 2012
How to Cite
Andersen, K., Hartman, D., Peppard, T., Hermann, D., Van Ess, P., Lefkowitz, M. and Trapani, A. (2012), The Effects of Aldosterone Synthase Inhibition on Aldosterone and Cortisol in Patients With Hypertension: A Phase II, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study. The Journal of Clinical Hypertension, 14: 580–587. doi: 10.1111/j.1751-7176.2012.00667.x
- Issue published online: 4 SEP 2012
- Article first published online: 7 JUN 2012
- Manuscript received February 29, 2012; revised March 22, 2012; accepted April 4, 2012
J Clin Hypertens (Greenwich). 2012; 14:580–587. © 2012 Wiley Periodicals, Inc.
Blockade of the renin-angiotensin-aldosterone system (RAAS) is an established method to lower blood pressure in patients with hypertension. Aldosterone, the end product of the RAAS cascade, acts by increasing salt reabsorption in the kidney and catecholamine release from the adrenal medulla. Currently available aldosterone inhibitors have the disadvantage of increasing circulating aldosterone and thus may lead to aldosterone breakthrough. Aldosterone synthase inhibition (ASI) is a novel approach to suppressing the RAAS. Due to homology between the enzymes responsible for aldosterone synthesis (CYP11B2) and cortisol synthesis (CYP11B1), the blockade of aldosterone synthesis may also suppress cortisol release. The authors evaluated the effect of the novel ASI LCI699 on the cortisol response to adrenocorticotropic hormone (ACTH) stimulation in patients with hypertension in order to find the maximally tolerated dose (MTD) in this patient population. Among the 63 patients evaluated, there was a dose- and time-dependent effect of LCI699 on both aldosterone and ACTH-stimulated cortisol. Based on exposure-response analysis, the MTD was estimated to be 1.30 mg once daily with a 90% prediction interval of 0.88 mg once daily to 1.81 mg once daily. No patients required intervention for adrenal insufficiency. LCI699 was well tolerated with no serious adverse events.