HORMONAL EFFECTS OF THE NEW DIRECT ALDOSTERONE SYNTHASE INHIBITOR, LCI699, IN PATIENTS WITH PRIMARY ALDOSTERONISM: 5C.06

Abstract

Objective: Aldosterone synthase inhibition with LCI699 is a new therapeutic option aimed at decreasing hormone concentrations in both plasma and tissues. We report the hormonal effects of LCI699 to patients with primary aldosteronism (PA). Design and Methods: After a two-week placebo run-in, patients with PA received oral LCI699 (0.5 mg bid) for two weeks, LCI699 (1 mg bid) for two weeks, and placebo for one week. We assessed changes in plasma and urinary aldosterone (PAC/UAldo), renin (PRC), cortisol and ACTH concentrations associated with correction of hypokalemia and decrease in BP. From the screening visit onwards, all patients received oral KCl (3–6 g/day) and 10/14 patients received a calcium channel blocker alone or in combination with prazosin to ensure that home BP remained ≤170/105 mmHg. Results: 14 patients (13 men, age: 50.3 ± 6.7yrs) with hypertension (office SBP/DBP: 151 ± 17/91 ± 12mmHg) and low plasma K (3.0mmol/L [min:2.5-max:3.5]) were included in the study. They had high plasma aldosterone (630pmol/L [359–997]), low plasma renin (4.5mU/L [1.0–9.5]) concentrations, and high aldosterone/renin ratio (123pmol/pg [84–553]). Baseline PAC decreased from 540pmol/L (95%CI:394;739) to 171pmol/L (95%CI:128;230) after 0.5 mg LCI699 (−68% [95%CI:−77;−55], P < 0.001 vs. baseline) and to 133pmol/L (95%CI:100;177) after 1 mg LCI699 (−75%, [95%CI:−84;−63]; P < 0.001 vs. baseline). UAldo was 82nmol/24 h (95%CI:61;109) at baseline and decreased by −78% ([95%CI:−82;−73]; P < 0.0001) after 0.5 mg LCI699 and by −88% ([95%CI:−92;−84]; P=0.0003) after 1 mg LCI699. PRC increased mildly from baseline by 26% to 39%; (P = 0.0007). Basal plasma cortisol remained unchanged, whereas plasma ACTH concentration increased by 35% after 0.5 mg LCI699 (P = 0.08) and by 113% after 1 mg LCI699 (P < 0.001). The PAC and the plasma cortisol response to an ACTH test (250 μg IV) after 1 mg LCI699 was blunted. All variables returned to initial levels after the placebo. LCI699 administration was well tolerated. Conclusion: The administration of LCI699, up to 1 mg bid, effectively and safely inhibits aldosterone synthase in patients with PA. The effects on the glucocorticoid axis were consistent with a latent inhibition of cortisol synthesis.