We report the first administration of an orally active
aldosterone synthase inhibitor,
LCI699, to 14 patients with primary
aldosteronism. After a 2-week placebo run-in, patients received oral
LCI699 (0.5 mg BID) for 2 weeks,
LCI699 (1.0 mg BID) for 2 weeks, and placebo for 1 week. We assessed changes in
hormone concentrations, plasma
potassium levels, and 24-hour ambulatory systolic blood pressure and safety. The supine plasma
aldosterone concentration decreased from 540 pmol/L (95% CI: 394 to 739 pmol/L) to 171 pmol/L (95% CI: 128 to 230 pmol/L) after 0.5 mg of
LCI699 (-68%; P<0.0001) and to 133 pmol/L (95% CI: 100 to 177 pmol/L) after 1.0 mg of
LCI699 (-75%; P<0.0001). Plasma 11-deoxycorticosterone concentrations increased by 710% after 0.5 mg of
LCI699 (P<0.0001) and by 1427% after 1.0 mg of
LCI699 (P<0.0001). The plasma
potassium concentration increased from 3.27±0.31 to 4.03±0.33 mmol/L (P<0.0001) after only 1 week on 0.5 mg of
LCI699. Twenty-four-hour ambulatory systolic blood pressure decreased by -4.1 mm Hg (95% CI: -8.1 to -0.1 mm Hg) after 4 weeks of treatment (P=0.046). Basal plasma
cortisol concentrations remained unchanged, whereas plasma
adrenocorticotropic hormone concentrations increased by 35% after 0.5 mg of
LCI699 (P=0.08) and by 113% after 1.0 mg of
LCI699 (P<0.0001), and the plasma
cortisol response to an
adrenocorticotropic hormone test was blunted. All of the variables except plasma 11-deoxycorticosterone concentration returned to initial levels after the placebo.
LCI699 was well tolerated. In conclusion, the administration of
LCI699, up to 1.0 mg BID, effectively and safely inhibits
aldosterone synthase in patients with primary
aldosteronism. This 4-week treatment corrected the
hypokalemia and mildly decreased blood pressure. The effects on the
glucocorticoid axis were consistent with a latent inhibition of
cortisol synthesis.