Treatment of Primary Aldosteronism With mTORC1 Inhibitors

J Clin Endocrinol Metab. 2019 Oct 1;104(10):4703-4714. doi: 10.1210/jc.2019-00563.


Context: Mammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA.

Objective: To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA.

Design: (i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout.

Main outcome measures: (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters.

Results: Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients.

Conclusion: In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aldosterone / blood
  • Angiotensin II / blood
  • Animals
  • Blood Pressure / drug effects
  • Everolimus / pharmacology
  • Everolimus / therapeutic use*
  • Female
  • Hemodynamics / drug effects
  • Humans
  • Hyperaldosteronism / blood
  • Hyperaldosteronism / drug therapy*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Middle Aged
  • Pilot Projects
  • Proof of Concept Study
  • Renin / blood
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use*


  • Angiotensin II
  • Aldosterone
  • Everolimus
  • Mechanistic Target of Rapamycin Complex 1
  • Renin
  • Sirolimus