title: Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome.
abstract: BACKGROUND
  Cushing's syndrome (CS) is a disorder associated with significant morbidity and mortality due to prolonged exposure to high cortisol concentrations.
  
  
  OBJECTIVE
  Our objective was to evaluate the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, in endogenous CS.
  
  
  METHODS
  We conducted a 24-wk multicenter, open-label trial after failed multimodality therapy at 14 U.S. academic medical centers and three private research centers.
  
  
  METHODS
  Participants included 50 adults with endogenous CS associated with type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT).
  
  
  METHODS
  Mifepristone was administered at doses of 300-1200 mg daily.
  
  
  METHODS
  We evaluated change in area under the curve for glucose on 2-h oral glucose test for C-DM and change in diastolic blood pressure from baseline to wk 24 for C-HT.
  
  
  RESULTS
  In the C-DM cohort, an area under the curve for glucose (AUC(glucose)) response was seen in 60% of patients (P < 0.0001). Mean ± sd glycated hemoglobin (HbA1c) decreased from 7.43 ± 1.52% to 6.29 ± 0.99% (P < 0.001); fasting plasma glucose decreased from 149.0 ± 75.7 mg/dl (8.3 ± 4.1 mmol/liter) to 104.7 ± 37.5 mg/dl (5.8 ± 2.1 mmol/liter, P < 0.03). In C-HT cohort, a diastolic blood pressure response was seen in 38% of patients (P < 0.05). Mean weight change was -5.7 ± 7.4% (P < 0.001) with waist circumference decrease of -6.78 ± 5.8 cm (P < 0.001) in women and -8.44 ± 5.9 cm (P < 0.001) in men. Overall, 87% (P < 0.0001) had significant improvement in clinical status. Insulin resistance, depression, cognition, and quality of life also improved. Common adverse events were fatigue, nausea, headache, low potassium, arthralgia, vomiting, edema, and endometrial thickening in women.
  
  
  CONCLUSIONS
  Mifepristone produced significant clinical and metabolic improvement in patients with CS with an acceptable risk-benefit profile during 6 months of treatment.
authors.affiliation: Northwest Pituitary Center, Department of Medicine, Oregon Health and Science University, Portland, Oregon 97239, USA. fleseriu@ohsu.edu
authors.forename: Maria
authors.initials: M
authors.lastname: Fleseriu
authors.forename: Beverly M K
authors.initials: BM
authors.lastname: Biller
authors.forename: James W
authors.initials: JW
authors.lastname: Findling
authors.forename: Mark E
authors.initials: ME
authors.lastname: Molitch
authors.forename: David E
authors.initials: DE
authors.lastname: Schteingart
authors.forename: Coleman
authors.initials: C
authors.lastname: Gross
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001823:Body Composition / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003480:Cushing Syndrome / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D018149:Glucose Intolerance / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D006727:Hormone Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000008:administration & dosage* / Q000009:adverse effects; D011788:Quality of Life; D011804:Quinolines / Q000097:blood; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D000959:Antihypertensive Agents; D001786:Blood Glucose; D006727:Hormone Antagonists; D011804:Quinolines; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D014508:Urea; C493249:1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea; D006854:Hydrocortisone