title: Modeling and simulations to confirm a controlled hypoglycemic stress test in healthy subjects is not associated with clinically significant QT prolongations.
abstract: OBJECTIVE
  A modified insulin tolerance test (ITT) can be used to simulate a physiological stress state through the induction of controlled hypoglycemia in healthy volunteers. This allows for evaluation of hypothalamic-pituitary-adrenocortical axis response to stress via a surge in cortical release. However, a consequence of severe, prolonged hypoglycemia is QT interval prolongation. The aim of this analysis was to confirm that blood glucose lowering to 60 mg/dL (previously identified as adequate for inducing stress) has low risk of inducing clinically significant QT prolongation.
  
  
  METHODS
  Continuous ECG monitoring was conducted as a planned sub study of an open-label, 2-period study involving 18 healthy male subjects. The QTcF response to hypoglycemia was measured over 2 identical periods, ~ 7 days apart.
  
  
  RESULTS
  An indirect- response model adequately described the pharmacological relationship between blood glucose and QTcF intervals over the time-course of the ITT. The model correctly identified the steep glucose-QT relationship as an on-off response with a large Hill coefficient of 59 and the threshold glucose, EC50, as ~ 57 mg/dL with narrow between-subject variability of 10%. Simulated QTcF profiles over the course of an ITT did not demonstrate any QTcF interval changes of clinical concern, defined as QTcF observation > 500 ms, if hypoglycemia did not reach below 60 mg/dL. The statistical prediction that the chance of a mean QTcF observation > 500 ms was < 0.0001.
  
  
  CONCLUSIONS
  Results support that an ITT maintained at or above 60 mg/dL is unlikely to cause QT prolongation in healthy volunteers and does not warrant continuous ECG monitoring in this group of subjects.
authors.forename: Lai San
authors.initials: LS
authors.lastname: Tham
authors.forename: Crystal Mei
authors.initials: CM
authors.lastname: Fen Zhao
authors.forename: Fanni
authors.initials: F
authors.lastname: Natanegara
authors.forename: Stephen
authors.initials: S
authors.lastname: Lowe
authors.forename: Christopher
authors.initials: C
authors.lastname: Chen
authors.forename: Chay Ngee
authors.initials: CN
authors.lastname: Lim
authors.forename: Helle
authors.initials: H
authors.lastname: Linnebjerg
authors.forename: Brian A
authors.initials: BA
authors.lastname: Willis
authors.forename: Malcolm I
authors.initials: MI
authors.lastname: Mitchell
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wise
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D003198:Computer Simulation; D003940:Diagnostic Techniques, Endocrine; D004562:Electrocardiography; D064368:Healthy Volunteers; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008954:Models, Biological; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin