title: Changes over time in glycemic control, insulin sensitivity, and beta-cell function in response to low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance.
abstract: OBJECTIVE
  In the Canadian Normoglycemia Outcome Evaluation (CANOE) trial, low-dose rosiglitazone/metformin reduced the risk of diabetes in subjects with impaired glucose tolerance by 66% over a median of 3.9 years. We evaluate the temporal changes in glycemic control, insulin sensitivity, and β-cell function during this trial.
  
  
  METHODS
  CANOE participants (n=207) underwent annual oral glucose tolerance testing, enabling temporal comparison of glycemia, insulin sensitivity (Matsuda index), and β-cell function (insulin secretion-sensitivity index-2 [ISSI-2]) between the rosiglitazone/metformin and placebo arms.
  
  
  RESULTS
  Glycemic parameters and insulin sensitivity improved in the rosiglitazone/metformin arm in year 1, but deteriorated in the years thereafter as in the placebo arm. Generalized estimating equation analysis confirmed that both insulin sensitivity and β-cell function decreased over time (Matsuda: β=-0.0515, P<0.0001; ISSI-2: β=-6.6507, P<0.0001), with no significant time-by-treatment interaction (Matsuda: P=0.57; ISSI-2: P=0.22).
  
  
  CONCLUSIONS
  Despite preventing incident diabetes, low-dose rosiglitazone/metformin did not modify the natural history of worsening insulin resistance and β-cell dysfunction.
authors.affiliation: Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, and Department of Nutritional Sciences, University of Toronto, Toronto, Canada. rretnakaran@mtsinai.on.ca
authors.forename: Ravi
authors.initials: R
authors.lastname: Retnakaran
authors.forename: Ying
authors.initials: Y
authors.lastname: Qi
authors.forename: Stewart B
authors.initials: SB
authors.lastname: Harris
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hanley
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D004338:Drug Combinations; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000627:therapeutic use; D008875:Middle Aged; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008687:Metformin