Changes Over Time in Glycemic Control, Insulin Sensitivity, and β-Cell Function in Response to Low-Dose Metformin and Thiazolidinedione Combination Therapy in Patients With Impaired Glucose Tolerance

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. RESEARCH DESIGN AND 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.