Changes Over Time in Glycemic Control, Insulin Sensitivity, and b-Cell Function in Response to Low-DoseMetformin and Thiazolidinedione Combination Therapy in PatientsWith Impaired Glucose Tolerance

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 b-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 sensi-tivity (Matsuda index), and b-cell function (insulin secretion-sensitivity index-2 [ISSI-2]) be-tween 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 b-cell function decreased over time (Matsuda: b = 20.0515, P, 0.0001; ISSI-2: b = 26.6507, 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 b-cell dysfunction. Diabetes Care 34:1601–1604, 201