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.

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.