Low-Dose Combination Therapy With Rosiglitazone And Metformin to Prevent Type 2 Diabetes Mellitus (CANOE Trial): A Double-Blind Randomized Controlled Study EDITORIAL COMMENT

Several drug regimens have demonstrated effectiveness in reducing the development of type 2 diabetes mellitus in patients with impaired glucose tolerance (IGT). Their adoption has been slow because of concern with adverse effects and long-term safety. Monotherapy with the thiazolidinedione rosiglitazone effectively reduces the risk of type 2 diabetes, but recommended maximum doses are associated with an increased risk of adverse outcomes, including, weight gain and increased risk of congestive heart failure. Metformin, a commonly used oral hypoglycaemic, is also effective therapy for type 2 diabetes; its use has been associated with substantial gastrointestinal side effects, even at submaximum doses. The Canadian Normoglycemia Outcomes Evaluation trial was a double-blind, randomized controlled study that investigated whether combination therapy with half the maximum dose of rosiglitazone and metformin would prevent type 2 diabetes in patients with IGT. A total of 207 patients with IGT were randomly assigned to receive twice daily a combination of rosiglitazone 2 mg and metformin 500 mg (n = 103) or a matching placebo (n = 104) for a median of 3.9 years. All patients and investigators were masked as to treatment allocation. The primary study outcome was the development of new onset type 2 diabetes diagnosed either by 2 fasting plasma glucose values of >= 7.0 mmol/L or an oral glucose tolerance test. Complete vital status was available for 96% (198/207) of the participants. Compliance was similar in the 2 groups: 78% of the treatment group and 81% in the placebo group (P = 0.60). Significantly fewer patients in the treatment group (n = 14 [14%]) than in the placebo group (n = 41 [39%]) developed incident diabetes (P < 0.0001). The relative risk reduction was 66%, with a 95% confidence interval (CI) of 41 to 80. Based on the absolute relative risk of 26% (95% CI, 14-37), the number needed to treat was calculated to be 4 (95% CI, 2.70-7.14). By the end of the study, a significantly greater proportion of patients in the treatment group than in the placebo had regressed to normal glucose tolerance (treatment group: 79.6% vs. placebo: 53.1%, P = 0.0002). Moreover, by the study end, insulin sensitivity had decreased by a greater extent in the placebo group (median, -1.24; interquartile range [IQR], -2.38 to -0.08) compared to the treatment group which had remained unchanged (median, -0.39; IQR, -1.30 to 0.84; P = 0.0006 between groups). There was no significant change in beta-cell function (measured by the insulin secretion-sensitivity index-2) between groups (placebo: median, -252.3; IQR, -382.2 to -58.0 vs. treatment group: median, -221.8; IQR, -330.4 to -87.8; P = 0.28 between groups). More diarrhea was noted among patients in the treatment group than those in the placebo (16% vs. 6%, P = 0.025). These findings demonstrate that combining half the maximum dose of rosiglitazone with metformin is effective in preventing type 2 diabetes in patients with IGT and appears to be safe, with few clinically relevant adverse events.