Title: Low-Dose Combination Therapy With Rosiglitazone and Metformin to Prevent Type 2 Diabetes Mellitus (CANOE trial): A Double-Blind Randomized Controlled Study
Date Posted: July 8, 2010
Authors: Zinman B, Harris SB, Neuman J, et al.
Citation: Lancet 2010;Jun 2:[Epub ahead of print].
Study Question:
What is the effect of low-dose combination therapy with rosiglitazone and metformin on development of type 2 diabetes?
Methods:
In this double-blind, randomized, controlled trial undertaken in clinics in Canadian centers, 207 patients with impaired glucose tolerance were randomly assigned to receive combination rosiglitazone (2 mg) and metformin (500 mg) twice daily or matching placebo for a median of 3.9 years (interquartile range [IQR], 3.0-4.6). Randomization was computer-generated in blocks of four, with both participants and investigators masked to treatment allocation. The primary outcome was time to development of diabetes, measured by an oral glucose tolerance test or two fasting plasma glucose values of 7.0 mmol/L or greater.
Results:
A total of 103 participants were assigned to rosiglitazone and metformin, and 104 to placebo; all were analyzed. Vital status was obtained in 198 (96%) participants, and medication compliance (taking at least 80% of assigned medication) was 78% (n = 77) in the metformin and rosiglitazone group, and 81% (n = 80) in the placebo group. Incident diabetes occurred in significantly fewer individuals in the active treatment group (n = 14 [14%]) than in the placebo group (n = 41 [39%]; p < 0.0001). The relative risk reduction was 66% (95% confidence interval, 41-80) and the absolute risk reduction was 26% (14-37), yielding a number needed to treat of 4 (2.70-7.14). Seventy (80%) patients in the treatment group regressed to normal glucose tolerance compared with 52 (53%) in the placebo group (p = 0.0002). Insulin sensitivity decreased by study end in the placebo group (median −1.24; IQR −2.38 to −0.08) and remained unchanged with rosiglitazone and metformin treatment (−0.39; −1.30 to 0.84; p = 0.0006 between groups). The change in β-cell function, as measured by the insulin secretion-sensitivity index-2, did not differ between groups (placebo −252.3, −382.2 to −58.0 vs. rosiglitazone and metformin −221.8, −330.4 to −87.8; p = 0.28). The investigators recorded an increase in diarrhea in participants in the active treatment group compared with the placebo group (16 [16%] vs. 6 [6%]; p = 0.0253).
Conclusions:
The authors concluded that low-dose combination therapy with rosiglitazone and metformin was highly effective in prevention of type 2 diabetes in patients with impaired glucose tolerance.
Perspective:
This study suggests that the combination of rosiglitazone with metformin at half the maximum dose was very effective in prevention of diabetes and in normalization of glucose tolerance in individuals with impaired glucose tolerance, with little evidence of adverse events of these two drugs. These results lend support to the use of low-dose combination therapies as an effective means to manage complex metabolic disorders. A comprehensive approach to the global epidemic of type 2 diabetes should include lifestyle intervention, focusing on obesity and physical activity, with the option of pharmacological intervention for the primary prevention of diabetes as needed.
Author(s):
Debabrata Mukherjee, M.D., F.A.C.C.
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