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Metformin + low-dose rosiglitazone better than placebo in delaying onset of DM in pts with IGT (CANOE)

Clinical Question:
Is the combination of rosiglitazone plus metformin, each at low dose, effective at delaying the onset of diabetes in adults with impaired glucose tolerance?

Bottom Line:
In this small study, adults with impaired glucose tolerance (IGT) treated with metformin (Glucophage) plus low-dose rosiglitazone (Avandia) were less likely to be diagnosed with type 2 diabetes after nearly 4 years. Other studies of chemoprophylaxis have found that diet and exercise was superior at delaying the development of frank diabetes than medications (metformin, rosiglitazone, acarbose, and so forth) or placebo. To date, no study (including this one) has shown that delaying the development of diabetes improves clinical outcomes. Since the long-term safety of rosiglitazone has been called into question, this regimen should not be used. (LOE = 1b)

Reference:
Zinman B, Harris SB, Neuman J, et al. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 2010;376(9735):103-111.  [PMID:20605202]

Study Design:
Randomized controlled trial (double-blinded)

Funding:
Industry

Allocation:
Concealed

Setting:
Outpatient (specialty)

Synopsis:
In this industry-sponsored study, adults with at least one risk factor for developing type 2 diabetes (body mass index between 25 and 45, a family history of type 2 diabetes, self-reported hypertension, prior gestational diabetes, or delivery of a macrosomic infant) and IGT were randomized to receive active treatment (n = 103) or placebo (n = 104). The authors defined IGT as a normal fasting plasma level but a plasma glucose level between 7.8 mmol/L and 11.1 mmol/L (140 - 200 mg/dL) after a 75-g oral glucose load. The active treatment consisted of 500 mg metformin plus 2 mg rosiglitazone administered twice daily. All patients in the study also received lifestyle training. The authors assessed the primary outcome -- development of type 2 diabetes -- by intention to treat. Although the authors assessed numerous biochemical markers, they did not design the study to assess any clinically relevant outcomes. The researchers gathered data on various events (such as myocardial infarction, fracture, and so forth), but they did not have enough patients in the study to be able to tell if any differences in these events were due to chance. After a median of 3.9 years of follow-up, the authors had final data on 96% of the study participants. By the end of the study, 39% of the patients taking placebo developed diabetes compared with 14% of those taking active treatment. One would need to treat 4 patients (95% CI, 3 - 8) for 4 years to delay the onset of diabetes in one patient with IGT. Gastrointestinal side effects, especially diarrhea (16% vs. 6%; number needed to treat to harm = 10), were more common in the treated patients than in those taking placebo.

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