Major Finding: A combination of 2 mg of rosiglitazone and 500 mg of metformin twice daily reduced the relative risk of developing type 2 diabetes in high-risk adults by 66%.
Data Source: A randomized, double-blind, placebo-controlled trial of 207 adults at increased risk for type 2 diabetes.
Disclosures: The study was funded by GlaxoSmithKline, from which Dr. Zinman has received consulting fees, honoraria, and grant support. Dr. Buchanan and Dr. Xiang have received research support from Takeda Pharmaceuticals, and Dr. Buchanan has served on a speakers panel and received travel and accommodation expenses from Takeda.
A combination of low doses of rosiglitazone and metformin reduced the relative risk of developing type 2 diabetes by 66% in high-risk adults, according to a study by Canadian researchers.
Both rosiglitazone and metformin can reduce the risk of developing type 2 diabetes in adults with impaired glucose tolerance, but this study is the first to combine the two drugs to test for similar effectiveness with fewer side effects, said Dr. Bernard Zinman of Mount Sinai Hospital in Toronto, and his colleagues.
In this study, 103 participants were randomized to a combination of 2 mg of rosiglitazone and 500 mg of metformin in a single capsule (Avandamet, GlaxoSmithKline) twice daily, while 104 participants received a placebo capsule. The study, known as the Canadian Normoglycemia Outcomes Evaluation (CANOE) trial, also included a structured lifestyle intervention of five individual counseling sessions during the first year of the study, followed by educational materials that were mailed or e-mailed to participants (Lancet 2010 June 3 [doi: 10.1016/S0140-6736(10)60746-5]).
The primary outcome was a diagnosis of type 2 diabetes, based on two fasting plasma glucose values of 7.0 mmol/L or more, or one positive oral glucose tolerance test with a 2-hour plasma glucose value greater than 11.0 mmol/L.
After an average follow-up period of 3.9 years, 14 patients (14%) in the treatment group and 41 (39%) patients in the placebo group developed type 2 diabetes, for a relative risk reduction of 66%. The absolute risk reduction was 26%, and the number needed to treat was 4.
In addition, significantly more individuals in the treatment group compared with the placebo group had attained normal glucose tolerance levels by the end of the study (80% vs. 53%, respectively). “The magnitude of this effect is equivalent to that of any of the published diabetes prevention strategies,” the researchers said.
The average age of the patients was 55 years in the placebo group and 50 years in the treatment group. The breakdown of gender and ethnicity, and the values of baseline risk factors including total cholesterol, blood pressure, body mass index, and insulin resistance were similar between the two groups.
The treatment group showed no significant increase in myocardial infarction, heart failure fractures, and weight gain or loss of 2 kg or more compared with the placebo group, and the researchers found no significant interaction between statin use and treatment outcome.
No significant differences in beta-cell function were noted, but decreased C-reactive protein levels and reduced alanine aminotransferase levels in the treatment group compared with baseline suggest reduced inflammation and improved liver function, the researchers noted.
Limitations of the study included the fact that it was not powered to address the long-term effects of combination therapy on cardiovascular safety, the researchers noted. The study also was limited by the inability to show whether the effects of the combination drug indicate the prevention or early treatment of type 2 diabetes.
The CANOE study data suggest that combining low doses of rosiglitazone and metformin can reduce the risk of type 2 diabetes with fewer side effects, but the conclusions are not definitive, wrote Dr. Thomas A. Buchanan of the University of Southern California, Los Angeles, and Dr. Anny H. Xiang of Kaiser Permanente Southern California in Pasadena.
“The issue of whether prevention provides better long-term outcomes than does early treatment remains unknown,” they said in a comment (Lancet 2010 June 3 [doi: 10.1016/S0140-6736(10)60900-2]).