Lancet: Avandia/Glucophage combo may be beneficial for diabetes prevention
Administering a low-dose combination of the thiazolidinedione rosiglitazone (Avandia; GlaxoSmithKline) and metformin (Glucophage, Bristol-Myers Squibb) to patients with impaired glucose tolerance (IGT) improved glucose levels and was effective in preventing type 2 diabetes, but had little effect on the adverse events of the two drugs, according to a study published online June 3 in the Lancet.

“Interest has grown in use of combination therapies early in the management of diabetes to effectively target the underlying abnormalities that cause this common metabolic disorder,” the authors wrote. “At the same time, the implementation of low-dose combination therapy in patients with type 2 diabetes could reduce the undesirable adverse effects associated with many oral anti-diabetic agents.”

To study the effect of a combination therapy, Bernard Zinman, MD, of the Mount Sinai Hospital and University of Toronto in Canada, conducted the CANOE (Canadian Normoglycemia Outcomes Evaluation) trial on 207 patients with poor glucose tolerance between April 28, 2004, and Oct. 30, 2006, to assess whether half of the maximum dose of the combination therapy—rosiglitazone and metformin—could prevent type 2 diabetes.

During the study, which was funded by GlaxoSmithKline, 103 patients received 2 mg of rosiglitazone and 500 mg of metformin twice a day while 104 patients were administered placebo.

While metformin is often the standard first-line therapy for type 2 diabetes, it has been known to produce adverse effects such as gastrointestinal side-effects. Additionally, use of rosiglitazone has been scorned by members of the Senate as it has been shown to increase cardiovascular-related events.

Because both drugs “have been shown to reduce the development of diabetes in patients with IGT,” the authors wrote, establishing "whether this combination at half the maximum dose would provide a robust effect on diabetes prevention, while minimizing undesirable side-effects, would be of interest.”

Additionally, patients underwent lifestyle intervention consisting of five one-on-one sessions lasting 30 minutes. The researchers looked at the onset of type 2 diabetes as the primary outcome and changes in blood pressure, microalbuminuria, C-reactive proteins and lipid profiles as secondary outcomes.

After a mean follow-up of 3.9 years, researchers found that a higher number of incidence of diabetes occurred in the placebo group compared to the treatment group, 41.8 percent versus 15.9 percent, respectively.

At final visit, 78 percent of patients in the treatment group were taking at least 80 percent of medications compared to 81 percent in the placebo group. According to the researchers, most patients who discontinued the treatment did so due to side effects of rosiglitazone.

Results showed that more patients in the treatment group established normal glucose tolerance compared to those in the placebo group, 79.6 percent versus 53.1 percent, respectively.

The researchers said that no cases of MI or heart failure were reported in the treatment group—one case was reported in the placebo group. Tolerance to glucose was similar in both groups, 5.1 percent versus 4.6 percent in the placebo and treatment groups, respectively.

While the authors said that lifestyle interventions can be useful and effective for preventing and treating diabetes, these standards and programs are not widespread.

To get a handle on the diabetes epidemic, the researchers suggested that lifestyle interventions, more effective management of blood pressures, glycemic levels and lipid abnormalities and the management of diabetics with end-organ complications via laser and other therapies be carried out.

“Although primary prevention is a particularly attractive option, little progress has been made in implementation of an effective diabetes prevention program,” the authors wrote. “Traditional efforts at lifestyle interventions at a healthcare professional level have been disappointing,” they said and suggested that community-based or societal-based programs may be needed to educate the public.

While the authors said that pharmacology treatments have been proven to improve the conditions, adverse effects and safety concerns could be main reason why these strategies have not been widely adopted.

While the researchers concluded that the combination treatment could be effective and have fewer adverse effects, they said that “CANOE cannot provide additional definitive data for the controversy relating to the specific cardiovascular safety of rosiglitazone.”

Zinman et al said that future long-term studies that look at the CV risks and benefits and overall safety of the combination treatments should be conducted.

In an accompanying editorial, Thomas A. Buchanan, MD, and Anny H. Xiang, PhD, from the University of Southern California, Los Angeles, wrote: “The larger issues that have cast doubt on use of drugs to prevent diabetes are not addressed by the CANOE trial.”

Buchanan and Xiang wrote that proof that prevention provides better long-term outcomes is lacking. “We need data on more intensive approaches, including high-dose combination therapy, to provide clinicians with a full range of evidence-based approaches to halt or reverse this progressive disease relatively early in its course,” they concluded.