Cape Town, South Africa - Results from a large international study have shown that initial treatment with rosiglitazone (Avandia, GlaxoSmithKline) slowed the progression to monotherapy failure more effectively than either metformin or glyburide [1]. Overall, the side-effect profile differed significantly among the agents, with the risk of congestive heart failure associated with rosiglitazone similar to metformin, a risk that was higher in both drugs when compared with glyburide.

"In terms of the primary outcome, it is clear that rosiglitazone prevents monotherapy failure as we defined it in this study," Dr William Herman (University of Michigan, Ann Arbor), one of the ADOPT investigators, told heartwire. "No matter how we looked at the outcome, rosiglitazone did considerably better than glyburide and moderately better than metformin, which has come to be standard of care. The side-effect profiles of the drugs are very different, though, and both treatment alternatives to rosiglitazone are generic, so there is a big cost difference. I think, based on this study, rosiglitazone would be preferred to glyburide as initial therapy, but it's more of a judgment call when it comes to metformin."

The results of study, known as A Diabetes Outcome Progression Trial (ADOPT), were presented today at the World Diabetes Congress in Cape Town, South Africa and published online in the New England Journal of Medicine. In their paper, investigators, led by Dr Steven Kahn (University of Washington, Seattle), conclude that "the relative costs of these medications, their profiles of adverse events, and their potential risks and benefits should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes."

In an editorial published online with the ADOPT paper, Dr David Nathan (Harvard Medical School, Boston, MA) argues that the data are simply not sufficient to consider the use of rosiglitazone as initial monotherapy in the treatment of type 2 diabetes [2]. "Given the modest glycemic benefit of rosiglitazone (with the risk of fluid retention and weight gain) and higher cost (including the need for more statins and diuretics), metformin remains the logical choice when initiating pharmacotherapy for type 2 diabetes," writes Nathan.

Speaking with heartwire, Herman said that data from the United Kingdom Prospective Diabetes Study (UKPDS) group showed that type 2 diabetes was progressive, despite lifestyle intervention and the use of sulfonylureas and metformin. While there was an initial improvement in glucose levels, glucose control deteriorated over time in the UKPDS. Early data showed that thiazolidinediones (TZDs) could stabilize glycemic control over time, said Herman, leading the ADOPT investigators to study the efficacy of rosiglitazone, a TZD, as compared with other oral glucose-lowering agents in maintaining long-term glucose levels.

ADOPT was a multicenter, randomized, double-blind clinical trial involving 4360 patients who had not received pharmacologic treatment for recently diagnosed type 2 diabetes. Patients, who were predominantly white, middle-aged, and obese, were treated with rosiglitazone 4 mg, metformin 500 mg, or glyburide 2.5 mg. For each drug, the dose was increased to the maximum daily effective dose—rosiglitazone 4 mg twice daily, metformin 1 g twice daily, and glyburide 7.5 mg twice daily—if fasting plasma glucose levels remained elevated. The primary end point of the study was the time from randomization to treatment failure, which was defined as confirmed hyperglycemia (fasting plasma glucose levels >180 mg/dL). Patients were treated for a median of four years.

Overall, monotherapy failed in 143 patients treated with rosiglitazone, 207 patients treated with metformin, and 311 patients who received glyburide. The cumulative incidence of treatment failure at five years was 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This translated into a 32% reduction in risk with rosiglitazone compared with metformin and a 63% reduction in risk with rosiglitazone compared with glyburide. When investigators used a more stringent measure of monotherapy failure, fasting plasma glucose levels >140 mg/dL, the results were similar.

Herman told heartwire that glycated hemoglobin levels were not selected as the primary outcome because the guidelines at the initiation of the study, which began enrollment in 2000, focused largely on plasma glucose levels. He noted that at four years, 40% of patients treated with rosiglitazone had a hemoglobin A1_c level <7%, significantly more than the 36% of patients treated with metformin and 26% of patients treated with glyburide. The mean glycated hemoglobin levels <7% were maintained until 60, 45, and 33 months in patients treated with rosiglitazone, metformin, and glyburide, respectively.

In his editorial, Nathan notes that the choice of time to failure based on confirmed fasting plasma glucose levels "seems anachronistic," adding that despite the reduction in the time to failure, the glycated hemoglobin results are less impressive. Although the differences are statistically significant, "the relatively small difference in glycated hemoglobin levels achieved over four years in the rosiglitazone group as compared with the metformin group is of questionable clinical significance," writes Nathan.

Moreover, the overall findings must be tempered by the fact that just 60% of patients completed the trial, which required an expansion of the number of patients and duration of follow-up, thereby weakening the results, he writes.

Regarding side effects, rosiglitazone was associated with weight gain (average increase 4.8 kg) and increased LDL-cholesterol levels, as well as more frequent use of statins, more frequent edema, and a reduction in hematocrit. Metformin, on the other hand, was associated with more frequent gastrointestinal effects, and glyburide with weight gain and hypoglycemia. Herman said the patients are considered low risk and that the proportion of patients with cardiovascular events was similar in the rosiglitazone and metformin arms but lower in the glyburide arm. The rate of congestive heart failure in rosiglitazone- and metformin-treated patients was similar, but higher than that associated with glyburide.

While Nathan contends that metformin remains the logical choice for type 2 diabetes, Herman, when asked about the clinical implications, said whether or not doctors should start with rosiglitazone remains at their discretion. Some patients, as many as 15% to 20% of the population, can't take metformin because of its gastrointestinal side effects, and patients with contraindications, including those with decreased renal function, would be candidates for initial rosiglitazone monotherapy, said Herman.

"In terms of the efficacy question, I think this study really answers it," he added. "I think we still have to weigh the risks and the costs, in terms of defining treatment, but I think it does, for the first time, provide some encouragement that the natural history of type 2 diabetes can perhaps be altered."