The combination was superior to monotherapy with metformin (P=0.006), Phil Zeitler, MD, PhD, from the University of Colorado in Denver, and colleagues reported online April 29 in the New England Journal of Medicine. Publication coincided with the study’s presentation at the Pediatric Academic Societies meeting in Boston.
Adding lifestyle interventions to metformin did not improve outcomes compared with metformin alone or with metformin-rosiglitazone combination therapy.
“These results suggest that a majority of youth with type 2 diabetes may require combination treatment or insulin therapy within a few years after diagnosis,” the researchers wrote.
Use of rosiglitazone (Avandia) has been on the decline in the U.S. and Europe because of concerns about cardiovascular side effects with thiazolidinedione (TZD) in adults, they noted, adding that future research should focus on finding safer alternative combination therapies.
The current study was designed in 2002, before safety concerns about TZDs. At the time, sulfonylureas were known to cause unacceptable levels of hypoglycemia in pediatric patients, and other oral drugs such as DPP-4 inhibitors and GLP-1 agonists were not yet available.
David Allen, MD, of the University of Wisconsin in Madison, called the overall findings of the trial “discouraging” in an accompanying editorial, because of the high rates of treatment failure among children in all three treatment groups.
About 52% of those on metformin monotherapy, 39% of those on combination drug therapy, and 47% of those in the metformin plus lifestyle intervention group experienced treatment failure during a mean follow up of about 4 years.
Despite rising rates of obesity and diabetes in children, few data are available to guide diabetes treatment in this age group. So Zeitler and colleagues conducted the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study in 699 patients, ages 10 to 17, who’d had diabetes for a mean of 7.8 months.
Participants were treated with metformin to reduce glycated hemoglobin A1c (HbA1c) to less than 8%, and were then randomly assigned to treatment with metformin alone (1,000 mg twice a day), metformin plus rosiglitazone (4 mg twice a day), or metformin plus a lifestyle intervention program focused on weight loss.
After an average follow-up of 3.86 years, the researchers found that 45.6% of patients did not maintain glycemic control. Only metformin plus rosiglitazone was statistically superior to metformin alone; metformin plus lifestyle intervention was not significantly different from metformin plus rosiglitazone or metformin alone.
After an average follow-up of 3.86 years, the researchers found that 45.6% of patients did not maintain glycemic control. Treatment failure was 51.7% for metformin alone, 38.6% for metformin plus rosiglitazone and 46.6% for metformin plus lifestyle intervention.
Subgroup analyses revealed that combination therapy appeared to be more effective in girls than boys (P=0.03), and metformin alone was less effective in blacks than it was in whites or Hispanics (P=0.01 and P<0.001, respectively).
Serious adverse events occurred in 19.2% of patients and a were greatest in the metformin-plus-lifestyle group at 24.8%, compared with 18.1% with metformin alone and 14.6% for metformin plus rosiglitazone (P=0.02).
In his editorial, Allen added that clinicians should not be discouraged by negative findings for lifestyle changes, as these interventions were found to decrease in baseline weight from 7% to 10%, but were not adopted by most participants.
He wrote that children today are “immersed from a young age in a sedentary, calorie-laden environment that may well have induced and now aggravates their type 2 diabetes,” and emphasized the importance of creating healthier “eat less, move more” environments. This will involve developing “sufficient economic incentives to produce and purchase healthy foods and to build safe environments that require physical movement,” Allen wrote.
The study was funded in part by the pharmaceutical industry; several researchers disclosed financial ties to pharmaceutical and/or weight-loss management companies.