Metformin and rosiglitazone together are best at controlling blood sugar in children and adolescents with type 2 diabetes, researchers found.

The combination was superior to monotherapy with metformin (P=0.006), even though the use of rosiglitazone (Avandia) has fallen off in the U.S. and Europe because of concerns about cardiovascular side effects with thiazolidinedione (TZD) in adults, reported Kathryn Hirst, PhD, of George Washington University in Washington. and colleagues in the New England Journal of Medicine.

“Monotherapy with metformin is not adequate in many kids, and combination therapy appears to bring benefits,” co-author Phil Zeitler, MD, of the University of Colorado in Denver, told MedPage Today in an email. “The challenge now is to determine what that combination therapy should look like given that thiazolidinediones are not a good option.”

Adding a lifestyle intervention to metformin didn’t offer any additional benefits beyond metformin alone, the researchers also found, nor did its effects differ significantly from those of metformin and rosiglitazone combination therapy. In an accompanying editorial, David Allen, MD, of the University of Wisconsin in Madison, called the overall findings of the trial “discouraging” because of the high rates of treatment failure across all three groups. Indeed, 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 had treatment failure during a mean follow up of about 4 years. “These data imply that most youth with type 2 diabetes will require multiple oral agents or insulin therapy within a few years of diagnosis,” Allen wrote. The rise in type 2 diabetes among American youth has increased with the incidence of childhood obesity. Yet there are few data to guide treatment of the condition in young people, the researchers said. They 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. Patients were randomized to metformin alone (1,000 mg twice a day), metformin plus rosiglitazone (4 mg twice a day), or to metformin plus a lifestyle intervention focused on weight loss. Zeitler said the study was designed in 2002, before concerns about the TZD class had arisen, and rosiglitazone “was a logical choice” at the time, particularly because sulfonylureas had been found to cause unacceptable levels of hypoglycemia in young patients. In addition, few of the other oral drugs commonly used today, including DPP-4 inhibitors and GLP-1 agonists, were available. He added that the study was wrapping up as the FDA put restrictions on the drug, but the agency gave his group the go-ahead to finish the trial based on a lack of evidence of safety concerns. The study-specific lifestyle program involved several components based on the best available evidence, and was delivered by trained personnel. The primary endpoint was achieving and maintaining an HbA1c level of less than 8%. Hirst and colleagues found that 45.6% of the entire study population achieved those levels during a mean follow up of 3.86 years. Treatment failure rates during that time were as follows:   51.7% for those on metformin alone   38.6% in the metformin and rosiglitazone combination therapy group   46.6% for those in the metformin plus lifestyle intervention group Why the failure rates in children are higher than those seen in adult trials should be the subject of further research, they added. Hirst and colleagues did find that metformin plus rosiglitazone was superior to metformin alone (P=0.006) in terms of lowering HbA1c, and that the lifestyle-plus-metformin group provided an “intermediate” benefit but didn’t differ significantly from either of the other two treatments. The effects didn’t appear to be because of differences in adherence and couldn’t be explained by baseline characteristics, body mass index (BMI), or differences in insulin secretion, insulin sensitivity, or body composition, they said. BMI did differ significantly according to treatment group over time (P<0.001), with metformin plus lifestyle offering the best weight loss and metformin plus rosiglitazone prompting the greatest weight gain, but again, this did not affect treatment outcomes, they said. In subgroup analyses, 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). Overall, serious adverse events occurred in 19.2% of patients, and were greatest in the metformin-plus-lifestyle group: 24.8% versus 18.1% with metformin alone and 14.6% for metformin plus rosiglitazone (P=0.02). The majority of adverse events (87%) were not considered to be related to the study treatment, but hospitalizations accounted for more than 90% of serious adverse events, including severe hypoglycemia, nonfatal transient lactic acidosis, and asthma exacerbation. The authors noted that rosiglitazone had no effects on bone mineral content or fracture rates, but that this result should be interpreted with caution given the small sample size. It's not clear if the benefits of combination therapy were due to the rosiglitazone, more general effects of the thiazolidinedione class, or some other feature of combination therapy, the researchers said. Allen said the results do not "put the nail in the coffin" of lifestyle modification for young type 2 diabetes patients. Changes in eating and activity didn't reduce patients' weight as much as they should have in the trial, "so the feasibility of lifestyle change was evaluated more than its effect," he wrote. Youths need to be taken out of a "sedentary, calorie-laden environment" to control their diabetes, he added.