Diabetes in Kids: Combo Treatment Tops

PHOTO: Bottles of Avandia diabetes medication are seen at Jacks Pharmacy May 21, 2007 in San Anselmo, California.PlayJustin Sullivan/Getty Images
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A combination of the diabetes staple drug metformin plus Avandia is best at controlling blood sugar in children and adolescents with type 2 diabetes, researchers found.

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

"Monotherapy with metformin is not adequate in many kids, and combination therapy appears to bring benefits," Dr. Phil Zeitler, of the University of Colorado Denver and a co-author on the paper, 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."

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Adding a lifestyle intervention to metformin didn't offer any additional benefits beyond metformin alone, the researchers found, nor did its effects differ significantly from those of metformin and Avandia combination therapy.

In an accompanying editorial, Dr. David Allen, 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 percent of those on metformin alone, 39 percent of those on combination drug therapy, and 47 percent of those in the metformin plus lifestyle intervention group had treatment failure during a mean follow up of about four 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 gone hand-in-hand with increases in childhood obesity. Yet there are few data to guide treatment of the condition in young people, the researchers said. So 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 about eight months.

Patients were randomized to metformin alone (1,000 mg twice a day), metformin plus Avandia (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 another class of diabetes drug, sulfonylureas, had been found to cause unacceptable levels of hypoglycemia in young patients, and 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 last few months of the trial "based on the lack of evidence of safety concerns in the study identified by our data safety monitoring board."

The lifestyle program was developed specifically for the study, 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 percent.

Hirst and colleagues found that about 45 percent of the entire study population achieved those levels during a mean follow up of 3.86 years.

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These rates suggest that the majority of youths with type 2 diabetes will have to go on insulin or another form of combination therapy a few years after their diagnoses, the researchers wrote.

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 Avandia was superior to metformin alone 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, Hirst and colleagues wrote.

BMI did differ significantly according to treatment group over time, with metformin plus lifestyle offering the best weight loss and metformin plus Avandia 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, and metformin alone was less effective in blacks than it was in whites or Hispanics.

Overall, serious adverse events occurred in about 19 percent of patients, and were greatest in the metformin-plus-lifestyle group: 25 percent versus 18 percent with metformin alone and 15 percent for metformin plus Avandia.

The majority of adverse events (87 percent) were not considered to be related to the study treatment, but hospitalizations accounted for more than 90 percent 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 Avandia, more general effects of the thiazolidinedione class, or some other feature of combination therapy, the researchers said.

Although Allen had called the results discouraging, he warned that by no means do they "put the nail in the coffin" of lifestyle modification for young type 2 diabetes patients.

The differences between metformin plus Avandia and metformin plus the lifestyle intervention weren't significant, he noted, and 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.

Instead, youths need to be taken out of a "sedentary, calorie-laden environment" to control their diabetes, Allen wrote.