NEJM: Are drugs or lifestyle changes best for obese, diabetic youths?

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Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes; however, the addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone, according to the TODAY study published online April 29 in the New England Journal of Medicine. Yet, the editorialist questioned the study’s design.

Despite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) was a multicenter, randomized clinical trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in which Kathryn Hirst, PhD, of George Washington University Biostatistics Center in Rockville, Md., and colleagues compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes.

The TODAY study compared metformin monotherapy with two alternative approaches, one combining metformin with rosiglitazone (Avandia, GlaxoSmithKline) and one combining metformin with an intensive lifestyle-intervention program, to test the hypothesis that combination therapy initiated early in the course of youth-onset type 2 diabetes would maintain acceptable glycemic control better than metformin alone.

The randomization scheme was computer-generated at a 1:1:1 ratio according to study site, with a block size of nine. The researchers randomly assigned participants to metformin (at a dose of 1,000 mg twice daily) given alone, metformin plus rosiglitazone (4 mg twice daily), or metformin plus a lifestyle-intervention program. The program, which focused on weight loss through family-based changes in eating and activity behaviors, was delivered in a series of in-person visits during the first two years, with continued contact at quarterly medical visits.

Site investigators, study personnel and participants were blinded to the assignments to the metformin-alone and metformin-plus-rosiglitazone groups and study medication was encapsulated to ensure masking—all participants took the same number of capsules each day.

The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8 percent for six months or sustained metabolic decompensation requiring insulin.

Of the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 45.6 percent reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7 percent, 38.6 percent and 46.6 percent for metformin alone, metformin plus rosiglitazone and metformin plus lifestyle intervention, respectively. Hirsch and colleagues found that metformin plus rosiglitazone was superior to metformin alone; metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone.

“The results of this study tell us it might be good to start with a more aggressive drug treatment approach in youth with type 2 diabetes,” said the study's chair Philip S. Zeitler, MD, PhD, a pediatric endocrinologist at Children's Hospital Colorado in Aurora, in a statement. “We are learning that type 2 diabetes is a more aggressive disease in youth than in adults and progresses more rapidly, which could be why metformin alone had a higher than expected failure rate.”

The study authors also reported that the prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-Hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2 percent of participants.

So, do these results put a nail in the coffin of lifestyle modification and endorse add-on drugs to treat type 2 diabetes in children, questioned the editorialist David B. Allen, MD, of the pediatrics department at the University of Wisconsin School of Medicine and Public Health in Madison. “Reasons to resist this notion may lie in the study design and analysis. The study's focus on the comparison of metformin alone with metformin plus lifestyle change or metformin plus rosiglitazone, without comparison of the two combination treatments, overshadows the fact that failure rates of the metformin-plus-lifestyle and metformin-plus-rosiglitazone groups did not differ significantly.”

In their conclusion Hirsch and colleagues acknowledged that further analysis of the effect of various components of the lifestyle intervention “is needed to understand the current findings and identify ways to effectively integrate behavioral self-management in the ongoing care of youth with type 2 diabetes.”

With regard to secondary outcomes, Allen said the participants in the metformin-plus-lifestyle group gained less fat mass than those in the metformin-plus-rosiglitazone group, “a result that could reduce the risk of other diseases associated with obesity. In addition, possible sex and racial differences in the effect of lifestyle change on glycemic control hint that effective strategies to prevent type 2 diabetes and slow its progression may vary.

“Solace can still be found in the TODAY study, if its larger message transcends its worrisome findings,” Allen concluded. “For a substantial proportion of those millions of children at risk for largely preventable type 2 diabetes, the findings of the TODAY study reinforce the idea that medications and even procedures will not stave off a lifetime of illness. Furthermore, lifestyle changes for youth are undermined by immersion in an obesogenic world, in which personal responsibility appears to be invalidated by the limits of willpower with respect to over-nutrition."

Moreover, he added that the "stark message" from TODAY is that, "tomorrow and beyond, public-policy approaches … and not simply the prescription of more and better pills will be necessary to stem the epidemic of type 2 diabetes and its associated morbidity.”

In addition to funding from the National Institutes of Health’s NIDDK, the TODAY study received support from Becton Dickinson, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, LifeScan, Pfizer and Sanofi-Aventis.