Combination therapy for youth with type 2 diabetes

A combination of 2 diabetes drugs, metformin and rosiglitazone (Avandia, GlaxoSmithKline), was more effective in treating youth with recent-onset type 2 diabetes than metformin alone, a study funded by the National Institutes of Health (NIH) has found. Adding an intensive lifestyle intervention to metformin provided no more benefit than metformin therapy alone.

Currently, metformin is the standard treatment for young people with type 2 diabetes and the only oral drug approved for this use by FDA.

The study, published in New England Journal of Medicine, also found that metformin therapy alone was not an effective treatment for many of these youth. In fact, metformin had a much higher failure rate in study participants than has been reported in studies of adults treated with metformin alone.

The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is the first major comparative effectiveness trial for the treatment of type 2 diabetes in young people. TODAY was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of NIH.

The study enrolled 699 youth who had type 2 diabetes for <2 years and a body mass index (BMI) at the 85th percentile or greater. Overweight children have a BMI at the 85th to 94th percentile for their age and sex, while obesity is defined as a BMI at the 95th percentile or more. The TODAY participants had an average BMI at the 98th percentile.

“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,” Philip Zeitler, MD, PhD, the TODAY study chair and a pediatric endocrinologist at Children's Hospital Colorado, Aurora, said in an NIH press release. “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 TODAY study tested how well and for how long each of 3 treatment approaches controlled blood glucose levels in youth enrolled from aged 10 to 17 with type 2 diabetes. Participants were randomly assigned to 1 of 3 treatment groups: metformin alone (at a dose of 1,000 mg twice daily), metformin and rosiglitazone together (4 mg twice a day), and metformin plus intensive lifestyle changes aimed at helping participants lose weight and increase physical activity.

The study found that treatment with metformin alone was inadequate for maintaining acceptable, long-term, blood glucose control in 51.7% (120 of 232 participants) of youth over an average follow-up of 46 months. The failure rate was 38.6% (90 of 233) in the metformin and rosiglitazone group, a 25.3% reduction from metformin alone. In the metformin plus lifestyle group the failure rate was 46.6% (109 of 234).

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% of participants.

“Despite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment,” the authors wrote.

In a commentary published alongside the study, pediatrician David Allen, MD, from the University of Wisconsin School of Medicine and Public Health in Madison, wrote: “Chronic caloric surplus (rather than obesity itself) is a central cause of epidemic type 2 diabetes, but differences in response to energy excess, disproportionately present among disadvantaged youth, increase susceptibility to type 2 diabetes in early life.”

The study was a needed study, according to Megan J. Ehret, PharmD, BCPP assistant professor, University of Connecticut, Storrs. “Diabetes in the youth population is a major problem and how to effectively treat it is a larger one,” Dr Ehret told Formulary, the sister publication of Drug Topics. “This study demonstrated that the combination of metformin and rosiglitazone reduced the rate of treatment failure. The effect, though meaningful, is challenging to interpret, given the current status of rosiglitazone in the United States. Whether or not these results can be applied to other combinations of medications is challenging. Additionally, should adolescents be started to multiple medications at diagnosis or should we wait until failure with monotherapy to implement combination therapy? These are questions that still remain unanswered.”  

In September 2010, FDA restricted the use of rosiglitazone because of studies linking the medicine to a higher risk of heart attacks and stroke in adults. The TODAY Data Safety and Monitoring Board-an independent group of health and science experts-carefully examined all safety data for TODAY participants and recommended that the study should continue to test rosiglitazone.

Studies have shown lifestyle-change programs to be effective in improving blood glucose control for adults with type 2 diabetes. However, the TODAY lifestyle intervention-a family-based weight-management program that included intensive education and activities delivered one-on-one by trained study staff-added no benefit to the metformin therapy. Some youth lost weight during the study, but the majority did not.

“Despite a rigorous lifestyle intervention, we were unable to achieve sustained lifestyle changes in these youth, though similar strategies have proven effective in adults,” said Barbara Linder, MD, PhD, NIDDK senior advisor for childhood diabetes research. “TODAY investigators will look more closely at those youth who succeeded in losing weight to better understand how to achieve effective lifestyle change in this population.”