The New England Journal of Medicine recently published (4/29/12) the results of the TODAY study (Treatment Options for Type 2 Diabetes in Adolescents and Youth). Unfortunately, the results were not encouraging. As everyone is slowly coming to realize, childhood obesity is increasing at an alarming rate. As such, the risk of developing type 2 diabetes in childhood, particularly in minority populations due to familial risk factors, is exponentially increased. Adolescence is fraught with challenges in children without chronic illness, let alone those with illnesses that require significant changes in lifestyle such as diabetes.
The TODAY study group was a multicenter, randomized clinical trial that was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Eligibility for the study included children ages 10 to 17 years with type 2 diabetes for less than two years, BMI at the 85th percentile for age and sex, negative antibodies (GAD-65 and tyrosine phosphatase), and a fasting C-peptide level greater than 0.6 ng/ml, as well as an adult caregivers to ensure adherence to medication and provide support. There were three arms in this prospective study that was initiated early in the course of the development of type 2 diabetes in adolescents and children.
- metformin (Glucophage) monotherapy 1000 mg twice daily (metformin without other medications or other interventions).
- metformin (glucophage) 1000 mg twice daily with rosiglitazone 4 mg twice daily (Avandia) (an insulin sensitizer that has been controversial in the adult world of diabetes recently).
- metformin (Glucophage) combined with an intensive lifestyle intervention program (focusing on weight loss and eating behaviors with family involvement). In person visits occurred during the first 2 years and then quarterly.
The goal of the study was to determine if combination therapy begun early after diagnosis of type 2 diabetes would improve blood sugar control better than metformin therapy alone. The study was blinded to both investigators and participants: no one was aware of the different assignments to the arms of the study as each participant took the same number of capsules each day. Participants were followed for 3.86 years.
The primary study objective was to compare the three treatment groups with “regard to treatment failure (persistently elevated hbA1c- greater than or equal to 8 percent during a 6-month period or persistent metabolic decompensation -inability to wean the participant from insulin within 3 months after its initiation for glycemic instability or the occurrence of a second episode of decompensation within 3 months after stopping insulin.)” Hb A1c was checked every 2 months in the first year and then every 3 months thereafter.
What were the results?
- There were 699 participants in the study.
- 45.6 percent (319) reached the primary outcome (see above) with a median time to treatment failure of 11.5 months.
- Overall rates of failure were 51.7 percent with metformin alone.
- 38.6 percent with metformin +rosiglitazone
- 46.6 percent with metformin +lifestyle
- Overall failure rates were 44.3 percent among girls and 48.2 percent among boys (p=0.02-statistically significant)
- Adherence to the medication before the primary outcome did not differ significantly among treatments.
What is the take-home message?
Sadly, the results of the study demonstrate that metformin alone resulted in blood sugar control in only 50 percent of the participants. The combination of metformin and rosiglitazone improved the “durability” of control and metformin combined with lifestyle intervention was no better than metformin alone in maintaining glycemic control. There did not appear to be any differences in adherence to the three arms of the study. Unfortunately, the treatment failure of metformin alone is higher than adults treated with metformin monotherapy. Because of the limited sample size in the combination metformin/rosiglatizone group, adverse effects were absent.
The results indicate that the majority of children and adolescents with type 2 diabetes seem to require treatment with combinations of oral medications or insulin therapy within a few years of their diagnosis. Unfortunately, this study confirms what clinicians have seen on a day-to-day basis with our type 2 diabetes patients.
The key, therefore, remains intervention before the onset of type 2 diabetes in our vulnerable populations. Intervention will require multiple tactics at different levels: the nuclear and extended family, school, extracurricular venues, fast food establishments, and ultimately, societal influence.