"At 6 months, we saw a dramatic difference between the rosiglitazone/metformin arm and the other arms," with a 20% increase in insulin sensitivity compared with no change in the other groups. Thereafter, however, insulin sensitivity started to decrease in the rosiglitazone group, until it plateaued.
By the end of the study, beta-cell function was also similar between the groups, but those in the rosiglitazone group showed a slower decline during the treatment period. This indicated that rosiglitazone was able to stabilize function for at least a period of time. "In contrast, we saw a dramatic fall-off in the beta-cell function in the other two groups, although by 24 months there were no differences among any of them."
"The favorable changes relative to insulin sensitivity were responsible for the observed reduced failure rate in the rosiglitazone group; telling is that this profound degree of insulin resistance in obese youth with type 2 diabetes is unresponsive to the effect of metformin, alone or with lifestyle therapy," Dr. Caprio said.
Because metformin failed those children, the better alternative appears to be more aggressive treatment early in the disease. "The introduction of such aggressive therapy early in the course of the disease appears to slow the decline of beta-cell adaptation and improve the chance or durable control."
Children in TODAY were plagued with much the same medical issues as are adults with type 2 diabetes, said Dr. Neil White, chairman of the TODAY data safety and monitoring committee.
The subjects had a very short duration of diabetes, having been diagnosed 5-7 months before the metformin stabilization period. At that point, 34% already had hypertension. Abnormal LDL cholesterol levels were present in 10%, and high triglycerides in 54%. Some 20% had microalbuminuria, suggesting possible progression to kidney disease.
All of the children, regardless of their treatment group or outcome, showed somewhat abnormal left ventricular and right auricular measurements, noted Dr. White, who is also director of the pediatric clinical research unit at Washington University.
Echocardiography showed that the children had a left auricular diameter of up to 2.4 cm/m height, greater than the population median. All also had a left ventricular mass greater than the population median of 30 g/m2, with some reaching almost 45 g/m2.
"These youngsters had big hearts that are going to predispose them to heart disease in the future," Dr. White said.
At the end of the study, most children (523) underwent fundus photography to evaluate retinopathy. About 14% of them had some degree of nonproliferative retinopathy, putting the young group’s prevalence squarely in line with prevalence in adults with type 2 diabetes.
"This profound insulin resistance was a culprit ... against which metformin had no effect at all," Dr. Caprio said. "Even with the two best drugs we had at the time of this study – metformin and rosiglitazone – we were not able to improve outcomes in 50% of these kids."
Dr. Copeland agreed.
"The finding that 50% of our children failed therapy indicates that this is an incredibly tough disease to treat by any modality we have. Our target as a society needs to be ‘How do we prevent diabetes in children?’ because once they get it, it’s going to be really tough to intervene effectively."
TODAY was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. All of the presenters disclosed financial relationships with Daiichi Sankyo, but said these were not relevant to the TODAY study.