This week’s New England Journal of Medicine has an article entitled, “A clinical trial to maintain glycemic control in youth with type 2 diabetes,” written by the TODAY Study Group. There was also an accompanying editorial entitled, “TODAY- a stark glimpse of tomorrow, ” written by DB Allen. You need to know about the study because the reported findings are important but also because of the rather bizarre way (in my opinion) the data were presented and the pitfalls of not knowing “the rest of the story.”
What was the study design?
The stated purpose of the study was to provide data to help guide treatment of youth with type 2 diabetes. This was a multicenter randomized clinical trial conducted by investigators very experienced in clinical trials of this sort. Based on the article, the eligibility criteria included recently diagnosed type 2 diabetes in patients ages 10-17 yrs. The article frequently referred to “the Supplementary Appendix” for details regarding the rationale, design, and methods of the study. I will come back to that little detail. Basically, eligible patients were randomly assigned to one of three groups: metformin, metformin plus rosaglitazone, or metformin plus a life-style intervention program. The program focused on weight loss and activity behaviors. Patients had to have been diagnosed with type 2 diabetes within the past 2 yrs, a body-mass index at or above the 85th percentile, negative tests for diabetes-related autoantibodies, and a fasting C-peptide level of greater than 0.6 ng/ml (these two eligibility criteria were used to minimize the likelihood that a patient with type 1 diabetes would end up in the study). Eligible patients had a “run=in period” of 2-6 months with metformin treatment and had to achieve a HbA1c level of <8% for 2 consecutive months to be eligible to enter the trial. Patients were enrolled between July 2004-February 2009 with follow-up through February 2011 to achieve a follow-up of at least 2 yrs; mean follow-up was 3.8 yrs with maximum of 6.5 yrs. The primary endpoint was a persistently elevated HbA1c equal to or greater than 8% over a period of 6 months or persistent metabolic decompensation defined as the inability to be weaned from insulin injections within 3 months after initiation for decompensation (or the occurrence of a second episode of decompensation within 3 mo after discontinuation of insulin).
What were the study results?
Of the 1211 children and adolescents screened, 927 entered the run-in phase and 699 were randomly assigned to one of the three treatment groups. The study subject demographics were interesting. Only 20% of study subjects were non-Hispanic whites while 73.2 % of study subjects were either blacks or Hispanics. In general, the study subjects were from low income families; as detailed in the Supplementary Appendix, only 24% of subjects came from families with yearly incomes >$50,000. At onset of the study, the mean age of subjects was 14 yrs and 65% were female. The study results showed that overall about 50% of subjects reached the primary endpoint with median time to treatment failure of about 1 year. Treatment failure was significantly greater in the metformin only group compared to the other groups but only by a bit (the metformin plus rosiglitazone group showed about a 20% decrease in treatment failure compared to the metformin only group. The metformin plus lifestyle showed the most weight loss and the metformin plus rosiglitazone group the least but overall the success was not impressive for any of the treatment groups. There was no relationship between the amount of weight lost and the treatment failure rate. The investigators concluded that “a majority of youth with type 2 diabetes may require combination treatment or insulin therapy within a few years after diagnosis.”
What about the editorial?
The editorial was mostly doom and gloom about the high prevalence of obesity and diabetes in children and adolescents. The author had little to say about the implications of the study results for treatment of children and adolescents diagnosed with type 2 diabetes and focused on the “larger picture,” the societal and cultural problem of illness from childhood overnutrition. The author’s “stark message” was the following: “…..tomorrow and beyond, public-policy approaches-sufficient economic incentives to produce and purchase healthy foods and to build safe environments that require physical movement-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.” Who could argue with such a message? But, I think there were other important messages from the study results with immediate practical implications that should have been addressed as well. I will explain.
The Supplemental Appendix
I love the New England Journal of Medicine. I have read every weekly issue since 1965. But, I have “a bone to pick” with the Journal this time. I read the article several times and had great difficultly fully understanding the experimental design and the study results. I finally made sense of things when I actually downloaded and read the Supplementary Appendix referred to numerous times in the article. I would be willing to bet that very few of the Journal readers did that. If they had, they would have learned that even at the start of the study, the characteristics of the subjects who ended up as treatment failures were different from those who were not treatment failures. The Supplementary Appendix had a lovely graph showing study subject HbA1cs from the start of the study until the end based on whether they were treatment failures or not. I was struck by the fact that the study subjects who did not fail, started the study as a group with much lower HbA1c levels (averaging about 5.7%) than those who failed (averaging about 6.5%). Furthermore, at the end of the study, the mean HbA1c in the study subjects who did not fail was still at about 5.7%, while the mean HbA1c level in the subjects who failed, was a bit over 7%. From the Supplementary Appendix, I learned that study subjects who failed were switched from whatever treatment group they had been in to a regimen consisting of metformin and insulin. Thus, even the treatment failure patients were able to do very well as a group. This little tidbit was not addressed at all in the article (or the editorial). These data are very important and raise questions about heterogeneity in children and adolescents with type 2 diabetes. The data also raise serious questions for me whether all of the study subjects who did not turn out to be treatment failures really had diabetes? If a patient meets the standard criteria for a diagnosis of diabetes based on plasma glucose levels yet has a normal HBA1c level, is that really diabetes? Maybe the investigators should have limited eligibility to patients who met both plasma glucose and HbA1c diagnostic criteria for diabetes? I assume that almost all of the study subjects had HbA1c levels measured when they were diagnosed with diabetes? Maybe the initial HbA1c is a strong predictor of a patient’s risk of treatment failure on a regimen that does not include insulin?
In my opinion, the important data and study design details I learned about only from the Supplementary Appendix should have been in the actual article. I am not sure who to blame for this problem, the study authors, the Journal editors, or both? Anyway, not having some of the Supplementary Appendix information in the article itself, takes away from value of the article for the average reader (i.e., not into downloading Supplementary Appendices). I do hope the investigators are still following these study subjects; it will be very important to learn if the study subjects who did not fail and who had low HbA1cs at the start of the study, are able to maintain well controlled diabetes on oral agents or even if many of them turn out not to have diabetes.
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