June 21, 2007
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) funds the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) study, which is comparing three different treatments for type 2 diabetes in youth.
In the TODAY study, participants are randomly assigned to one of three treatment groups: metformin alone; metformin and rosiglitazone in combination (Avandamet); and metformin plus intensive lifestyle changes aimed at losing weight and increasing physical activity. Researchers in 15 medical centers plan to enroll 750 children and teens 10 to 17 years old diagnosed with type 2 diabetes in the past 2 years. Nearly 500 patients have been enrolled so far. Results are expected in 2011.
The TODAY study’s main goal is to determine how well and for how long each treatment controls blood glucose levels. The study is also evaluating
• the safety of each treatment;
• each treatment’s effects on insulin production, insulin resistance (a hallmark of type 2 diabetes in which cells do not effectively use insulin), body composition, nutrition, physical activity and aerobic fitness, risk factors for eye, kidney, nerve, and heart disease, quality of life, and psychological outcomes;
• the influence of individual and family behaviors on treatment response;
• the cost-effectiveness of each treatment.
Patient safety is the NIDDK’s foremost priority. Following recently published articles on rosiglitazone’s affect on cardiovascular disease and death1,2 and the Food and Drug Administration’s labeling change for the drug, the NIDDK asked the Data and Safety Monitoring Board (DSMB) for the TODAY study to reexamine any adverse events that may have occurred in the study, to report any concerns regarding participants’ safety, and to consider the need for changes to the study in light of the recent reports. The seven-member DSMB, a non-federal advisory group with expertise in diabetes, adult and pediatric endocrinology, patient care, public health, biostatistics, medical ethics, and clinical trial design, advises the NIDDK on all matters related to patient safety in the TODAY study. The Board meets every 6 months and on an ad hoc basis as needed.
After carefully reviewing all safety data, including analyses that specifically examine rosiglitazone’s effects on cardiovascular risk factors and bone density, the TODAY study DSMB found no cause for concern and recommended that the TODAY trial continue without change. The DSMB will continue to monitor closely TODAY safety data as well as other available data related to rosiglitazone. The DSMB will also continue to meet regularly and to reconvene as appropriate in response to any new developments. In addition, the Board reviewed and approved plans from TODAY study researchers group to inform participants of recent concerns about rosiglitazone and the risk of cardiovascular disease
The NIDDK has accepted the DSMB’s recommendation. TODAY study participants, given their age, are at low risk for heart disease, and they receive careful ongoing monitoring for cardiovascular risk factors, such as elevations in lipids, blood pressure, and urinary albumin secretion, as well as bone density and body composition.
Many drugs are available to treat type 2 diabetes in adults, but metformin, which lowers the liver’s production of glucose, is the only oral drug approved by the Food and Drug Administration to treat type 2 diabetes in children. Rosiglitazone (Avandia), which belongs to a class of insulin-sensitizing drugs called the thiazolidinediones (TZDs), helps fat, muscle, and liver cells respond to insulin and use glucose more efficiently. By improving insulin resistance during puberty, a time when insulin resistance tends to peak, researchers hope to spare the insulin-secreting beta cells, thus facilitating blood glucose control and delaying the complications of diabetes.
One of the recent published reports reviewed by the DSMB, an analysis that combined data from 42 clinical trials in adults, concluded that rosiglitazone may be associated with an increased risk of heart attack. The report also found a trend, though not statistically significant, for increased cardiovascular deaths from rosiglitazone.
The other report reviewed by the DSMB was from a clinical trial called RECORD, which is being conducted by the drug’s manufacturer. RECORD reported no significant increase in cardiovascular deaths or death from any cause, and no significant increase in heart attack rates, but did report an increased risk of congestive heart disease from rosiglitazone. This report was based on an interim analysis of trial data, however, and the small number of cardiovascular events that had occurred so far limited the study’s statistical power to detect increased risk of cardiovascular disease.
Although the published studies are not considered definitive, NIDDK takes these reports seriously. In overseeing the TODAY trial, the Institute will continue to vigilantly monitor data on any adverse affects linked with the treatments being studied.
The NIDDK also contributes funding to the ACCORD and BARI 2D trials sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the NIH. For more information on the use of rosiglitazone in these studies, see public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=287
About 20.8 million people in the United States—7 percent of the population—have diabetes, the most common cause of blindness, kidney failure, and amputations in adults and a major cause of heart disease and stroke. Type 2 diabetes, which accounts for up to 95 percent of all diabetes cases, is closely linked to obesity, physical inactivity, and a family history of the disease. As the rate of type 2 diabetes in adults continues to climb, the disease is also becoming increasingly common in youth. Some diabetes centers are now seeing more new cases of type 2 diabetes than type 1 diabetes, an autoimmune disease. The trend is alarming because the longer a person has diabetes, the greater the chances of developing serious damage to the eyes, nerves, heart, kidneys, and blood vessels.
1Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356:2457-71
2Home, PD, Pocock, S, et al. Rosiglitazone evaluated for cardiovascular outcomes – an interim analysis. N Engl J Med 2007; 10.1056/ NEJM oa073394 at www.nejm.org on June 5, 2007.
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