(+) A clinical trial to maintain glycemic control in youth with type 2 diabetes (New Eng J Med) - Apr 29, 2012 - P3, N=699; TODAY; Rates of failure were 51.7% (120 of 232 pts), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively; Metformin plus rosiglitazone was superior to metformin alone (p=0.006)
P3 data • Diabetes
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BACKGROUND
Despite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. We compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes.
METHODS
Eligible patients 10 to 17 years of age were treated with metformin (at a dose of 1000 mg twice daily) to attain a glycated hemoglobin level of less than 8% and were randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg twice a day) or a lifestyle-intervention program focusing on weight loss through eating and activity behaviors. The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8% for 6 months or sustained metabolic decompensation requiring insulin.
RESULTS
Of the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P=0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. 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.
CONCLUSIONS
Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT00081328.)
Related
Two Drugs Better Than 1 for Children With Diabetes
http://www.medscape.com/viewarticle/762957
Apr 30 2012
A combination of metformin plus rosiglitazone is more effective in treating youth with type 2 diabetes than metformin alone. Adding an intensive lifestyle intervention to metformin is no more effective than metformin alone.
Philip Zeitler, MD, PhD, section head of endocrinology at Children's Hospital Colorado in Aurora and professor of pediatrics and clinical sciences at the University of Colorado School of Medicine in Denver, reported these findings here at the Pediatric Academic Societies 2012 Annual Meeting. They are also published online April 29 in the New England Journal of Medicine.
The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study involved 699 youth 10 to 17 years of age diagnosed with type 2 diabetes within the previous 2 years, with a body mass index (BMI) in the 85th percentile or above, and without pancreatic autoimmunity. The average BMI of the study participants was in the 98th percentile.
During a 2- to 6-month run-in period, participants received standard diabetes education, were weaned off all other diabetes medications, received metformin at doses of 500 mg to 1000 mg twice daily as tolerated, and were evaluated for their ability to adhere to the protocol.
After the run-in period, they were randomly assigned to 1 of 3 treatment regimens: metformin alone, metformin plus rosiglitazone, or metformin plus a program of intensive lifestyle change aimed at weight loss and increasing physical activity. The primary end point was time to failure of glycemic control, defined as a glycated hemoglobin value of 8.0% or greater for at least 165 days or of 10.0% or greater at the end of the study. Participants were followed for 2 to 6 years.
More Than 1 Drug Needed to Control Blood Glucose
Over an average follow-up of 46 months, 51.7% of the children taking metformin alone experienced failure to control long-term blood glucose levels, with median time to failure of 11.8 months. Adding rosiglitazone reduced the failure rate to 38.6% — a reduction of 25% over metformin alone (P = .006) — with median time to failure of 10.3 months.
The failure rate for metformin plus lifestyle intervention was 46.6% (P = .17 vs metformin alone), with median time to failure of 12.0 months. The differences in time to failure were not significant.
"The failures rates in these children overall are much greater than we expected from adult literature," Dr. Zeitler told Medscape Medical News.
Children in the metformin and the metformin plus lifestyle intervention groups tended to lose weight over the course of the study, whereas those in the metformin plus rosiglitazone group gained about 1% at 6 and 24 months. The greatest reduction in weight occurred in the metformin plus lifestyle group — a decrease of about 5% at 24 months. However, the decreases did not result in any improvement in sustained glycemic control.
The differences in failure rates among the groups could not be accounted for by differences in treatment adherence, which were similar.
In prespecified subanalyses, differences in glycemic control failure rates emerged by sex and race/ethnicity. Boys experienced a higher rate of failure than girls (48.2% vs 44.3%). Non-Hispanic blacks had the highest failure rate (52.9%), followed by Hispanics (44.8%), Native Americans (39.0%), and non-Hispanic whites (36.9%).
Aggressive Therapy Needed From the Start
Because of evidence linking rosiglitazone, a thiazolidinedione, to an increased risk for heart attacks and strokes in adults, the US Food and Drug Administration restricted its use in September 2010. In examining the safety of all participants, the TODAY Data Safety and Monitoring Board recommended that the trial continue to test rosiglitazone.
Thiazolidinediones "made sense when we were designing the study in 2002," Dr. Zeitler told Medscape Medical News. "Since then, it's become clear that there are enough concerns about it that we're not going to give this as a recommendation.... We see this as an argument for a need to consider intensification of therapy in these kids."
He explained that it makes little sense to give them metformin and wait for the therapy to fail before initiating another drug, so he recommends "early combination therapy of some sort in most of these kids." One option may be early initiation of insulin, although weight gain and the management burden are concerns. "Or we need to start looking at all the other drug classes, although none of them are problem-free these days," Dr. Zeitler cautioned. "Somehow, we need to figure out how to prevent loss of beta cell function."
Session moderator Janet Silverstein, MD, professor and division chief of pediatric endocrinology at the University of Florida in Gainesville, told Medscape Medical News that "this is really the first trial in which we've had any of the glitazones used in type 2 diabetes in children. I think that understanding the role of rosiglitazone, or any of the glitazones for that matter, in the treatment of type 2 diabetes [in children] is important. It's just as important to understand the reason for failure — that's still coming."
She said it will be important to investigate the reasons for the different responses in the various ethnic groups, and suggested looking at the psychological aspects of the disease, including depression. "It's been shown to affect adherence in other conditions and type 1 diabetes," she said. "I think that we have to be more diligent about recognizing psychological issues and addressing them early.... Diabetes is a hard disease to deal with, and anything that affects lifestyle change is difficult."
Foster Lifestyle, Not Lifestyle Changes
Excess weight and obesity are leading to an epidemic of diabetes in adults and children. In an editorial accompanying the TODAY study, David Allen, MD, from the Department of Pediatrics at the University of Wisconsin School of Medicine and Public Health in Madison, writes that 50 years ago children did not need to make healthy choices to avoid obesity because "they simply lived in an environment that provided fewer calories and included more physical activity for all."
He says that "until a healthier 'eat less, move more' environment is created for today's children, lifestyle interventions like that in the TODAY study will fail."
Dr. Allen laments that "illness from childhood overnutrition is a societal and cultural problem that current medicines treat, but they cannot "stave off a lifetime of illness."
Children's willpower and ability to make healthy food choices are undermined by an "obesogenic" environment. In the grander scheme, Dr. Allen sees the solution to diabetes and its morbidity lying not in better treatments but in public-policy approaches that provide economic incentives to consume healthy foods and environments that require physical movement.
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