The alarming increase in type 2 diabetes mellitus (T2DM) among children and adolescents has researchers scrambling for effective treatments. Amid growing evidence that the disease progresses more quickly in children than in adults, some doctors are advocating aggressive drug treatment, and nearly all experts are stressing prevention as a priority to combat the condition.
“The time to intervene with major lifestyle changes is not after diabetes has happened,” said Kenneth Copeland, M.D., a pediatric endocrinologist at the University of Oklahoma. “Our focus needs to be on the kids who are at risk before they develop diabetes because effecting a major lifestyle change—enough to change the course of established diabetes in youth—is exceedingly difficult to do.”
Copeland is a co-author of the recent study, “Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY),” the first major trial to compare the effectiveness of three treatments for T2DM in young people. Results published in June in The New England Journal of Medicine showed that none of the treatments controlled glycemic levels in more than 61 percent of patients.
These findings are important, considering the increasing number of American youth with T2DM; from 2001 to 2009, the number of cases rose 21 percent. Some 3,700 children are diagnosed with the condition every year. Twenty years ago, T2DM was almost nonexistent among children, according to Philip Zeitler, M.D., Ph.D., a pediatric endocrinologist at Children’s Hospital Colorado in Aurora and professor of pediatrics and clinical science at the University of Colorado School of Medicine. He is another co-author of the TODAY trial.
The incidence of the disease is likely to continue to grow because of the obesity epidemic. Seventeen percent of children between the ages of 2 and 19 are obese. This puts a large segment of the population at risk for developing high blood pressure, high cholesterol, and T2DM. Developing T2DM at a young age also increases the risk of heart disease, retinopathy, and kidney disease.
With such dire medical complications facing the nation’s youth, TODAY researchers compared the efficacy of three treatments in maintaining glycemic control for a four-year period. One protocol used metformin, the standard treatment for children with T2DM; another treatment combined metformin with lifestyle intervention; and the third used metformin in combination with the insulin-sensitizing drug rosiglitazone. Failure of control was defined as the glycated hemoglobin, or A1C, level rising to 8 percent or more for six months.
Treatment with metformin alone failed 52 percent of the time, compared with a 47 percent failure rate for metformin plus lifestyle intervention and 39 percent for metformin and rosiglitazone combined. The researchers deemed the addition of lifestyle intervention not significantly different from metformin alone, but the two-drug combination led to a 25 percent improvement.
The 700 patients in the study were ages 10 to 17 years and had had T2DM for less than 2 years at study outset. Although the enrollment criteria specified that they have a body mass index (BMI) at or above the 85th percentile for age and sex, participants exceeded this requirement, with an average BMI in the mid-30s, putting them in the 98th percentile. After being weaned from any other diabetes medications, they were given a metformin dose of up to 1,000 mg twice daily to attain glycemic control, defined as a glycated hemoglobin level less than 8 percent for at least two months.
Because insulin sensitivity declines in all children during puberty and then improves at puberty’s end, researchers wanted to test whether aggressive steps to maintain insulin sensitivity might offer patients a safe passage through this period, Zeitler said. But they found that the failure rate of metformin monotherapy was higher in the children than in adults.
Faster Progression of the Disease
One of the reasons for this lack of efficacy could be that T2DM seems to progress more quickly in young people than adults, the researchers said in a presentation at the American Diabetes Association’s Scientific Sessions in June. By the end of the TODAY study, nearly one-third of the participants exhibited high blood pressure (compared with 12 percent at the beginning), 10 percent–30 percent had dyslipidemia, about 17 percent exhibited elevated urinary albumin levels (compared with 6 percent at the start), and 13 percent had retinopathy. These numbers represent a much faster progression of the complications of the disease than in adults.
In light of these results, “it might be good to start with a more aggressive drug treatment approach,” Zeitler said. “The good news is nearly 50 percent of the kids did well on metformin therapy.” Fortunately, patients who will respond well to metformin can be identified early on based on their A1C level, he said. “Those kids who had an A1C in the normal range did much better than those kids who got their A1C down but did not get a normal A1C. The kids you can get under control quickly and easily stay that way,” Zeitler explained. The median time to a loss of glycemic control was less than a year. If the drug is not going work, physcians will know fairly quickly.
A question arises about where to turn when metformin, the only oral drug approved by the U.S. Food and Drug Administration (FDA) for treatment of children, fails to ameliorate T2DM. Rosiglitazone, used in the study’s combination treatment, is not an option; in September 2010 the FDA imposed prescribing restrictions after studies linked it to a higher risk of heart attacks and stroke in adults. (Those concerns arose after the TODAY trial was designed and inaugurated, and the study was allowed to continue with careful monitoring of participants.) Whether other drugs in the thiazolidinedione family, such as pioglitazone, would be salutary without the risks of rosiglitazone requires more research. The fact remains that rosiglitazone still failed for many of these patients.
For now, the “only other well-studied option is combination with insulin,” Zeitler said. The loss of insulin secretion was very rapid in the patients who lost glycemic control, and physicians may, therefore, want to move to insulin therapy quickly because the faster progression to comorbidities underscores the need to keep glycemic control in the adolescent age group.
Increase Efforts to Modify Lifestyle
The TODAY researchers and other experts agreed that the failure of the lifestyle modification efforts should not be seen as reason to abandon them, but instead to redouble their efforts to help children adopt healthier habits. The lifestyle intervention treatment model required assigning a behavioral interventionist called a “pal” to each participant. The pals held weekly meetings with the children, advised their families on being role models, chaperoned trips to the gym to exercise, and more.
In general, the results were similar to previous adolescent weight-loss efforts and T2DM development. “Although metformin plus lifestyle intervention significantly decreased percent overweight, this did not translate into sustained glycemic control, as compared with metformin monotherapy,” the study said. Zeitler was surprised that the intervention was not able to budge the patients out of their overall environment of excess calories and a sedentary lifestyle enough to make a long-term difference.
“The key message from this study wasn’t so much about the need for add-on medications as it was about the need for prevention,” David Allen, M.D., head of pediatric endocrinology at the University of Wisconsin School of Medicine, told Endocrine News. “By demonstrating that a large proportion of children were not retrievable by medical intervention, as well as the accelerated rate at which they deteriorated in spite of medical intervention, this study should add a tremendous impetus to focusing our energy on correcting the dangerous mismatch of calories consumed versus energy expended that these children experience.” The focus on looking for more drug therapies could be a distraction from the need for prevention, he added.
Allen’s call for prevention echoed The Endocrine Society’s pediatric obesity clinical treatment guideline, which recommends physicians become much more active as community advocates for healthier school lunches, policies to ban advertising of unhealthful foods to children, and design of neighborhoods that emphasize walking instead of driving. School food programs are an important target because children who participate in the school lunch and breakfast programs consume one-third to one-fifth of their daily recommended caloric intake in school.
The Society’s guidelines also note that pediatricians are lax in complying with the American Academy of Pediatricians guidelines on obesity. Clinicians in general should be more proactive in screening for obesity and become involved with the entire family in prescribing dietary, physical activity, and behavioral modifications in pursuit of a healthier lifestyle.
Allen compared the challenge of the obesity epidemic with that of coping with climate change. Both issues, he said, are “so complex, embedded in culture and economics, and intertwined with conflicts between individual freedom and societal health that solutions are difficult to envision.”