BETHESDA, MD—With the continuing rise in the rates of diabetes and obesity, researchers are exerting more and more effort to find a viable pharmaceutical treatment to combat weight gain. The pediatric population is especially at risk. Obesity in children and young adults is becoming more and more prevalent, but there is very scant data on pharmacotherapy for that age group.
Scarce Approved Therapies
According to Jack Yanovski, MD, PhD, chief of obesity research at the National Institute of Child Health and Human Development’s program in developmental endocrinology and genetics, the consequences of pediatric obesity look a lot like the consequences of obesity in adults. Obese children can expect greater rates of pulmonary disorders, livers disease, long-term risk for cancer, and impaired glucose homeostasis. Obese children and teens—especially those in the highest BMI percentile—are at enormous risk for metabolic syndrome (50-60%). All of this can lead to heart disease in adulthood.
“The consequences are severe,” Yanovski said at an NIH talk last month, “but what do we do about it?”
The first line of treatment is usually behavioral: diet, exercise, and behavioral therapy. However, even the most successful trials using these treatments show less than a 50% long-term improvement rate. “There is a need to study other mechanisms, especially pharmacotherapy,” Yanovski said.
There are several weight-loss drugs approved for obesity in adults, most of which are similar to amphetamines and which decrease appetite. Orlistat is the only long-term drug for obesity that is also approved for children, though not for children younger than 12.
While it was shown to decrease weight slightly, NIH researchers wondered whether the drug actually impacted complications due to obesity. In an NIH follow-up study on orlistat, researchers found no change in the prevalence of metabolic syndrome in either the orlistat or control groups. They also noted a number of gastrointestinal side effects, along with unexpectedly higher liver enzymes in the orlistat group. FDA is currently investigating whether this is evidence of a serious adverse event.
“We failed in producing the effect we really wanted to produce, which is improving health, not just weight,” Yanovski said. “My conclusion is that even though this is the one drug approved for use in adolescents, it should not be routinely recommended for treatment of obese adolescents with metabolic syndrome.”
This leaves physicians seeking a treatment with only one hope: experimental drugs yet to be approved by the FDA. One of these is leptin—a hormone secreted by fat cells, deficiency in which leads to obesity. A certain percentage of obese people are overweight because of leptin deficiency. Small trials in leptin-deficient patients show that over a four-year period of leptin treatment, fat mass is lost while lean mass remains.
However, most obese people are thought to be leptin resistant, making them immune to the therapy.
Another pharmacotherapy currently being studied is metformin. Found in the French lilac, the drug modulates lipid synthesis. It also inhibits hepatic gluconeogenesis and is approved by FDA for treatment of Type 2 diabetes in adults and children older than 10.
It has the secondary effect of decreasing food intake. Researchers at NIH’s Diabetes Prevention Program found that four years of metformin treatment led to weight loss or weight stabilization in nondiabetic adults. Other small, randomized clinical trials found similar results in obese adolescents.
An NIH trial on the effects of metformin on obesity in children and adolescents looked at 100 children with BMIs in the 34% range who were extremely insulin resistant. The trial saw a modest decrease in body fat mass. However, it also saw considerable side effects with 16% having liquid stool, 24% experiencing nausea, and 13% experiencing fatigue. “Those symptoms decreased over time, but this is not a benign therapy,” Yanovski said. “Perhaps is can be used to prevent Type 2 diabetes as children enter adolescence.”
Yanovski’s conclusion is that the efficacy of non-selective pharmacotherapies for pediatric obesity is modest at best and cannot be recommended outside the context of clinical trials. However, the one successful selective therapy—leptin—suggests that other such therapies may be crucial to combating obesity. “There may be other specific therapies that will work on other patients. Our plan is to test them over the next several years, hopefully as part of NIH’s Bench to Bedside Program.”