Pro/Con: Metformin for pediatric patients with insulin resistance

Is metformin a much-needed treatment for pediatric patients or an ineffective substitute for lifestyle intervention?

Issue: June 2006

Although metformin is widely-used as a treatment for adults with diabetes and insulin resistance, its use in pediatric patients is somewhat controversial.

At the Pediatric Academic Societies’ 2006 Annual Meeting, held recently in San Francisco, two leading physicians debated the use of metformin as a treatment for insulin resistance in pediatric patients.

Michael Freemark, MD, chief of the division of endocrinology and diabetes in the pediatrics department of Duke University Medical Center, said he supports metformin treatment in pediatric patients. In contrast, Philip Scott Zeitler, MD, PhD, associate professor of pediatrics at the University of Colorado School of Medicine, was opposed to metformin treatment in this population, saying lifestyle interventions should be encouraged for these patients.

A needed treatment?

Freemark said metformin can and should be used to treat selected pediatric patients with insulin resistance. “We are dealing with a very serious problem,” he said. “This can be seen in the recent surges in the complications of obesity and insulin resistance among pediatric patients, including type 2 diabetes, dyslipidemia and hypertension. We must intervene effectively and, given the progressive nature of these conditions, we cannot dally.”

Freemark warned that if treatments for this patient population are not improved soon, there may be an increase in consequences such as cardiovascular disease and malignancy at earlier ages.

Like most physicians, Freemark agreed that lifestyle interventions, including improved diet and increased physical activity, should be the first treatment for all patients with obesity or insulin resistance. “It is clear that diet and exercise can reduce body fat content and reverse some of these complications,” he said.

But for some patients, lifestyle intervention may not be enough. “Lifestyle intervention represents the core treatment for any obese child,” Freemark said. “But if this were universally effective, we wouldn’t be having this discussion.”

For many patients, the response to lifestyle intervention is often inadequate and fleeting for several reasons. Because of this, Freemark said some patients may require pharmacologic assistance.

He said metformin may be the best for many of these patients. “Any drugs used in therapy should help to counteract insulin resistance or prevent or reverse its complications,” he said. “Metformin is beneficial in these respects.”

Freemark noted that results from the Diabetes Prevention Program (DPP) indicated that metformin was as effective as intensive lifestyle intervention in preventing diabetes in younger adults and those patients with the highest BMI.

Although metformin has not been studied extensively in pediatric patients, Freemark mentioned three randomized, double-blind, placebo-controlled clinical trials of metformin in obese adolescents. The trials showed that in pediatric patients with insulin resistance, metformin was associated with reductions in BMI, waist circumference, fasting insulin and fasting glucose. Insulin sensitivity was variably increased.

Metformin also reduced hirsutism scores and increased ovulation rates and insulin sensitivity in insulin-resistant teenage girls with PCOS. In general, metformin has a good safety record and, according to Freemark, the cost of the generic formulation ($180 to $360 per year) is considerably less than the cost of individual intensive lifestyle intervention.

Freemark said that although he recommends metformin for some patients, he believes lifestyle intervention should be a priority for all at-risk patients. “We should begin with lifestyle intervention,” he said. “Metformin should be considered for patients who have persistent glucose intolerance or other comorbidities of insulin resistance, particularly if there is a family history of complications. However, lifestyle intervention should be continued even in patients who begin metformin.”

Benefits not well-documented

Zeitler agreed that the public health consequences associated with the increase of obesity and insulin resistance in pediatric patients represents a very serious problem. But he discouraged the use of metformin as a general treatment. He said he did not think metformin offered enough benefits or was cost-effective.

“I agree that lifestyle is generally disappointing,” he said. “But the question is not whether we need something better, but whether metformin is that better treatment.”

Zeitler’s main concern about metformin was that its benefits in pediatric patients have not been well-documented. “There is not strong enough evidence that metformin is beneficial in weight loss for pediatric patients,” he said. “The evidence is mostly limited results from [case-controlled] studies. For the most part, these studies have shown relatively small amounts of weight loss among pediatric patients on metformin.”

Zeitler and his colleagues recently conducted a trial examining the use of metformin in pediatric patients. The trial included 58 pediatric patients aged 12 to 19. All study participants’ BMI was in the 95th percentile or higher and all had insulin resistance. The patients received metformin or placebo for six months. All patients also received lifestyle intervention with specific goals to be achieved by the end of the six-month trial.

Zeitler said at the end of the study there was no difference in overall weight loss. There were also no significant differences in glucose, insulin or lipid levels at the end of the trial. However, Zeitler noted that among the subset of children who attained their lifestyle goals and were compliant in taking their medicine, more weight loss was seen among patients in the metformin group than in the placebo group.

“Children who were able to make lifestyle changes were more likely to lose weight on metformin than placebo,” Zeitler said. “This indicates that metformin may not be an effective weight loss medication on its own.”

Zeitler also warned about the psychological effects that metformin treatment may have on pediatric patients. “When patients are treated with both lifestyle intervention and metformin, they often misunderstand the benefits of lifestyle intervention because they attribute the benefits to a pill,” he said. “Telling patients, ‘you need to change your lifestyle but we’ll give you a pill anyway,’ sends a mixed message.”

Finally, Zeitler stressed concern that metformin may not be cost-effective. By his estimates, depending on monthly cost, metformin treatment costs can range from $250 to $1,000 per year. At the same time, evidence indicates that metformin reduces the risk of diabetes in adolescents by about 7% over eight years. By this estimate, it would cost from $30,000 to $100,000 to prevent one case of diabetes. – by Jay Lewis

For more information:

Freemark M. Zeitler PS. Controversies in pediatric endocrinology: Should metformin be used to treat pediatric patients with insulin resistance? Presented at the Pediatric Academic Societies’ 2006 Annual Meeting. April 29 – May 2, 2006. San Francisco.