Metformin Treatment of Pediatric Obesity

Childhood obesity has steadily become a contemporary epidemic with serious public health implications.¹  Approximately 70% of children with obesity will remain obese in adulthood.²  Obesity is a risk factor for development of atherosclerosis and type 2 diabetes mellitus (T2DM),³  and its prevention and management represents a priority for pediatric primary care providers. This underscores the need for evidence-based interventions for children and adolescents with obesity, including pharmacotherapy.⁴ 

Metformin is US Food and Drug Administration (FDA) approved for use in children 10 years of age and older with T2DM and has been used off label to achieve weight loss in children. In the current issue of Pediatrics, Masarwa et al⁵  present a systematic review of the safety and efficacy of metformin use from randomized controlled trials (RCTs) in children and adolescents. The authors demonstrated that metformin therapy resulted in modest benefits in reduction of BMI in those with obesity. Among the 14 RCTs in which BMI was reported, metformin was modestly efficacious at decreasing BMI (range of mean changes: −2.70 to 1.30) compared with a placebo (−1.12 to 1.90). As pointed out by the authors, the results across the studies were heterogeneous, with 11 RCTs suggesting that it decreased BMI, whereas 3 RCTs revealed an increase in BMI. Among the 7 RCTs in which a BMI z score was reported, metformin consistently resulted in a decrease in the BMI z score (range of mean changes: −0.37 to −0.03) when compared with a placebo (−0.22 to 0.15), with the largest decrease in BMI z score observed in children and adolescents with nonalcoholic fatty liver disease. Among the 11 RCTs in which insulin resistance was examined, metformin resulted in modest but favorable effects on insulin resistance. Metformin therapy, however, was associated with a doubling of the rate of gastrointestinal adverse events compared with a placebo. This brings up the issue of whether metformin is a reasonable adjunct to behavioral and lifestyle modifications for treatment of childhood obesity.

Options for weight management in pediatric patients are significantly limited.^6,7  Lifestyle modification therapy, which incorporates nutritional, physical activity, and behavior modification, has been the mainstay of management, for both children and adults. Although successful weight loss is underpinned by lifestyle modification, achieving durable weight loss by this approach is challenging. The biology of weight gain and the regulation of appetite, satiety, and energy use through basal metabolism and exercise are tightly controlled by central and peripheral mechanisms that undermine the ability to lose weight. Therefore, additional therapies, such as pharmacologic treatments, are attractive options before proceeding to bariatric surgery.

Several antiobesity drugs have been approved by the FDA for use among adult patients with obesity, and numerous clinical trials have been conducted to support their use.⁸  In children, the only FDA-approved pharmacotherapies for obesity are orlistat and liragutide in persons 12 and older and phenteremine in persons 16 years of age and older. Orlistat has been associated with modest BMI reduction but may cause intolerable gastrointestinal side effects and possible fat-soluble vitamin deficiency. Phentermine is approved for short-term therapy only and may increase heart rate and blood pressure and cause irritability and insomnia. Long-term studies of its use in children are not available. Glucagon-like peptide-1 receptor agonist, such as liraglutide, is a second-line treatment for T2DM in adolescents. Liragutide is approved for obesity in adults since 2014 and has shown weight loss in obese adolescents in a RCT.⁷  About 43% of liragutide treated patients and 18% of placebo patients had a 5% reduction in BMI and in 26% and 8% respectively, a reduction of 10% was seen. It was recently approved by the FDA for treatment of pediatric obesity in December 2020. The dose for obesity differs from the dose for T2DM. It is approved for use in adolescents >12 years of age with a body weight of >60 kg and a BMI for age and sex corresponding to 30 kg/m2 or greater in adults, as an adjunct to reduced calorie diet and increased physical activity. Its use is limited by the need for daily subcutaneous injections and high frequency of gastrointestinal side effects and high cost.

The combination of topiramate and phentermine is available in adults for weight management. Small studies in children of topiramate alone suggest meaningful weight loss may occur, but its use has been associated with cognitive dysfunction.⁹  Other weight loss agents approved in adults include lorcaserin, a 5-hydroxytryptamine receptor 2C agonist, and naltrexone and bupropion. Setmelanotide, a melanocortin-4-receptor agonist was recently approved by the FDA for children >6 years with monogenic obesity due to three rare genetic conditions: pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency. There are several other drugs that are in pediatric trials for monogenic obesity.¹⁰ 

Understandably, those caring for children with moderate or severe obesity are looking for adjuncts to lifestyle modification to promote weight loss. In a recent study, Borzutzky et al⁴  indicated that antiobesity pharmacotherapy prescribing appears to be increasing among providers treating pediatric obesity despite the lack of FDA approval for such drugs in youth. According to the study, metformin was the most prescribed drug for obesity in 2014, and topiramate was the most prescribed drug for obesity in 2017.

Metformin reduces hepatic glucose production, decreases intestinal glucose absorption, and increases peripheral insulin sensitivity and may reduce appetite by raising glucagon-like peptide-1 levels. Its precise mechanism of action for weight reduction is not completely understood. It has a reasonable safety profile, and its gastrointestinal side effects can be minimized by slowly increasing the dosage. The sustainability of metformin effects on weight loss is unknown, such that most authors recommend that metformin be reserved for use in T2DM and, perhaps, polycystic ovary syndrome in youth.

Ideally, children with obesity should be entered into a clinical trial rather than placed on an off-label medication. Metformin is a low-cost option and may provide modest clinical benefit for weight loss with minimal side effects. If lifestyle modification has been pursued but has achieved minimal weight loss, it may be reasonable to try an agent such as metformin as adjunctive therapy. Many gaps remain in the knowledge of effective and durable therapies for childhood obesity, which is more prevalent in families and neighborhoods with low socioeconomic status.¹¹  We clearly need novel cost-effective approaches and more clinical trials in children to help reduce the burden of this disease on our youth and on public health in general.

FDA

US Food and Drug Administration

RCT

randomized controlled trial

T2DM

type 2 diabetes mellitus