Metformin has a modest favorable effect on body mass index z score and insulin resistance in children and adolescents with obesity, compared with placebo, according to a systematic review of trial data.
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“The available evidence is of varying quality,” however, and the drug increases the likelihood of gastrointestinal adverse effects, reported Reem Masarwa, PharmD, PhD, and colleagues in Pediatrics. “Nonetheless, metformin may be considered for use as a pharmacologic therapy in this pediatric population because of its modest efficacy, availability, cost, and safety profile.”
The Food and Drug Administration has approved metformin for the treatment of type 2 diabetes in children and adolescents. Doctors have used the drug off label for weight loss in children with obesity, but this use “remains controversial,” the review authors said.
To assess the efficacy and safety of metformin plus lifestyle interventions compared with placebo plus lifestyle interventions in children and adolescents with obesity, Dr. Masarwa, with the Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, and the department of epidemiology, biostatistics, and occupational health, McGill University, Montreal, and colleagues systematically reviewed data from randomized controlled trials (RCTs). Their review was published online in Pediatrics.
The investigators focused on studies that examined outcomes such as body mass index, BMI z score, insulin resistance, and gastrointestinal adverse effects. They excluded studies of children with type 2 diabetes.
The researchers included 24 RCTs in their review. The studies included 1,623 children and adolescents who received metformin (861 participants) or placebo (762 participants). Indications included uncomplicated obesity in 10 studies, obesity with insulin resistance in 9 studies, prediabetes in 3 studies, and nonalcoholic fatty liver disease in 2 studies. One of the trials did not incorporate a lifestyle cointervention.
Participants ranged in age from 4 years to 19 years, and trial durations ranged from 2 months to 2 years. The total daily dose of metformin ranged from 500 mg to 2,000 mg.
In 14 RCTs that reported BMI, metformin generally decreased BMI (range of mean changes: –2.70 to 1.30), compared with placebo (range of mean changes: –1.12 to 1.90), although three trials suggested that metformin increased BMI. The average difference in the treatment effect between the metformin and placebo groups ranged from –2.72 to 0.70. “Importantly, the authors of many RCTs reported variable treatment effects, preventing definitive conclusions from being drawn from individual trials,” Dr. Masarwa and coauthors wrote.
In seven RCTs that reported BMI z score, metformin consistently decreased BMI z score (range of mean changes: –0.37 to –0.03), compared with placebo (range of mean changes: –0.22 to 0.15). The mean difference in the treatment effect between treatment groups ranged from –0.15 to –0.07. The largest decrease occurred in patients with nonalcoholic fatty liver disease.
The rate of gastrointestinal adverse events nearly doubled with metformin treatment, relative to placebo (rate range: 2%-74% for metformin vs. 0%-42% for placebo).
Metformin adherence rates ranged from 60% to 90%, and lifestyle cointerventions varied substantially across the trials, the researchers noted. The clinical significance and long-term effects of metformin treatment in this population “remain uncertain,” they said.