Systematic review finds some benefits with agent, but supportive data are weak

The anti-diabetic medication metformin led to modest benefits on weight and insulin resistance in children and adolescents with obesity, although the evidence driving that conclusion was of “varying quality,” according to a systematic review from Canada.

The review of two dozen randomized controlled trials (RCTs; n=1,623 patients) showed that metformin resulted in a modest decrease in BMI, BMI z score, and homeostatic model assessment of insulin resistance (HOMA-IR) relative to placebo:

  • BMI: range of mean values −2.70 to 1.30 versus −1.12 to 1.90.
  • BMI z score: range of mean values −0.37 to −0.03 versus −0.22 to 0.15.
  • HOMA-IR: range of mean values −3.74 to 1.00 versus −1.40 to 2.66.

However, “the available evidence is of varying quality, with high drop-out rates, and higher-quality studies had smaller estimated treatment effects, suggesting some uncertainty in its clinical benefits,” stated Kristian B. Filion, PhD, of McGill University in Montreal, and co-authors.

Moreover, metformin therapy in this population resulted in a higher frequency of gastrointestinal adverse effects, including diarrhea, abdominal pain, epigastric pain, vomiting, nausea, and loose stool, with a range of 2% to 74% versus 0% to 42%, they reported in Pediatrics.

Use of the agent for weight loss in most kids is generally off-label, as metformin is not approved for use in patients ages <18 years in Canada, while in the U.S. it is currently FDA-approved as an oral medication in children ages >10 years with type 2 diabetes.

While Filion’s group revealed some good with “metformin therapy in pediatric patients with obesity,” the question remains as to whether it is “a reasonable adjunct to behavioral and lifestyle modifications for treatment of childhood obesity,” wrote Vandana Raman, MD, and Carol M. Foster, MD, both of the University of Utah School of Medicine in Salt Lake City, in a commentary accompanying the study.

They pointed out that lifestyle modification through better nutrition, physical activity, and behavior modification are viable ways to manage excess weight, yet “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.”

So, it’s not surprising that pharmacology-based obesity management for children and adolescents — FDA-approved orlistat, liraglutide, and phentereminetopiramate — offer “attractive options before proceeding to bariatric surgery,” Raman and Foster wrote.

However, all of those agents may carry serious side effects, such as fat-soluble vitamin deficiency, increased heart rate and blood pressure, and cognitive dysfunction, and they may come with delivery-restrictions (high cost, daily injections), they noted.

Still, according to the current study, “metformin was the most prescribed drug for obesity in 2014… [it] is a low-cost option and may provide modest clinical benefit for weight loss with minimal side effects” in the pediatric population, Raman and Foster wrote. Nonetheless, they cautioned that metformin’s “precise mechanism of action for weight reduction is not completely understood… The sustainability of metformin effects on weight loss is unknown… Ideally, children with obesity should be entered into a clinical trial rather than placed on an off-label medication.”

Filion and co-authors evaluated RCTs that assessed the efficacy and safety of metformin versus placebo, both with lifestyle interventions in children and adolescents with obesity. The ages ranged from 4 to 19 years, and follow-up ranged from two months to two years. They found that of the 24 RCTs, more than half were of “low to moderate quality. Nine trials had some concern of bias in the randomization process. A total of 14 RCTs had some concern for bias due to the selection of the reported outcomes.”

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The authors also highlighted the fairly high rates of loss to follow-up across the studies, from 5% to 80% among those randomized to metformin and from 5% to 50% among those randomized to a placebo. As a result, the treatment effects may have been attenuated and the loss “reveals the challenges of drug adherence among this population,” they wrote.

With regard to the modest efficacy of metformin versus placebo at cutting BMI, results across trials were “heterogeneous, with 11 RCTs suggesting that metformin decreases BMI and three RCTs suggesting that it increases BMI,” Filion’s group wrote. “Importantly, the authors of many RCTs reported variable treatment effects, preventing definitive conclusions from being drawn from individual trials.”

They added that future RCTs should use standardized lifestyle interventions, along with testing metformin monotherapy and combination therapy, to get a better handle of which pediatric patients with obesity will get the most from the agent. One such study is in the work in Canada: Researchers at the University of Alberta plan to assess a fiber-metformin combination therapy in adolescents with severe obesity and insulin resistance (estimated study completion date 2025).

Other future studies may be jumpstarted by data indicating that the pandemic has exacerbated the childhood obesity epidemic in the U.S. A 2021 report in the Journal of Pediatric Nursing stressed that “The once familiar environments of family, home, school, and community and their multi-factorial interactions have changed to unrecognizable scenarios, increasing stress for children and families. The impact of stress on both diseases, characterized by inflammation and weakened immune response and exacerbated by disparities, affects health, economic, and social outcomes. As healthcare providers focus on the comprehensive care of children and their families, a systematic assessment of their health and biopsychosocial needs is critical to the reduction of the negative impact of obesity and Covid-19.”

  1. Metformin had modest but favorable effects on weight and insulin resistance in children and adolescents with obesity.

  2. This systematic review found source evidence of varying quality, with high heterogeneity between randomzied controlled trials.

Shalmali Pal, Contributing Writer, BreakingMED™

Filion reported support from the Fonds de Recherche du Québec-Santé (FRQS) and a William Dawson Scholar award from McGill University. Co-authors reported support from FRQS and the Canadian Institutes of Health Research Drug Safety and Effectiveness Cross-Disciplinary Training Program.

Raman and Foster reported no relationships relevant to the contents of this paper to disclose.

Cat ID: 252

Topic ID: 85,252,730,795,252,518,917