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Metformin for Obesity in Children: Questions Still Remain

Among obese children without diabetes, metformin improves body mass index (BMI) and inflammatory and cardiovascular-related obesity parameters in prepubertal children but not in pubertal children, a new study shows.

Belén Pastor-Villaescusa, PhD, from the University of Granada, Spain, and colleagues published  the results of their randomized controlled trial (RCT) online June 12 in Pediatrics.  

"A lack of effect of metformin in the pubertal children who were obese might be related to the lower doses used for these subjects (milligrams of metformin per kilograms of body weight), providing dose-dependent efficacy according to body weight," the authors write.

Childhood obesity is a challenging healthcare issue, and although making lifestyle changes can help to reverse the problem, this is often insufficient as a single management strategy.

However, although metformin treatment effectively induces substantial weight loss in adults who are obese, evidence for its effectiveness in managing pediatric obesity is lacking. And although puberty could potentially modify the effect of metformin in children, RCTs have not accounted for this in their study design.

Dr Pastor-Villaescusa and colleagues therefore conducted an RCT to examine the effect of metformin (1 g/d) compared with placebo in children who are obese. The study used, for the first time, a design to stratify participants according to sex and pubertal stage (based on the Tanner scale of physical development).

The prospective, double-blind, placebo-controlled trial was conducted at four hospitals in Spain and included 140 obese children (72 boys) who were nondiabetic. The children's ages ranged from 6.8 years to 15.3 years, with 67 categorized as prepubertal (Tanner stage I) and 73 as pubertal (Tanner stages I to V).

The study's primary outcome was a reduction in body mass index (BMI) z score. Secondary outcomes included insulin resistance, cardiovascular risk, and inflammation biomarkers.

Metformin treatment for 6 months resulted in a significantly decreased BMI z score compared with placebo in prepubertal children (-0.8 vs -0.6; difference, 0.2; P = .04). It also significantly improved inflammatory and cardiovascular-related obesity parameters in these children, including the quantitative insulin sensitivity check index ( 0.010 vs -0.007; difference, 0.017; P = .01), the adiponectinleptin ratio (0.96 vs 0.15; difference, 0.81; P = .01), interferon-? (-5.6 vs 0; difference, 5.6; P = .02) and total plasminogen activator inhibitor-1 (-1.7 vs 2.4; difference, 4.1; P = .04).

In contrast, however, metformin treatment in pubertal children resulted in no significant effect compared with placebo on BMI z score (P = .19). It also did not significantly improve quantitative insulin sensitivity check index (P = .60), adiponectin–leptin ratio (P = .32), interferon-? (P = .37), or total plasminogen activator inhibitor-1 (P = .79).

Overall, the children tolerated metformin treatment well, and none had to stop treatment because of serious adverse effects.

The authors suggest that the lack of effect of metformin in pubertal children might relate to the relatively lower doses of the drug used in these participants. Both groups of children received the same dose of metformin (500 mg twice daily), so the lack of effect in the pubertal children may have been because the dose was approximately 50% lower on a milligram per kilogram basis.

Dr Pastor-Villaescusa and colleagues also acknowledge the limitations of their study, including the difficulties in evaluating the children's treatment adherence by using pill counts and in assessing their lifestyle changes.

Nevertheless, the authors conclude that their findings highlight puberty as "an important physiologic stage that plays a key role in the differential response to metformin that should be explored further, particularly in terms of the dose–effect relationships."

In an accompanying editorial, Paul Kaplowitz, MD, PhD, from Children's National Health System, Washington, DC, expresses disappointment that metformin was effective only in the prepubertal children.

However, he concurs with the authors' opinion that the lack of effect in the pubertal group may relate to a dose-dependent efficacy of metformin according to body weight.   

"Most other published metformin-obesity studies have used escalating doses up to either 850 mg or 1000 mg twice daily," he notes. Other such studies have reduced BMI in teenagers and in children younger than 12 years, he says, so there is no evidence that puberty per se reduces the efficacy of metformin.

And because most of these metformin-obesity studies have also lasted 6 months or less, Dr Kaplowitz also wonders whether longer treatment duration would further reduce BMI.

Dr Kaplowitz emphasizes that the findings of Dr Pastor-Villaescusa and colleagues' study leave more questions unanswered than answered. However, he acknowledges that the results suggest a limited role for metformin in treating some children with prediabetes and a strong family history of type 2 diabetes, or those who have substantially improved their lifestyle but remain challenged to lose weight.

"In such situations, it is suggested that clinicians push the dose, if tolerated, to the maximum recommended dose of 1000 mg twice daily to take advantage of the important effect of decreased appetite, which likely is a major factor accounting for its variable and modest effect on BMI," he concludes.

This study was supported by grants from the Spanish Ministry of Health, Social and Equality, General Department for Pharmacy and Health Products. The authors and editorialist have disclosed no relevant financial relationships.

Pediatrics. Published online June 12, 2017.

SOURCES:

Metformin for Obesity in Children: Questions Still Remain. Medscape. June 13, 2017.


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