Metformin lowers BMI in prepubertal but not pubertal children
Use of metformin for 6 months may yield reductions in body mass index (BMI), as well as improvements in inflammatory and cardiovascular-related obesity parameters in prepubertal but not pubertal children, according to a study.
The study equally randomized a total of 160 obese, nondiabetic children aged 7 to 14 years (50 percent male; BMI >95th percentiles) to receive either metformin 500 mg twice daily or placebo for 6 months. The children were grouped according to their pubertal stage: prepubertal (Tanner stage I; n=80) and pubertal (Tanner stages II to IV; n=80). None of the children had an underlying disease or history of pathology and received treatment for weight control in the previous 12 months.
At 6 months, with only 140 children completing the study, the primary outcome of a reduction in BMI z score was greater with metformin vs placebo in the prepubertal group (−0.8 vs −0.6; difference, 0.2; p=0.04). BMI z score was independently associated with metformin treatment (odds ratio, 0.18; 95 percent CI, 0.050 to 0.636; p=0.01) in binary logistic regression analysis. These observations, however, were not made in the pubertal group. [Pediatrics 2017;doi:10.1542/peds.2016-4285]
Other notable improvements observed with metformin vs placebo in the prepubertal group included increased quantitative insulin sensitivity check index (0.010 vs −0.007; difference, 0.017; p=0.01) and adiponectin–leptin ratio (0.96 vs 0.15; difference, 0.81; p=0.01), as well as decreased interferon-γ (−5.6 vs 0; difference, 5.6; p=0.02) and total plasminogen activator inhibitor-1 (−1.7 vs 2.4; difference, 4.1; p=0.04). No serious adverse effects were reported.
“Metformin has previously been found to be efficacious in childhood obesity, especially in reducing BMI z score, the most appropriate and precise internationally accepted body mass parameter for children,” the authors noted. “Previous investigators have reported similar effects of 1,500 to 2,000 mg/d after 6 months in prepubertal and pubertal children who are obese.” [Diabetes 2011;60:477–485; J Clin Endocrinol Metab 2013;98:322–329; 2006;91:2074–2080]
The authors pointed out that the lack of effect of metformin in obese pubertal children in the present study may be attributed to the lower doses used in the present study (mg per kg of body weight), providing dose-dependent efficacy according to body weight.
“Nevertheless, we cannot exclude the fact that the failure of a metformin effect … could also be due to the physiologic and hormonal changes in [the pubertal] stage. Indeed, puberty is associated with a marked decrease in insulin sensitivity, and an insulin-sensitizing therapy would therefore have to be increased proportionately to observe a similar effect in prepubertal children,” they said. [Curr Diab Rep 2016;16:64]
“Accordingly, future [trials] should consider higher doses of metformin for adolescents to obtain a beneficial effect, taking into account the maximum dosing described for youngsters aged 10 to 16 years (2,000 mg/d),” they added. [Pediatr Diabetes 2011;12:580–588]
Despite the presence of several limitations, including the use of pill count to assess treatment compliance as well as lifestyle changes in the children, the current data suggest that “puberty is 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,” the authors said.
Role of metformin in childhood obesity management
Dr Paul Kaplowitz from the George Washington University School of Medicine and the Health Sciences in Washington, US, wrote in an accompanying editorial that the effect metformin demonstrated on BMI over 6 months only in the prepubertal children was both unexpected and disappointing. [Pediatrics 2017;doi:10.1542/peds.2017-1205]
“The authors correctly point out that because they used the same relatively small dose of metformin in both groups, the failure to see an effect in the pubertal group may have been due to the metformin dose being ∼50 percent lower on a milligram per kilogram basis,” Dr Kaplowitz said.
He noted that a number of other published metformin-obesity studies have used escalating doses up to either 850 or 1,000 mg twice daily. Furthermore, some have reported a BMI reduction in teens as well as in children younger than 12 years. As such, there is no evidence that puberty per se weakens metformin responsiveness.
The key takeaway point from the current and other similar studies is that “[a]lthough metformin should not be considered standard of care for obesity, it may have a limited role in treating carefully selected patients with prediabetes and a strong family history of type 2 diabetes, or those who have made a major effort at improving their lifestyle and are frustrated by their inability to lose weight,” Dr Kaplowitz said.
“In such situations, it is suggested that clinicians push the dose, if tolerated, to the maximum recommended dose of 1,000 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 added.