Childhood-onset obesity presages the development of disorders that predispose to cardiovascular disease in later life (47
). Prevention of the complications of obesity, including type 2 diabetes, thus is a primary medical goal for weight-reduction therapy in children. On the basis of evidence suggesting that adolescents given metformin have salutary changes in adiposity and obesity-related comorbid conditions (27
) and data from adults suggesting that metformin can delay the incidence of type 2 diabetes (22
), we tested the hypothesis that metformin could improve glucose homeostasis and decrease the weight and body fat gained by obese insulin-resistant 6- to 12-year-old children who participated in a low-intensity clinic-based weight-reduction program.
Metformin produced modest differences in BMI Z
that, as found for adolescents (33
), largely persisted during 1 year of treatment. Compared with placebo treatment, metformin improved several other measures of body fatness, although consistent with some (33
) but not all (29
) studies, metformin did not significantly change intra-abdominal adipose tissue. As might be anticipated because of its major effect to suppress hepatic gluconeogenesis (14
), metformin improved fasting insulin, glucose, and the HOMA-IR index, measures of insulin sensitivity that appear principally to reflect hepatic sensitivity to insulin’s actions (49
), but metformin did not greatly alter whole-body (primarily muscle) insulin sensitivity. Among young adult Israeli army recruits, individuals with fasting glucose concentrations >86 mg/dL had monotonically increasing risks for developing diabetes during ~6 years of follow-up (50
). Our subjects’ mean baseline plasma glucose was 92 mg/dL, decreasing slightly among metformin-treated children but increasing an additional 3.5 mg/dL in the placebo-treated group. The finding that metformin enabled study subjects to maintain fasting plasma glucose at a lower level suggests the possibility that metformin treatment might prevent or delay the onset of type 2 diabetes in children at high risk for this disorder. Other aspects of the insulin resistance–related metabolic syndrome did not change significantly with metformin treatment. The limited weight change observed, perhaps combined with the worsening of whole-body insulin resistance that commonly occurs as children enter adolescence, may account for the failure to find greater improvements in metabolism as a result of metformin treatment in this and prior studies conducted among adolescents (33
Metformin therapy was associated with dose-limiting side effects in almost 17% of participants, particularly among younger subjects. Inability to tolerate 2,000 mg/day despite efforts made to reach the full dose may have limited the efficacy that could be observed. To some extent, the variability in the dose administered makes determination of metformin’s efficacy more difficult. Our data suggest that a target total daily dose of 2,000 mg/day may not be achievable for all young children treated with metformin. Other studies report good toleration of lower doses (39
) but a similar side effect profile among adolescents treated with 2,000 mg/day extended-release metformin (33
). In addition to nausea and loose stools, we also observed fatigue symptomatology previously reported among children given metformin. Lastly, there was a relative diminution of serum vitamin B12
despite provision of a cyanocobalamin-containing multivitamin. B12
deficiency is unlikely to be reported among children treated with metformin because a long period of inadequate dietary B12
intake is required before clinical deficiency becomes manifest, but metformin has been reported to diminish serum B12
by 14–30% in adults, with the greatest effects observed among individuals treated with metformin for the longest time at the highest dosage (51
). Our data reinforce the importance of monitoring potential adverse events among patients treated chronically with metformin.
Although this study is among the largest randomized controlled trials to date of a pharmacotherapeutic agent conducted for amelioration of obesity among young children, a limitation of this study is that only 100 children were studied; thus, there may have been insufficient power to detect differences between placebo- and metformin-treated groups for some obesity-related comorbid conditions examined. The placebo-controlled interval was only 6 months in duration and the maximal treatment duration was 1 year; thus, the study did not explore the efficacy of metformin in the longer term, which is required for a chronic condition like obesity. The study’s generalizability is also somewhat limited by the fact that only severely obese insulin-resistant children were enrolled; it remains unclear how efficacious metformin is among children who are less obese and insulin resistant. Wilson et al. (33
) have found quite similar results among adolescents who were not required to have insulin resistance. Finally, because the weight loss intervention was intended to model to some extent what might be available in clinical practice, it consisted solely of monthly visits with a dietitian, and the magnitude of metformin-associated weight reduction that might occur among children treated with an intensified behavioral modification regimen is not established. Strengths include the recruitment of children who were racially and ethnically diverse, the use of intensive assessments of body composition and insulin sensitivity, the careful determination of adverse events using structured reporting tools, and the excellent subject retention rate.
We conclude that metformin treatment modestly reduces body weight and adiposity and improves measures of glucose homeostasis in obese insulin-resistant 6- to 12-year-old children. Although the weight loss produced is small, metformin treatment may hold promise as a method to prevent or delay the appearance of impaired glucose homeostasis in children at high risk for the development of type 2 diabetes.