The Journal of Pediatrics
Volume 152, Issue 6 , Pages 750-752, June 2008

Metformin as a Weight-Loss Tool in “At-Risk” Obese Adolescents: A Magic Bullet?

  • Josephine Z. Kasa-Vubu, MD, MS

      Affiliations

    • Corresponding Author InformationReprint requests: Josephine Z. Kasa-Vubu, MD, MS, Department of Pediatrics, Endocrine Division, University of Michigan Medical Center, Ann Arbor, MI 48019-0718.

Department of Pediatrics, Division of Pediatric Endocrinology, University of Michigan Health System, Ann Arbor, Michigan

Article Outline

Abbreviations: IGT, Impaired glucose tolerance

 

The list of predictors of childhood overweight has gotten longer and more varied and includes maternal history of gestational diabetes mellitus,1 birth weight, weight velocity during infancy,2 parental perceptions,3 precocious adrenarche,4, 5 urban planning,6, 7 voluntary exercise,8 and involuntary exercise.9 Although new perspectives on obesity have broadened the range of possible targets for prevention, lifestyle changes remain the cornerstone of all weight-loss strategies, regardless of age.

See related article, p 817

In contrast to type 1 diabetes mellitus, which is not related to body weight,10 obesity predisposes patients to type 2 diabetes mellitus. Indeed, the childhood obesity epidemic has redefined the natural history of type 2 diabetes mellitus, which now affects younger individuals and can masquerade as type 1 diabetes mellitus.10 Obesity is an insulin-resistant state, especially when it is associated with a sedentary lifestyle,11 central adiposity,12 or both. In adults, fasting hyperinsulinemia characteristic of insulin resistance can predate the onset of type 2 diabetes mellitus for several years, as suggested by the presence of complications at the time of diagnosis.13 The insidious loss of beta cell function that accompanies the onset of so-called “pre-diabetic” states and the resulting post-prandial hyperglycemia, can span several years, if not decades, before detection. In youth however, the transition from pre-diabetes to frank type 2 diabetes mellitus may occur in a matter of months rather than years.14 The potentially more aggressive nature of type 2 diabetes mellitus in youth underscores the need for prevention. Adding to the alarm are recent reports of enhanced cardiovascular risk in obese children with microalbuminuria.15

There is agreement that children who are at risk may benefit from screening if it results in the delay or prevention of type 2 diabetes mellitus at a young age. In screening for long-term metabolic risk, the same challenges documented in the adult population apply to youth.16 The lack of consensus on suitable metabolic predictors for this age group add a level of uncertainty.17, 18, 19 For example, fasting glucose level is of limited value in identifying metabolic risk in the adolescent population.20 Thus, the oral glucose tolerance test is recommended as a screening tool for obese adolescents with significant metabolic risk.20 Once there is evidence of altered glucose metabolism as indicated by an elevated fasting insulin level, impaired fasting glucose (IFG), or impaired glucose tolerance (IGT), the physician needs to explore the tools available to decrease the long-term risk for metabolic deterioration toward type 2 diabetes mellitus.

Puberty accelerates the development of type 2 diabetes mellitus in populations at risk, including obese first-degree relatives of affected patients, particularly when they have a non-Caucasian background.21, 22 Obesity during puberty has an additive effect to the insulin resistance inherent to puberty, when insulin-like growth factor 1 reaches life-time peak concentrations.23 Because of the considerable financial cost and high failure rates of behavioral weight loss programs,24 pharmacotherapy for the treatment of obesity is an attractive option.

Most drugs are initially tested, then approved for use in adults, and metformin is no exception. In North American adults with IGT, metformin reduced the rate of conversion to type 2 diabetes mellitus after 3 years by 30%, and an intensive lifestyle intervention reduced the rate of conversion by 58% compared with placebo.25 Similar results were reported for an Indian population with comparable metabolic characteristics.26

In this issue of The Journal, Love-Osborne et al27 present a study in which they evaluated the effectiveness of metformin as a weight loss agent when added to a lifestyle intervention in adolescents with risk factors for type 2 diabetes mellitus and insulin resistance defined by a fasting insulin level >25 μU/mL. A secondary outcome was improvement in glucose tolerance. They randomized 85 adolescents to receive either metformin or placebo in a ratio of 2-to-1. They observed that there were no differences in weight change between the metformin group and the placebo group. However, with further analysis, they determined that adherence to metformin and reduction of portion size were significantly associated with a body mass index decrease >5% after 6 months.

The authors are to be commended on their use of a double-blind randomized design. They purposely applied a lifestyle intervention that is applicable in a private practice setting. Although their outreach into the community for follow-up might not be always feasible, it demonstrated an admirable willingness to reach out to at-risk youth. Despite these efforts to optimize follow-up, the dropout rate was substantial, highlighting the immense challenge of implementing weight-loss programs for high-risk adolescents.

The data presented suggest that metformin might increase the odds of weight loss when there is adherence to treatment and when there is a reduction in caloric intake as reflected by a decrease in portion size. However, the results also suggest that, overall, the odds of continuing to gain weight after the initiation of metformin are greater than those of losing weight, because 42% of patients were heavier at the end of treatment, compared with 23% of patients who lost weight. When taking into account adherence and reducing portion size, the odds are better, but still quite modest: The best case scenario could be represented by an adolescent girl who weighs 250 lb and can expect to loose approximately 12 lb after 6 months of reducing portion sizes and taking metformin.

The decision to randomize in a 2-to-1 ratio of active intervention versus placebo likely facilitated enrollment. However, as a result of differential attrition, the number in the placebo group was reduced, thereby limiting the power to detect differences in the treatment groups. There was not sufficient power to show whether motivation and reduced portion size could promote weight loss regardless of the addition of metformin.

More than two-thirds of participants were female. This should come as no surprise because non-Caucasian obese adolescent girls outnumber obese adolescent boys, and the prevalence of extreme obesity (body mass index ≥40) is twice as high in adult women as it is in men.28 The use of metformin as a means to facilitate weight loss in young women of reproductive age has been reported before in studies related to polycystic ovary syndrome. Because obesity and insulin resistance are strongly linked to androgen excess in women,29 there is reasonable likelihood of emerging polycystic ovary syndrome30 in the adolescents studied by Love-Osborne and collaborators. If that is the case, then their response to metformin treatment would be consistent with earlier studies reporting improved insulin sensitivity with metformin and weight loss31 as long as there was evidence of lifestyle changes.32 In boys, the difference in response to metformin needs a closer look, with larger numbers than those reached in the study. The diverging patterns of response between boys and girls might reflect, as the authors suggest, a different physiology, but it might also be the result of differences in body composition,2 which can be very dramatic at this young age, particularly when there is a substantial increase in muscle mass with puberty. Because the age group studied spanned from early adolescence to young adulthood, pubertal status and growth velocity are likely to have modulated the response to treatment in pubescent boys. Boys may also have responded differently to the education program for lifestyle changes.

In the adolescents at risk for type 2 diabetes mellitus enrolled in the study, the rates of IFG and IGT were <10%, and the combination of both defects was <5%. Thus the ability to detect future diabetes mellitus risk on the basis of these metabolic variables is likely to be low in youth.17 At the end of treatment, there was no improvement in glucose or insulin variables in the groups, but there were only 7 participants with altered glucose metabolism remaining in the treatment group, making it difficult to generalize the results. In contrast to this, the systolic blood pressure reported was elevated considering the young age of the participants, and whether there was any effect from the lifestyle intervention on this important metabolic variable is not reported.

Finally, it is important to recognize that the recruited participants had an increased risk of diabetes mellitus on the basis of family history, clinical presentation, biochemical features, and non-Caucasian ethnic background. The authors comment that the results might have been different in a population with a higher proportion of Caucasian subjects because there is evidence that as a population they may be more responsive to metformin. These observations highlight that sex and ethnicity do matter and that there is not a “one size fits most” approach when it comes to the treatment of obesity. Much work needs to be done in addressing health disparities and ethnic differences in the rates of obesity and the associated metabolic risk in populations that bear a disproportionate burden of disease. Even when there are some difficulties in recruiting racially diverse populations, the reporting of all ethnic groups involved will provide useful information for subsequent metanalyses, with the ultimate goal of tailoring the management of obesity and maximizing response to treatment.

In conclusion, the addition of metformin to lifestyle modification may enhance weight loss in adolescents who are motivated to reduce their portion sizes. One of the greatest hurdles in achieving weight loss is the articulation of realistic goals and persistence. The modest results achieved by the most successful participants in this study should serve as a reference to health care providers in adolescent weight clinics across the country as they set goals for their patients. The same modest results (or lack thereof) may also have fueled the dropout rate and bring into question the most common target for lifestyle intervention: absolute weight loss. Is it a sufficient target, and if not, what additional target(s) should be included after lifestyle intervention? Most important, how we can convince obese adolescents with a documented increased risk for diabetes mellitus to adhere to a weight-loss program long enough to see results, is an open question. If they can be convinced, then metformin might be of some help, but only if they eat less. Metformin is not a magic bullet, but is worth a try as long as there is a weight loss program that is meaningful to the patient33 and as long as alternate plans are agreed on when there is no response after a pre-determined duration of treatment.

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PII: S0022-3476(08)00198-4

doi:10.1016/j.jpeds.2008.03.006

Refers to article:

  • Addition of Metformin to a Lifestyle Modification Program in Adolescents with Insulin Resistance , 20 March 2008

    Kathy Love-Osborne, Jeanelle Sheeder, Phil Zeitler
    The Journal of Pediatrics June 2008 (Vol. 152, Issue 6, Pages 817-822)

The Journal of Pediatrics
Volume 152, Issue 6 , Pages 750-752, June 2008

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