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

Abstract

The list of predictors of childhood overweight has gotten longer and more varied and includes maternal history of gestational diabetes mellitus,1Metzger B.E. Long-term outcomes in mothers diagnosed with gestational diabetes mellitus and their offspring.Clin Obstet Gynecol. 2007; 50: 972-979Crossref PubMed Scopus (208) Google Scholar birth weight, weight velocity during infancy,2Bouhours-Nouet N. Dufresne S. de Casson F.B. Mathieu E. Douay O. Gatelais F. et al.High birth weight and early postnatal weight gain protect obese children and adolescents from truncal adiposity and insulin resistance: metabolically healthy but obese subjects?.Diabetes Care. 2008; (In press)PubMed Google Scholar parental perceptions,3Watkins M.G. Clark K.M. Foster C.M. Welch K.B. Kasa-Vubu J.Z. Relationships among body mass index, parental perceptions, birthweight and parental weight after referral to a weight clinic.J Natl Med Assoc. 2007; 99: 908-913PubMed Google Scholar precocious adrenarche,4de Zegher F. Ibanez L. Prenatal growth restraint followed by catch-up of weight: a hyperinsulinemic pathway to polycystic ovary syndrome.Fertil Steril. 2006; 86: S4-S5Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 5Vuguin P. Grinstein G. Freeman K. Saenger P. DiMartino Nardi J. Prediction models for insulin resistance in girls with premature adrenarche The premature adrenarche insulin resistance score: PAIR score.Horm Res. 2006; 65: 185-191Crossref PubMed Scopus (12) Google Scholar urban planning,6Lumeng J.C. Appugliese D. Cabral H.J. Bradley R.H. Zuckerman B. Neighborhood safety and overweight status in children.Arch Pediatr Adolesc Med. 2006; 160: 25-31Crossref PubMed Scopus (166) Google Scholar, 7Sallis J.F. Glanz K. The role of built environments in physical activity, eating, and obesity in childhood.Future Child. 2006; 16: 89-108Crossref PubMed Scopus (488) Google Scholar voluntary exercise,8Taylor R.W. McAuley K.A. Williams S.M. Barbezat W. Nielsen G. Mann J.I. Reducing weight gain in children through enhancing physical activity and nutrition: the APPLE project.Int J Pediatr Obes. 2006; 1: 146-152Crossref PubMed Scopus (54) Google Scholar and involuntary exercise.9Levine J.A. Nonexercise activity thermogenesis—liberating the life-force.J Intern Med. 2007; 262: 273-287Crossref PubMed Scopus (141) Google Scholar 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 See related article, p 817 In contrast to type 1 diabetes mellitus, which is not related to body weight,10Silverstein J. Klingensmith G. Copeland K. Plotnick L. Kaufman F. Laffel L. et al.Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association.Diabetes Care. 2005; 28: 186-212Crossref PubMed Scopus (1051) Google Scholar 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.10Silverstein J. Klingensmith G. Copeland K. Plotnick L. Kaufman F. Laffel L. et al.Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association.Diabetes Care. 2005; 28: 186-212Crossref PubMed Scopus (1051) Google Scholar Obesity is an insulin-resistant state, especially when it is associated with a sedentary lifestyle,11Kasa-Vubu J.Z. Lee C.C. Rosenthal A. Singer K. Halter J.B. Cardiovascular fitness and exercise as determinants of insulin resistance in postpubertal adolescent females.J Clin Endocrinol Metab. 2005; 90 (Epub 2004 Nov 30): 849-854Crossref PubMed Scopus (56) Google Scholar central adiposity,12Maffeis C. Banzato C. Talamini G. Waist-to-height ratio, a useful index to identify high metabolic risk in overweight children.J Pediatr. 2008; 152: 207-213Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar 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.13Harris M.I. Klein R. Welborn T.A. Knuiman M.W. Onset of NIDDM occurs at least 4-7 years before clinical diagnosis.Diabetes Care. 1992; 15: 815-819Crossref PubMed Scopus (1085) Google Scholar 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.14Saad R. Gungor N. Arslanian S. Progression from normal glucose tolerance to type 2 diabetes in a young girl: longitudinal changes in insulin sensitivity and secretion assessed by the clamp technique and surrogate estimates.Pediatr Diabetes. 2005; 6: 95-99Crossref PubMed Scopus (38) Google Scholar 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.15Nguyen S. McCulloch C. Brakeman P. Portale A. Hsu C.Y. Being overweight modifies the association between cardiovascular risk factors and microalbuminuria in adolescents.Pediatrics. 2008; 121: 37-45Crossref PubMed Scopus (70) Google Scholar 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.16Kahn R. Metabolic syndrome: is it a syndrome? Does it matter?.Circulation. 2007; 115: 1806-1811Crossref PubMed Scopus (128) Google Scholar The lack of consensus on suitable metabolic predictors for this age group add a level of uncertainty.17Goodman E. Daniels S.R. Meigs J.B. Dolan L.M. Instability in the diagnosis of metabolic syndrome in adolescents.Circulation. 2007; 115: 2316-2322Crossref PubMed Scopus (186) Google Scholar, 18Yamada S. Tsukamoto Y. Irie J. Waist circumference in metabolic syndrome.Lancet. 2007; 370: 1541-1542Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 19Zimmet P. Alberti G. Kaufman F. Tajima N. Silink M. Arslanian S. et al.The metabolic syndrome in children and adolescents.Lancet. 2007; 369: 2059-2061Abstract Full Text Full Text PDF PubMed Scopus (706) Google Scholar For example, fasting glucose level is of limited value in identifying metabolic risk in the adolescent population.20Weiss R. Taksali S.E. Tamborlane W.V. Burgert T.S. Savoye M. Caprio S. Predictors of changes in glucose tolerance status in obese youth.Diabetes Care. 2005; 28: 902-909Crossref PubMed Scopus (288) Google Scholar Thus, the oral glucose tolerance test is recommended as a screening tool for obese adolescents with significant metabolic risk.20Weiss R. Taksali S.E. Tamborlane W.V. Burgert T.S. Savoye M. Caprio S. Predictors of changes in glucose tolerance status in obese youth.Diabetes Care. 2005; 28: 902-909Crossref PubMed Scopus (288) Google Scholar 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.21Gahagan S. Silverstein J. Prevention and treatment of type 2 diabetes mellitus in children, with special emphasis on American Indian and Alaska Native children American Academy of Pediatrics Committee on Native American Child Health.Pediatrics. 2003; 112: e328Crossref PubMed Google Scholar, 22Goran M.I. Ball G.D. Cruz M.L. Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents.J Clin Endocrinol Metab. 2003; 88: 1417-1427Crossref PubMed Scopus (570) Google Scholar 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.23EndocrineSciences aEC. 3rd ed. Las Calabasa, California2003Google Scholar Because of the considerable financial cost and high failure rates of behavioral weight loss programs,24Kruger J. Galuska D.A. Serdula M.K. Jones D.A. Attempting to lose weight: specific practices among US adults.Am J Prev Med. 2004; 26: 402-406Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar 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.25Ratner R.E. An update on the Diabetes Prevention Program.Endocr Pract. 2006; 12: 20-24Crossref PubMed Google Scholar Similar results were reported for an Indian population with comparable metabolic characteristics.26Ramachandran A. Snehalatha C. Mary S. Mukesh B. Bhaskar A.D. Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1).Diabetologia. 2006; 49: 289-297Crossref PubMed Scopus (1291) Google Scholar In this issue of The Journal, Love-Osborne et al27Love-Osborne K. Sheeder J. Zeitler P. Addition of metformin to a lifestyle modification program in adolescents with insulin resistance.J Pediatr. 2008; 152: 817-822Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar 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.28Ogden C.L. Carroll M.D. Curtin L.R. McDowell M.A. Tabak C.J. Flegal K.M. Prevalence of overweight and obesity in the United States, 1999-2004.JAMA. 2006; 295: 1549-1555Crossref PubMed Scopus (7321) Google Scholar 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,29Ehrmann D.A. Barnes R.B. Rosenfield R.L. Cavaghan M.K. Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.Diabetes Care. 1999; 22: 141-146Crossref PubMed Scopus (1035) Google Scholar there is reasonable likelihood of emerging polycystic ovary syndrome30McCartney C.R. Prendergast K.A. Chhabra S. Eagleson C.A. Yoo R. Chang R.J. et al.The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism.J Clin Endocrinol Metab. 2006; 91 (Epub 2006 Feb 21): 1714-1722Crossref PubMed Scopus (136) Google Scholar 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 loss31Arslanian S.A. Lewy V. Danadian K. Saad R. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance.J Clin Endocrinol Metab. 2002; 87: 1555-1559Crossref PubMed Scopus (210) Google Scholar as long as there was evidence of lifestyle changes.32Hoeger K.M. Kochman L. Wixom N. Craig K. Miller R.K. Guzick D.S. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study.Fertil Steril. 2004; 82: 421-429Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar 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,2Bouhours-Nouet N. Dufresne S. de Casson F.B. Mathieu E. Douay O. Gatelais F. et al.High birth weight and early postnatal weight gain protect obese children and adolescents from truncal adiposity and insulin resistance: metabolically healthy but obese subjects?.Diabetes Care. 2008; (In press)PubMed Google Scholar 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.17Goodman E. Daniels S.R. Meigs J.B. Dolan L.M. Instability in the diagnosis of metabolic syndrome in adolescents.Circulation. 2007; 115: 2316-2322Crossref PubMed Scopus (186) Google Scholar 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 patient33Kumanyika S.K. Special issues regarding obesity in minority populations.Ann Intern Med. 1993; 119: 650-654Crossref PubMed Google Scholar and as long as alternate plans are agreed on when there is no response after a pre-determined duration of treatment. Addition of Metformin to a Lifestyle Modification Program in Adolescents with Insulin ResistanceThe Journal of PediatricsVol. 152Issue 6PreviewTo evaluate whether metformin, when added to a program of personal goal setting, improves weight loss and clinical status in obese adolescents. Full-Text PDF