Objective: Childhood obesity has become epidemic and has been accompanied by an increase in prevalence of type 2 diabetes (T2DM) in youth. Addressing obesity and insulin resistance by drug treatment represents a rational strategy for the prevention of T2DM. A systematic review was performed to evaluate the effectiveness of metformin in reducing weight and ameliorating insulin resistance in obese nondiabetic children. Methods: A PubMed database search was conducted, using ‘metformin', ‘obesity', ‘insulin resistance', ‘children', ‘adolescents' as search terms. Results: Eleven trials were included in the present review. Metformin was administered for 6-12 months at a dosage of 1,000-2,000 mg/daily, decreasing BMI by 1.1-2.7 compared with placebo or lifestyle intervention alone. Concomitantly, fasting insulin resistance improved after metformin therapy. Posttreatment follow-up was performed in one study, showing that after 1 year of discontinuation of therapy the decrease in BMI disappears. Conclusions: Short-term metformin treatment appears to moderately affect weight reduction in severely obese children and adolescents, with a concomitant improvement in fasting insulin sensitivity. Further studies with longer treatment period are needed to establish how much metformin can reduce weight and its real utility in preventing T2DM development in pediatric patients.

Keywords:
Metformin, Obesity, Children, Insulin resistance
1.
Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-1350.
2.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
3.
Goran MI, Ball GD, Cruz ML: Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents. J Clin Endocrinol Metab 2003;88:1417-1427.
4.
Crocker MK, Yanovski JA: Pediatric obesity and treatment. Pediatr Clin North Am 2011;58:1217.
5.
Catoira N, Nagel M, Di Girolamo G, De Gonzalez C: Pharmacological treatment of obesity in children and adolescents: current status and perspectives. Expert Opin Pharmacother 2010;11:2973-2983.
6.
Quinn SM, Baur LA, Garnett SP, Cowell CT: Treatment of clinical insulin resistance in children: a systematic review. Obesity Rev 2010;11:722-730.
7.
Bailey C, Turner RC: Metformin. N Engl J Med 1996;334:574-579.
8.
Brufani C, Fintini D, Nobili V, Patera PI, Cappa M, Brufani M: Use of metformin in pediatric age. Pediatr Diabetes 2011;12:580-588.
9.
TODAY Study Group: A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Eng J Med 2012;366:2247-2256.
10.
Nestler JE: Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008;358:47-54.
11.
Nobili V, Manco M, Ciampalini P, Alisi A, Devito R, Bugianesi E, Marcellini M, Marchesini G: Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther 2008;30:1168-1176.
12.
Hsia Y, Dawoud D, Sutcliffe AG, Viner RM, Kinra S, Wong ICK: Unlicensed use of metformin in children and adolescents in the UK. Br J Clin Pharmacol 2011;73:135-139.
13.
Park MH, Kinra S, Ward KJ, White B, Viner RM: Metformin for obesity in children and adolescents: a systematic review. Diabetes Care 2009;32:1743-1745.
14.
Matthews DR, Hosker JP, Rudenski AS: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-419.
15.
Freemark M, Bursey D: The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001;107:E55.
16.
Kay JP, Alemzadeh R, Langley G, D'Angelo L, Smith P, Holshouser S: Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism 2001;50:1457-1461.
17.
Srinivasan S, Ambler GR, Baur LA, Garnett SP, Tepsa M, Yap F, Ward GM, Cowell CT: Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab 2006;91:2074-2080.
18.
Atabek ME, Pirgon O: Use of metformin in obese adolescents with hyperinsulinemia: a 6-month, randomized, double-blind, placebo-controlled clinical trial. J Pediatr Endocrinol Metab 2008;21:339-348.
19.
Love-Osborne K, Sheeder J, Zeitler P: Addition of metformin to a lifestyle modification program in adolescents with insulin resistance. J Pediatr 2008;152:817-822.
20.
Burgert TS, Duran EJ, Goldberg-Gell R, Dziura J, Yeckel CW, Katz S, Tamborlane WV, Caprio S: Short-term metabolic and cardiovascular effects of metformin in markedly obese adolescents with normal glucose tolerance. Pediatr Diabetes 2008;9:567-576.
21.
Clarson CL, Mahmud FH, Baker JE, Clark HE, McKay WM, Schauteet VD, Hill DJ: Metformin in combination with structured lifestyle intervention improved body mass index in obese adolescents, but did not improve insulin resistance. Endocrine 2009;36:141-146.
22.
Wiegand S, l'Allemand D, Hübel H, Krude H, Bürmann M, Martus P, Grüters A, Holl RW: Metformin and placebo therapy both improve weight management and fasting insulin in obese insulin resistant adolescents: a prospective, placebo-controlled, randomized study. Eur J Endocrinol 2010;163:585-592.
23.
Rezvanian H, Hashemipour M, Kelishadi R, Tavakoli N, Poursafa P: A randomized, triple masked, placebo-controlled clinical trial for controlling childhood obesity. World J Pediatr 2010;6:317-322.
24.
Wilson DM, Abrams SH, Aye T, Lee PDK, Lenders C, Lusting RH, Osganian SV, Feldman HA: Metformin extended release treatment of adolescent obesity. Arch Pediatr Adolesc Med 2010;164:116-123.
25.
Yanovski JA, Krakoff J, Salaita CG, McDuffie JR, Kozlosky M, Sebring NG, Reynolds JC, Brady SM, Calis KA: Effects of metformin on body weight and body composition in obese insulin-resistant children. Diabetes 2011;60:477-485.
26.
Rynders C, Weltman A, Delgiorno C, Balagopal P, Damaso L, Killen K, Mauras N: Lifestyle intervention improves fitness independent of metformin in obese adolescents. Med Sci Sports Exerc 2012;44:786-792.
27.
Mauras N, DelGiorno C, Hossain J, Bird K, Killen K, Merinbaum D, Weltman A, Damaso L, Balagopal P: Metformin use in children with obesity and normal glucose tolerance-effects on cardiovascular markers and intrahepatic fat. J Pediatr Endocrinol Metab 2012;25:33-40.
28.
Kendall D, Vail A, Amin R, Barrett T, Dimitri P, Ivison F, Kibrige M, Mathew V, Matyka K, McGovern A, Stirling H, Tetlow L, Wales J, Wright N, Clayton P, Hall C: Metformin in obese children and adolescents: the MOCA trial. J Clin Endocrinol Metab 2013;98:322-329.
29.
Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ: Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402-2410.
30.
Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999;22:1462-1470.
31.
DeFronzo RA, Barzilai N, Simonson DC: Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 1991;73:1294-1301.
32.
Hoffman RP: Indices of insulin action calculated from fasting glucose and insulin reflect hepatic, not peripheral, insulin sensitivity in African-American and Caucasian adolescents. Pediatr Diabetes 2008;9:57-61.
33.
Salpeter SR, Buckley NS, Kahn JA, Salpeter EE: Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med 2008;121:149-157.
© 2013 S. Karger AG, Basel
2013
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