Skip to main content

Metformin in the Treatment of Obese Children and Adolescents at Risk of Type 2 Diabetes

Pediatric Drugs volume 16, pages 13–20 (2014)Cite this article

Abstract

Metformin is the first-line treatment for type 2 diabetes (T2D) in adults, children and young people, particularly in obese or overweight patients. Many studies have demonstrated that metformin is associated with weight reduction in adults and in prevention or delay of T2D onset in those who are at increased risk. In 2012, metformin was recommended by the UK National Institute for Health and Care Excellence as a treatment option in adults aged 18 years or over, who remain at high risk of T2D, despite participation in an intensive lifestyle-change programme. Prevalence of childhood obesity is increasing and is associated with elevated long-term risk of T2D and other adverse cardio-metabolic events; however, consensus is lacking on intervention strategies aimed at reducing this risk. This article discusses the rationale and evidence for the use of metformin in obese children and young people at high risk of T2D.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Haines L, Chong Wan K, Lynn R, Barrett T, Shield J. Rising incidence of type 2 diabetes in children in the UK. Diabetes Care. 2007;30:1097–101.

    PubMed  Article  Google Scholar 

  2. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care. 2000;23:386.

    Google Scholar 

  3. Reilly JJ, Kelly J. Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: systematic review. Int J Obes. 2011;35:891–8.

    CAS  Article  Google Scholar 

  4. Pan XR, Li GW, Hu YH, et al. The Da Quing IGT and diabetes study: effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. Diabetes Care. 1997;20:537–44.

    CAS  PubMed  Article  Google Scholar 

  5. Tuomilehto J, Lindstrom J, Erikssson JG, Finnish Diabetes Prevention Study Group, et al. Prevention of type 2 diabetes by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–50.

    CAS  PubMed  Article  Google Scholar 

  6. Knowler WG, Barrett-Connor E, Fowler SE, Diabetes Prevention Program Research Group, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.

    Google Scholar 

  7. Golay A. Metformin and body weight. Int J Obes. 2008;32:61–72.

    CAS  Article  Google Scholar 

  8. NICE. Preventing type 2 diabetes—risk identification and interventions for individuals at high risk: guidance. 2012 http://guidance.nice.org.uk/PH38/Guidance/pdf/English.

  9. International Obesity Taskforce. The global epidemic. http://www.iaso.org/iotf/obesity/obesitytheglobalepidemic/.

  10. Broyles S, Katzmarzyck P, Srinivasan S, et al. The pediatric obesity epidemic continues unabated in Bogalusa, Louisiana. Pediatrics. 2010;125(5):900–5.

    PubMed Central  PubMed  Article  Google Scholar 

  11. The NHS Information Centre, Lifestyles statistics. Statistics on obesity, physical activity and diet: England 2010. The Health Survey for England. http://www.ic.nhs.uk.

  12. Sjoberg RL, Nilsson KW, Leppert J. Obesity, shame, and depression in school-aged children: a population-based study. Pediatrics. 2005;116:389–92.

    Article  Google Scholar 

  13. Fiorino EK, Brooks LJ. Obesity and respiratory diseases in childhood. Clin Chest Med. 2009;30:601–8.

    PubMed  Article  Google Scholar 

  14. Yanovski JA. Pediatric obesity. Rev Endocr Metab Disord. 2001;2:371–83.

    CAS  PubMed  Article  Google Scholar 

  15. Leiba A, Kark JD, Afek A, Derazne E, Barchana M, Tzur D, Vivante A, Shamiss A. Adolescent obesity and paternal country of origin predict renal cell carcinoma: a cohort study of 1.1 million 16 to 19-year-old males. J Urol. 2013;189(1):25–9.

    PubMed  Article  Google Scholar 

  16. Levi Z, Kark JD, Afek A, Derazne E, Tzur D, Furman M, Gordon B, Barchana M, Liphshitz I, Niv Y, Shamiss A. Measured body mass index in adolescence and the incidence of pancreatic cancer in a cohort of 720,000 Jewish men. Cancer Causes Control. 2012;23(2):371–8.

    PubMed  Article  Google Scholar 

  17. Levi Z, Kark JD, Barchana M, Liphshitz I, Zavdi O, Tzur D, Derazne E, Furman M, Niv Y, Gordon B, Afek A, Shamiss A. Measured body mass index in adolescence and the incidence of colorectal cancer in a cohort of 1.1 million males. Cancer Epidemiol Biomarkers Prev. 2011;20(12):2524–31.

    PubMed  Article  Google Scholar 

  18. Ojaniemi M, Tapanainen P, Morin-Papunen L. Management of polycystic ovary syndrome in childhood and adolescence. Horm Res Paediatric. 2010;74:372–5.

    CAS  Article  Google Scholar 

  19. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118:1388–93.

    PubMed  Article  Google Scholar 

  20. Alfire ME, Treem WR. Nonalcoholic fatty liver disease. Pediatr Ann. 2006;35:290–4, 297–9.

    Google Scholar 

  21. Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH. Long-term morbidity and mortality of overweight adolescents: a follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med. 1992;327:1350–5.

    Google Scholar 

  22. Steinberger J, Daniels S, Eckel R, Hayman L, Lustig R, McCrindle B, Mietus-Snyder M. Progress and challenges in metabolic syndrome in children and adolescents. Circulation. 2009;119:628–47.

    PubMed  Article  Google Scholar 

  23. American Academy of Paediatrics. Management of newly diagnosed T2D in children and adolescents. Pediatrics. 2013;131:364–82.

    Article  Google Scholar 

  24. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetes Med. 1998;15:539–53.

    CAS  Article  Google Scholar 

  25. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143–421.

    Google Scholar 

  26. Drake AJ, Smith R, Betts PR, Crowne EC, Shield JP. Type 2 diabetes in obese white children. Arch Dis Child. 2002;86:207–8.

    CAS  PubMed  Article  Google Scholar 

  27. Ehtisham S, Hattersley AT, Dunger DB, et al. First UK survey of paediatric type 2 diabetes and MODY. Arch Dis Child. 2004;89:526–9.

    CAS  PubMed  Article  Google Scholar 

  28. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an epidemiological review and a public health perspective. J Paediatr. 2000;136:664–72.

    CAS  Article  Google Scholar 

  29. Kittiwaga T, Owada M, Urakami T, Yamanchi K. Increased incidence of non insulin dependent diabetes mellitus among Japanese school children correlates with an increased intake of animal protein and fat. Clin Pediatr. 1998;37:111–6.

    Article  Google Scholar 

  30. Ramachandran A, Snehelatha C, Satyavani S, Vijay V. Type 2 Diabetes in Asian-Indian urban children. Diabetes Care. 2003;26:1022–5.

    PubMed  Article  Google Scholar 

  31. Braun B, Zimmerman M, Kretchmer N, Spargo R, Smith R, Gracey M. Risk factors for diabetes and cardiovascular disease in young Australian Aborigines. Diabetes Care. 1996;19:472–9.

    CAS  PubMed  Article  Google Scholar 

  32. Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes. 2004;53:S16–21.

    CAS  PubMed  Article  Google Scholar 

  33. Weir GC, Bonner-Weir S. Islet β cell mass in diabetes and how it relates to function, birth, and death. Ann N Y Acad Sci. 2013;1281:92–105.

    Google Scholar 

  34. Levy-Marchal C, Arslanian S, Cutfield W, Sinaiko A, Druet M, Marcovecchio L, Chiarelli F. On behalf of ESPE-LWPES-ISPAD-APPES-APEG-SLEP-JSPE, and the Insulin Resistance in Children Consensus Conference Group 2010 insulin resistance in children: consensus, perspective, and future directions. J Clin Endocrinol Metab. 2010;95:5189–98.

    CAS  PubMed  Article  Google Scholar 

  35. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for diagnosing prediabetes and diabetes in obese children and adolescents. Diabetes Care. 2011;34:1306–11.

    CAS  PubMed  Article  Google Scholar 

  36. Viner RM, Segal TY, Lichtarowicz-Krynska E, Hindmarsh P. Prevalence of the insulin resistance syndrome in obesity. Arch Dis Child. 2005;90:10–4.

    CAS  PubMed  Article  Google Scholar 

  37. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med. 2002;346(11):802–10.

    CAS  PubMed  Article  Google Scholar 

  38. Weiss R, Dziura J, Tania S, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350:2362–74.

    CAS  PubMed  Article  Google Scholar 

  39. August GP, Caprio S, Fennoy I, Freemark M, Kaufman FR, Laustig RH, et al. Prevention and treatment of pediatric obesity: an endocrine society clinical practice guideline based on expert opinion. J Clin Endocrin Metab. 2008;93:4576–99.

    CAS  Article  Google Scholar 

  40. Viner R, White B, Barrett T, Candy D, Gibson P, Gregory J, Matyka K, Ong K, Roche E, Rudolf M, Shaikh G, Shield J, Wales J. Assessment of childhood obesity in secondary care: OSCA consensus statement. Arch Dis Child Educ Pract Ed. 2012;97:98–105.

    PubMed  Article  Google Scholar 

  41. George L, Bacha F, Lee S, Tfayli H, Andreatta E, Arslanian S. Surrogate estimates of insulin sensitivity in obese youth along the spectrum of glucose tolerance from normal to prediabetes to diabetes. J Clin Endocrinol Metab. 2011;96:2136–45.

    CAS  PubMed  Article  Google Scholar 

  42. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics. 2011;128(Suppl 5):S213–56.

  43. Wu B, Sheng L, Zhu J, Gu L, Shen H, La D, Hambly BD, Bao S, Di W. Metformin inhibits the development and metastasis of ovarian cancer. Oncol Rep. 2012;28:903–8.

    CAS  PubMed  Google Scholar 

  44. Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer’s disease-like neuropathy in obese, leptin-resistant mice. Pharmacol Biochem Behav. 2012;101:564–74.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  45. Cusi K, Consoli A, De Fronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in non insulin dependent diabetes. J Clin Endocrinol Metab. 1996;81:4059–67.

    CAS  PubMed  Google Scholar 

  46. Gunton J, Delhanty P, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin receptor substrate-2. J Clin Endocrinol Metab. 2003;88(3):1323–32.

    Google Scholar 

  47. Mannucci E, Tesi F, Bardini G, Ognibene A, Petracca MG, Ciani S, Pezzatini A, Brogi M, Dicembrini I, Cremasco F, Messeri G, Rotella CM. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without Type 2 diabetes. Diabetes Nutr Metab. 2004;17(6):336–42.

    CAS  PubMed  Google Scholar 

  48. Cleasby ME, Dzamko N, Hegarty BD, et al. Metformin prevents the development of acute lipid induced insulin resistance in the rat through altered hepatic signalling mechanisms. Diabetes. 2004;53:3258–66.

    CAS  PubMed  Article  Google Scholar 

  49. Musi N, Hirshman MF, Nygren J, et al. Metformin increases AMP-activated protein kinase activity in the muscles of patients with type 2 diabetes. Diabetes. 2002;51:2074–81.

    CAS  PubMed  Article  Google Scholar 

  50. Glueck CJ, Fontaine RN, Wang P, et al. Metformin reduces weight, centripetal obesity, insulin, leptin and low density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with BMI >30. Metabolism. 2011;50:856–61.

    Article  Google Scholar 

  51. Lord J, Wilkin T. Metformin in polycystic ovarian syndrome. Curr Opin Obstet Gynaecol. 2004;16:481–6.

    Article  Google Scholar 

  52. Mannucci E, Ognibene A, Cremasco F, et al. Effect of metformin on GLP-1 and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001;24:489–94.

    CAS  PubMed  Article  Google Scholar 

  53. UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes. Lancet. 1998;352:854–65.

    Article  Google Scholar 

  54. Hsia Y, Dawoud D, Sutcliffe AG, Viner RM, Kinra S, Wong IC. Unlicensed use of metformin in children and adolescents in the UK. Br J Clin Pharmacol. 2012;73:135–9.

    CAS  PubMed  Article  Google Scholar 

  55. Kostev K, Richter H. Unlicensed use of metformin in children and adolescents in Germany and France. Br J Clin Pharmacol. 2012;73:307–8.

    CAS  PubMed  Article  Google Scholar 

  56. Jones KL, Arslanian S, et al. Effect of metformin in pediatric patients with type 2 diabetes: a randomised controlled trial. Diabetes Care. 2002;25:89–94.

    CAS  PubMed  Article  Google Scholar 

  57. Park MH, White B, Kinra S, Viner R, Ward J. Metformin for obesity in children and adolescents. A systematic review. Diabetes Care. 2009;32:1743–5.

    CAS  PubMed  Article  Google Scholar 

  58. Freemark M, Bursey D. The effect of metformin on BMI and glucose tolerance in obese adolescents with fasting hyperinsulinaemia and a family history of type 2 diabetes. Pediatrics. 2001;107:E55.

    CAS  PubMed  Article  Google Scholar 

  59. Kay JP, Alemzadeh R, Langley G, D’Angelo L, Smith P, Holshouser S. Beneficial effects of metformin in normoglycaemic morbidly obese adolescents. Metabolism. 2001;50:1457–61.

    CAS  PubMed  Article  Google Scholar 

  60. 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;91:2074–80.

    CAS  PubMed  Article  Google Scholar 

  61. Love-Osbourne K, Sheeder J, MSPH, Zeitler P. Addition of metformin to a lifestyle modification program in adolescents with insulin resistance. J Pediatr. 2008;152:817–22.

  62. 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;163:585–9.

    Google Scholar 

  63. Atabek ME, Pirgon O. Use of metformin in obese adolescents with hyperinsulinemia: a 6-month, randomized, double-blind, placebo-controlled clinical trial. J Ped Endocrin Metab. 2008;21:339–48.

    CAS  Google Scholar 

  64. 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;60:477–85.

    CAS  PubMed  Article  Google Scholar 

  65. Clarson C, Mahmud F, Baker J, et al. Metformin in combination with structured lifestyle intervention improved body mass index in obese adolescents, but did not improve insulin resistance. Endocrine. 2009;36:141–6.

    CAS  PubMed  Article  Google Scholar 

  66. Wilson DM, Abrams SH, Aye T, Lee PD, Lenders C, Lustig RH, Osganian SV, Feldman HA, Glaser Pediatric Research Network Obesity Study Group. Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up. Arch Paediatr Adolesc Med. 2010;164:116–23.

    Article  Google Scholar 

  67. 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.

    PubMed  Article  Google Scholar 

  68. Kendall D, Vail A, Amin R, Barrett T, Dimitri P, Ivison F, Kibirige 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;98:322–9.

    CAS  PubMed  Article  Google Scholar 

  69. Arslanian S, Pyle L, Washington G, Payan M, Bacha F, Caprio S, Haymond MW, Levitsky LL, Goland R, White NH, Willi SM. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and β-cell function in TODAY. Diabetes Care. 2013;36(6):1749–57.

    Article  Google Scholar 

  70. Roche C, Nau A, Peytel E, Moalic JL, Oliver M. Severe lactic acidosis due to metformin: report of 3 cases. Ann Biol Clin (Paris). 2011;69:705–11.

    Google Scholar 

  71. Kos E, Liszek MJ, Emanuele MA, Durazo-Arvizy R, Camacho P. The effect of metformin therapy on vitamin D and B12 levels in patients with T2D. Endocr Pract. 2011;22:1–16.

    Google Scholar 

Download references

Funding and Conflicts of interest

No funding was used to support the preparation of this manuscript. Drs Kendall, Amin and Clayton declare that they have no relevant conflicts of interest relevant to the content of this article.

Author information

Affiliations

  1. Lancashire Teaching Hospitals NHS Foundation Trust, Royal Preston Hospital, Sharoe Green Lane, Preston, PR2 9HT, UK

    Deborah L. Kendall

  2. Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, WC1N 1EH, UK

    Rakesh Amin

  3. Child Health and Paediatric Endocrinology, Faculty of Medical and Human Sciences, Institute of Human Development, University of Manchester, Manchester, UK

    Peter E. Clayton

  4. Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK

    Peter E. Clayton

Authors
  1. Deborah L. Kendall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rakesh Amin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter E. Clayton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Deborah L. Kendall.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kendall, D.L., Amin, R. & Clayton, P.E. Metformin in the Treatment of Obese Children and Adolescents at Risk of Type 2 Diabetes. Pediatr Drugs 16, 13–20 (2014). https://doi.org/10.1007/s40272-013-0045-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-013-0045-1

Keywords

  • Metformin
  • Rosiglitazone
  • Impaired Glucose Tolerance
  • Obese Child
  • Lifestyle Intervention