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Drugs

, Volume 63, Issue 18, pp 1879–1894 | Cite as

Metformin

New Understandings, New Uses
  • Ripudaman S. Hundal
  • Silvio E. InzucchiEmail author
Leading Article

Abstract

Metformin, a biguanide, has been available in the US for the treatment of type 2 diabetes mellitus for nearly 8 years. Over this period of time, it has become the most widely prescribed antihyperglycaemic agent. Its mechanism of action involves the suppression of endogenous glucose production, primarily by the liver. Whether the drug actually has an insulin sensitising effect in peripheral tissues, such as muscle and fat, remains somewhat controversial. Nonetheless, because insulin levels decline with metformin use, it has been termed an ‘insulin sensitiser’. Metformin has also been shown to have several beneficial effects on cardiovascular risk factors and it is the only oral antihyperglycaemic agent thus far associated with decreased macrovascular outcomes in patients with diabetes. Cardiovascular disease, impaired glucose tolerance and the polycystic ovary syndrome are now recognised as complications of the insulin resistance syndrome, and there is growing interest in the management of this extraordinarily common metabolic disorder. While diet and exercise remain the cornerstone of therapy for insulin resistance, pharmacological intervention is becoming an increasingly viable option. We review the role of metformin in the treatment of patients with type 2 diabetes and describe the additional benefits it provides over and above its effect on glucose levels alone. We also discuss its potential role for a variety of insulin resistant and prediabetic states, including impaired glucose tolerance, obesity, polycystic ovary syndrome and the metabolic abnormalities associated with HIV disease.

Keywords

Metformin NASH Impaired Glucose Tolerance Sulfonylurea Lactic Acidosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

Dr Hundal and Dr Inzucchi have received honoraria from and/or are on speaker’s bureaus for Glaxo-Smith Kline, Takeda Pharmaceuticals North America, and Bristol-Myers Squibb. Dr Inzucchi has also received research grant support from Bristol-Myers Squibb.

References

  1. 1.
    Witters LA. The blooming of the French lilac. J Clin Invest 2001; 108: 1105–7PubMedGoogle Scholar
  2. 2.
    Kolata GB. The phenformin ban: is the drug an imminent hazard? Science 1979; 203: 1094–6PubMedCrossRefGoogle Scholar
  3. 3.
    Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334: 574–9PubMedCrossRefGoogle Scholar
  4. 4.
    Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998; 338: 867–72PubMedCrossRefGoogle Scholar
  5. 5.
    Inzucchi SE. Metformin or thiazolidinediones as first-line therapy for type 2 diabetes: focus on cardiovascular protection. Pract Diabetol 2002; 21: 7–12Google Scholar
  6. 6.
    Stadtmauer LA, Wong BC, Oehninger S. Should patients with polycystic ovary syndrome be treated with metformin?: benefits of insulin sensitizing drugs in polycystic ovary syndrome: beyond ovulation induction. Hum Reprod 2002; 17(12): 3016–26PubMedCrossRefGoogle Scholar
  7. 7.
    Cohn G, Valdes G, Capuzzi DM. Pathophysiology and treatment of the dyslipidemia of insulin resistance. Curr Cardiol Rep 2001; 3(5): 416–23PubMedCrossRefGoogle Scholar
  8. 8.
    Mehnert H. Metformin, the rebirth of a biguanide: mechanism of action and place in the prevention and treatment of insulin resistance. Exp Clin Endocrinol Diabetes 2001; 109 Suppl. 2: S259–64PubMedCrossRefGoogle Scholar
  9. 9.
    DeFronzo RA. The triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes 1988; 37: 667–87PubMedGoogle Scholar
  10. 10.
    Jeng CY, Shen WH, Fuh MM, et al. Relationship between hepatic glucose production and fasting glucose concentration in patients with NIDDM. Diabetes 1994; 43: 1440–4PubMedCrossRefGoogle Scholar
  11. 11.
    Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000; 49: 2063–9PubMedCrossRefGoogle Scholar
  12. 12.
    Magnusson I, Rothman DL, Katz LD, et al. Increased rate of gluconeogenesis in type II diabetes mellitus. J Clin Invest 1992; 90: 1323–7PubMedCrossRefGoogle Scholar
  13. 13.
    Cusi K, DeFronzo RA. Metformin: a review of its metabolic effects. Diabetes Rev 1998; 6: 89–131Google Scholar
  14. 14.
    Garber AJ, Duncan TG, Goodman AM, et al. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997; 102: 491–7CrossRefGoogle Scholar
  15. 15.
    DeFronzo RA, Goodman AM, for the Multicenter Metformin Study Group. Efficacy of metformin in NIDDM patients poorly controlled on diet alone or diet plus sulfonylurea. N Engl J Med 1995; 333: 541–9PubMedCrossRefGoogle Scholar
  16. 16.
    Stumvoll M, Nurjhan N, Periello G, et al. Metabolic effects of metformin in non-insulin dependent diabetes mellitus. N Engl J Med 1995; 333: 550–4PubMedCrossRefGoogle Scholar
  17. 17.
    Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in non insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996; 81: 4059–67PubMedCrossRefGoogle Scholar
  18. 18.
    Christiansen MP, Linfoot PA, Neese RA, et al. Metformin: effects upon postabsorptive intrahepatic carbohydrate fluxes [abstract]. Diabetes 1997; 46 Suppl. 1: 244AGoogle Scholar
  19. 19.
    Yu JG, Kruszynska YT, Mulford MI, et al. A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients. Diabetes 1999; 48: 2414–21PubMedCrossRefGoogle Scholar
  20. 20.
    Radziuk J, Zhang Z, Wiernperger N, et al. Effects of metformin on lactate uptake and gluconeogenesis in the perfused rat liver. Diabetes 1997; 46: 1406–13PubMedCrossRefGoogle Scholar
  21. 21.
    Argaud D, Roth H, Wiernsperger N, et al. Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur J Biochem 1993; 213: 1341–8PubMedCrossRefGoogle Scholar
  22. 22.
    Large V, Beylot M. Modifications of citric acid cycle activity and gluconeogenesis in streptozocin-induced diabetes and effects of metformin. Diabetes 1999; 48: 1251–7PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in the mechanism of metformin action. J Clin Invest 2001; 108: 1167–74PubMedGoogle Scholar
  24. 24.
    Owen MR, Doran E, Halestrap AP, et al. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348: 607–14PubMedCrossRefGoogle Scholar
  25. 25.
    Hawley SA, Gadalla AE, Olsen GS, et al. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleoside-independent mechanism. Diabetes 2002; 51: 2420–5PubMedCrossRefGoogle Scholar
  26. 26.
    Lochhead PA, Salt IP, Walker KS, et al. 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 2009; 49: 896–903CrossRefGoogle Scholar
  27. 27.
    Bergeron R, Russell RR, Young LH, et al. Effects of AMPK activation on muscle glucose metabolism in conscious rats. Am J Physiol 1999; 276: E938–44PubMedGoogle Scholar
  28. 28.
    Dominguez LJ, Davidoff AJ, Srinivas PR, et al. Effects of metformin on tyrosine kinase activity, glucose transport, and intracellular calcium in rat vascular smooth muscle. Endocrinology 1996; 137: 113–21PubMedCrossRefGoogle Scholar
  29. 29.
    Yki-Jarvinen H, Nikkila K, Makimattila S. Metformin prevents weight gain by reducing dietary intake during insulin therapy in patients with type 2 diabetes mellitus. Drugs 1999; 58 Suppl. 1: 53–4PubMedCrossRefGoogle Scholar
  30. 30.
    Davidoff F, Bertolini D, Haas D. Enhancement of the mitochondrial Ca2+ uptake rate by phenethylbiguanide and other organic cations with hypoglycemic activity. Diabetes 1978; 27: 757–65PubMedCrossRefGoogle Scholar
  31. 31.
    Wiernsperger NF, Bailey CJ. The antihyperglycemic effect of metformin: therapeutic and cellular mechanisms. Drugs 1999; 58 Suppl. 1: 31–9PubMedCrossRefGoogle Scholar
  32. 32.
    Hundal HS, Ramlal T, Reyes R, et al. Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cell. Endocrinology 1992; 131: 1165–73PubMedCrossRefGoogle Scholar
  33. 33.
    Stith BJ, Goalstone ML, Espinoza R, et al. The antidiabetic drug metformin elevates receptor tyrosine kinase activity and inositol 1,4,5-trisphosphate mass in Xenopus oocytes. Endocrinology 1996; 137: 2990–9PubMedCrossRefGoogle Scholar
  34. 34.
    DeFronzo RA, Barzilai N, Siminson DC. Mechanism of metformin action in obese and lean non-insulin dependent diabetic subjects. J Clin Endocrinol Metab 1991; 73: 1294–301PubMedCrossRefGoogle Scholar
  35. 35.
    Perriello G, Misericordia P, Volpi E, et al. Acute antihyperglycemic mechanisms of metformin in NIDDM: evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 1994; 43: 920–8PubMedCrossRefGoogle Scholar
  36. 36.
    Sindelar DK, Chu CA, Rohlie M, et al. The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog. Diabetes 1997; 46: 187–96PubMedCrossRefGoogle Scholar
  37. 37.
    Bergman RN, Mittleman SD. Central role of the adipocyte in insulin resistance. J Basic Clin Physiol Pharmacol 1998; 9: 205–21PubMedCrossRefGoogle Scholar
  38. 38.
    Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999; 103: 253–9PubMedCrossRefGoogle Scholar
  39. 39.
    Patane G, Piro S, Rabuazzo AM, et al. Metformin restores insulin secretion altered by chronic exposure to free fatty acids or high glucose: a direct metformin effect on pancreatic beta-cells. Diabetes 2000; 49: 735–40PubMedCrossRefGoogle Scholar
  40. 40.
    Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1999; 24: 49–57CrossRefGoogle Scholar
  41. 41.
    Ikeda T, Iwata K, Murakami H. Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine. Biochem Pharmacol 2000; 59: 887–90PubMedCrossRefGoogle Scholar
  42. 42.
    Scheeen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996; 30: 359–71CrossRefGoogle Scholar
  43. 43.
    DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999; 131: 281–303PubMedGoogle Scholar
  44. 44.
    Misbin RI, Green L, Stadel BV, et al. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 1998; 338: 265–6PubMedCrossRefGoogle Scholar
  45. 45.
    Lalau JD, Race JM. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999; 20: 377–84PubMedCrossRefGoogle Scholar
  46. 46.
    Bailey CJ, Wilcock C, Day C. Effect of metformin on glucosemetabolism in the splanchic bed. Br J Pharmacol 1992; 105: 1009–13PubMedCrossRefGoogle Scholar
  47. 47.
    Hermann LS, Schersten B, Bitzen PO, et al. Therapeutic comparisons of metformin and sulfonylurea, alone and in various combinations: a double blind controlled study. Diabetes Care 1994; 17: 1100–9PubMedCrossRefGoogle Scholar
  48. 48.
    United Kingdom Prospective Diabetes Study (UKPDS) Group. Relative efficacy of randomly allocated diet, sulfonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years (UKPDS 13). BMJ 1995; 310: 83–8CrossRefGoogle Scholar
  49. 49.
    Johnson K. Efficacy of metformin in the treatment of NIDDM. Meta-analysis. Diabetes Care 1999; 22: 33–7CrossRefGoogle Scholar
  50. 50.
    United Kingdom Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65CrossRefGoogle Scholar
  51. 51.
    Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002; 137: 25–33PubMedGoogle Scholar
  52. 52.
    Inzucchi SI. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002; 287: 360–72PubMedCrossRefGoogle Scholar
  53. 53.
    Dornan T, Heller S, Peck G, et al. Double blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care 1991; 14: 342–4PubMedCrossRefGoogle Scholar
  54. 54.
    Fontbonne A, Charles MA, Juhan-Vague I, et al. The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution: BIGPRO Study Group. Diabetes Care 1996; 19(9): 920–6PubMedCrossRefGoogle Scholar
  55. 55.
    Glueck CJ, Wang P, Fontaine R, et al. Metformin induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome. Metabolism 1999; 48: 511–9PubMedCrossRefGoogle Scholar
  56. 56.
    Pasquali R, Gambineri A, Biscotti D, et al. Effect of long term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000; 85: 2161–74CrossRefGoogle Scholar
  57. 57.
    Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirements for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999; 281: 2005–12Google Scholar
  58. 58.
    Haupt E, Knick B, Koschinsky T, et al. Oral antidiabetic combination therapy with sulphonylurea and metformin. Diabetes Metab 1991; 17: 224–31Google Scholar
  59. 59.
    Reaven GM, Johnston P, Hollenbeck CB, et al. Combined metformin-sulfonylurea treatment of patients with non-insulin dependent diabetes in fair to poor glycemic control. J Clin Endocrinol Metab 1992; 74: 1020–6PubMedCrossRefGoogle Scholar
  60. 60.
    Riddle M. Combining sulfonylureas and other oral agents. Am J Med 2000; 108 Suppl. 6a: 15S–22SPubMedCrossRefGoogle Scholar
  61. 61.
    Jaber LA, Nowak SN, Slaughter RR. Insulin-metformin combination therapy in obese patients with type 2 diabetes. J Clin Pharmacol 2002; 42: 89–94PubMedCrossRefGoogle Scholar
  62. 62.
    Hermann LS, Kalen J, Katzman P, et al. Long term glycemic improvement after addition of metformin to insulin in insulin treated obese type 2 diabetes patients. Diabetes Obes Metab 2001; 3: 428–34PubMedCrossRefGoogle Scholar
  63. 63.
    Bailey CJ. Metformin: a useful adjunct to insulin therapy? Diabet Med 2000; 17: 83–4PubMedCrossRefGoogle Scholar
  64. 64.
    Rosenstock J, Brown A, Fischer J, et al. Efficacy and safety of acarbose in metformin treated patients with type 2 diabetes. Diabetes Care 1998; 21: 2050–5PubMedCrossRefGoogle Scholar
  65. 65.
    Chiasson JL, Naditch L. Canadian University Investigator Group. The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes. Diabetes Care 2001; 24: 989–94Google Scholar
  66. 66.
    Einhorn D, Rendell M, Rosenzweig J, et al. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 2000; 22: 1395–409Google Scholar
  67. 67.
    Fonesca V, Rosenstock J, Patwardhan R, et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000; 283: 1695–702CrossRefGoogle Scholar
  68. 68.
    Moses R. Repaglinide in combination therapy with metformin in type 2 diabetes. Exp Clin Endocrinol Diabetes 1999; 107 Suppl. 4: 136–9CrossRefGoogle Scholar
  69. 69.
    Moses R, Slobodunik R, Boyages S, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 1999; 22: 119–24PubMedCrossRefGoogle Scholar
  70. 70.
    Marre M, Van Gaal L, Usadel KH, et al. Nateglinide improves glycemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients. Diabetes Obes Metab 2002; 4: 177–86PubMedCrossRefGoogle Scholar
  71. 71.
    Horton ES, Clinkingbeard C, Gatlin M, et al. Nateglinide alone and in combination with metformin improves glycemic control by reducing meal time glucose levels in type 2 diabetes. Diabetes Care 2000; 23: 1660–5PubMedCrossRefGoogle Scholar
  72. 72.
    Hirschberg Y, Karara AH, Pietri AO, et al. Improved control of mealtime glucose excursions with coadministration of nateglinide and metformin. Diabetes Care 2000; 23: 349–53PubMedCrossRefGoogle Scholar
  73. 73.
    Pagano G, Tagliaferro V, Carta Q, et al. Metformin reduces insulin requirement in type 1 (insulin-dependent) diabetes. Diabetologia 1983; 24: 351–4PubMedCrossRefGoogle Scholar
  74. 74.
    Stratton IM, Adler AI, Neil HA, et al. Association of glycemia with microvascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–12PubMedCrossRefGoogle Scholar
  75. 75.
    Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects: a study of two ethnic groups. Diabetes Care 1993; 16: 621–9PubMedCrossRefGoogle Scholar
  76. 76.
    Olsson J, Lindberg G, Gottsater M, et al. Increased mortality in type II diabetic patients using sulfonylurea and metformin in combination: a population based observational study. Diabetolgia 2000; 43: 558–60CrossRefGoogle Scholar
  77. 77.
    Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996; 334: 952–7PubMedCrossRefGoogle Scholar
  78. 78.
    Haffner SM. Epidemiology of insulin resistance and its relation to coronary artery disease. Am J Cardiol 1999; 84: 11J-4JCrossRefGoogle Scholar
  79. 79.
    Simplicini A, Del Prato S, Giusto M, et al. Short term effects of metformin on insulin sensitivity and sodium homeostasis in essential hypertensives. J Hypertens 1993; 11 Suppl. 5: S276–7Google Scholar
  80. 80.
    Robinson AC, Burke J, Robinson S, et al. The effects of metformin on glycemic control and serum lipids in insulin treated NIDDM patients with suboptimal control. Diabetes Care 1998; 21: 701–5PubMedCrossRefGoogle Scholar
  81. 81.
    Abasi F, Kamath V, Rizvi AA, et al. Results of a placebo controlled study of the metabolic effects of the addition of metformin to sulfonylurea treated patients: evidence for a central role of adipose tissue. Diabetes Care 1997; 20: 1863–9CrossRefGoogle Scholar
  82. 82.
    Wu MS, Johnston P, Sheu WH, et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990; 13: 1–8PubMedCrossRefGoogle Scholar
  83. 83.
    Velazquez EM, Mendoza SG, Wang P, et al. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein (a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997; 46: 454–7PubMedCrossRefGoogle Scholar
  84. 84.
    Bell DS, Ovalle F. Metformin lowers lipoprotein (a) levels. Diabetes Care 1998; 21: 2028Google Scholar
  85. 85.
    Fontbonne A, Charles MA, Juhan-Vague I, et al. The effect of metformin on the metabolic abnormalities associated with upper body fat distribution: BIGPRO study group. Diabetes Care 1996; 19: 920–6PubMedCrossRefGoogle Scholar
  86. 86.
    Grant PJ, Stickland MH, Booth NA, et al. Metformin causes a reduction in basal and post-venous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. Diabet Med 1991; 8: 361–5PubMedCrossRefGoogle Scholar
  87. 87.
    Charles MA, Morange P, Eschwege E, et al. Effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese non-diabetic subjects: the BIGPRO study. Biguanides and the prevention of the risk of obesity. Diabetes Care 1998; 21: 1967–72Google Scholar
  88. 88.
    Marfella R, Acampora R, Verrazzo G, et al. Metformin improves hemodynamic and rheological responses to L-arginine in NIDDM patients. Diabetes Care 1998; 19: 934–9CrossRefGoogle Scholar
  89. 89.
    Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Intern Med 1991; 229: 181–7PubMedCrossRefGoogle Scholar
  90. 90.
    Desouza C, Keebler M, McNamara DB, et al. Drugs affecting homocysteine metabolism. Drugs 2002; 62: 605–16PubMedCrossRefGoogle Scholar
  91. 91.
    Vrbikova J, Bicikova M, Tallova J, et al. Homocysteine and steroid levels in metformin treated women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 2002; 110: 74–6PubMedCrossRefGoogle Scholar
  92. 92.
    Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317: 350–7PubMedCrossRefGoogle Scholar
  93. 93.
    Taylor AA. Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes. Endocrinol Metab Clin North Am 2001; 30: 983–97PubMedCrossRefGoogle Scholar
  94. 94.
    Giugliano D, Quatraro A, Consoli G, et al. Metformin for obese, insulin treated diabetic patients: improvement in glycemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol 1993; 44: 107–12PubMedCrossRefGoogle Scholar
  95. 95.
    Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 2001; 37: 1344–50PubMedCrossRefGoogle Scholar
  96. 96.
    Diamanti-Kandarakis E, Spina G, Kouli C, et al. Increased endothelial-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. J Clin Endocrinol Metab 2001; 86: 4666–73PubMedCrossRefGoogle Scholar
  97. 97.
    Ridker PM, Glyn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97: 2007–11PubMedCrossRefGoogle Scholar
  98. 98.
    Chu NV, Kong AP, Kim DD, et al. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 2002; 25: 542–9PubMedCrossRefGoogle Scholar
  99. 99.
    Ludwig DS, Ebbeling CB. Type 2 diabetes mellitus in children: primary care and public health considerations. JAMA 2001; 286: 1427–30PubMedCrossRefGoogle Scholar
  100. 100.
    Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr 2000; 136: 664–72PubMedCrossRefGoogle Scholar
  101. 101.
    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(4): E55PubMedCrossRefGoogle Scholar
  102. 102.
    Lustig R. Childhood obesity. In: A current review of pediatric endocrinology 1999. Rockland (MA): Serono Symposia, 1999: 133–9Google Scholar
  103. 103.
    Jones KL, Arslanian S, Peterokova VA, et al. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002; 25: 89–94PubMedCrossRefGoogle Scholar
  104. 104.
    Morrison JA, Cottingham EM, Barton BA. Metformin for weight loss in pediatric patients taking psychotropic drugs. Am J Psychiatry 2002; 159: 655–7PubMedCrossRefGoogle Scholar
  105. 105.
    Pi-Sunyer FX. Medical hazards of obesity. Ann Intern Med 1993; 119: 655–60PubMedGoogle Scholar
  106. 106.
    Ford ES, Williamson DF, Liu S. Weight change and diabetes incidence: finding from a national cohort of US adults. Am J Epidemiol 1997; 146: 214–22PubMedCrossRefGoogle Scholar
  107. 107.
    Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–50PubMedCrossRefGoogle Scholar
  108. 108.
    Knowler WC, Barrett Connor E, Fowler SE, et al. Reduction inthe incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346(6): 393–403PubMedCrossRefGoogle Scholar
  109. 109.
    Futterweit W. Polycystic ovary syndrome: clinical perspectives and management. Obstet Gynecol Surv 1999; 54: 403–13PubMedCrossRefGoogle Scholar
  110. 110.
    Dunaif A, Graf M, Mandeli J, et al. Characterization of groups of hyperandrogenemic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987; 65: 499–507PubMedCrossRefGoogle Scholar
  111. 111.
    Dunaif A, Segal KR, Futterweit W, et al. Profound insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989; 38: 1165–74PubMedCrossRefGoogle Scholar
  112. 112.
    Nestler JE, Stovall D, Akhter N, et al. Strategies for the use of insulin sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Fertil Steril 2002; 77: 209–15PubMedCrossRefGoogle Scholar
  113. 113.
    Pugeat M, Ducluzeau PH. Insulin resistance, polycystic ovary syndrome and metformin. Drugs 1999; 58 Suppl. 1: 41–6PubMedCrossRefGoogle Scholar
  114. 114.
    Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanisms and implications for pathogenesis. Endocr Rev 1997; 18: 774–800PubMedCrossRefGoogle Scholar
  115. 115.
    Nestler JE, Powers LP, matt DW, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991; 72: 83–9PubMedCrossRefGoogle Scholar
  116. 116.
    Bloomgarden ZT, Futterweit W, Poretsky L. Use of insulin sensitizing agents in patients with polycystic ovary syndrome. Endocr Pract 2001; 7: 279–86PubMedGoogle Scholar
  117. 117.
    Morin-Papunen LC, Vanhkonen I, Koivunen RM, et al. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 2000; 85: 3161–8PubMedCrossRefGoogle Scholar
  118. 118.
    Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double blind, placebo-controlled 6 month trial, followed by open, long term clinical evaluation. J Clin Endocrinol Metab 2000; 85: 139–46PubMedCrossRefGoogle Scholar
  119. 119.
    Valazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin treatment in polycystic ovary syndrome. Obstet Gynecol 1997; 90: 392–5CrossRefGoogle Scholar
  120. 120.
    La Marca A, Egbe TO, Morgante G, et al. Metformin treatment reduces ovarian cytochrome p-450c17alpha response to human gonadotropin in women with insulin resistance-related polycystic ovary syndrome. Hum Reprod 2000; 15: 21–3PubMedCrossRefGoogle Scholar
  121. 121.
    Kelly CJ, Gordon D. The effects of metformin on hirsuitism in polycystic ovary syndrome. Eur J Endocrinol 2002; 147: 217–21PubMedCrossRefGoogle Scholar
  122. 122.
    Velazquez EM, Mendoza S, Hamer T, et al. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenism, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994; 43: 647–54PubMedCrossRefGoogle Scholar
  123. 123.
    Morin-Papunen LC, Koivunen RM, Ruokonen A, et al. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998; 69: 691–6PubMedCrossRefGoogle Scholar
  124. 124.
    Nestler JE, Jakubowicz DJ, Evans WS, et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic syndrome. N Engl J Med 1998; 338: 1876–80PubMedCrossRefGoogle Scholar
  125. 125.
    Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001; 75: 310–5PubMedCrossRefGoogle Scholar
  126. 126.
    Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 1996; 65: 946–9PubMedGoogle Scholar
  127. 127.
    Ehrmann DA, Cavaghan MK, Imperial J, et al. Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 524–30PubMedCrossRefGoogle Scholar
  128. 128.
    De Leo V, La Marca A, Ditto A, et al. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999; 72: 282–5PubMedCrossRefGoogle Scholar
  129. 129.
    Stadtmauer LA, Toma SK, Riehl RM, et al. Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors. Fertil Steril 2001; 75(3): 505–9PubMedCrossRefGoogle Scholar
  130. 130.
    Glueck CJ, Phillips H, Cameron D, et al. Continuing metformin throughout pregnancy in women in polycystic ovary syndrome appears to safely reduce first trimester spontaneous abortion: a pilot study. Fertil Steril 2001; 75: 46–52PubMedCrossRefGoogle Scholar
  131. 131.
    Jakubowicz DJ, Iuorno MJ, Jakubowicz S, et al. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87(2): 524–9PubMedCrossRefGoogle Scholar
  132. 132.
    Coetzee EJ, Jackson WPU. Metformin in management of pregnant insulin-independent diabetics. Diabetologia 1979; 16: 241–5PubMedCrossRefGoogle Scholar
  133. 133.
    Coetzee EJ, Jackson WP. The management of non-insulin dependent diabetes during pregnancy. Diabetes Res Clin Pract 1985; 1: 281–7PubMedCrossRefGoogle Scholar
  134. 134.
    Azziz R, Ehramann D, Legro RS, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2001; 86: 1626–32PubMedCrossRefGoogle Scholar
  135. 135.
    Dunaif A, Scott D, Finewood D, et al. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996; 81: 3299–306PubMedCrossRefGoogle Scholar
  136. 136.
    Glueck CJ, Wang P, Kobayashi S, et al. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril 2002; 77: 520–5PubMedCrossRefGoogle Scholar
  137. 137.
    Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidemia, and diabetes mellitus: a cohort study. Lancet 1999; 353: 2093–9PubMedCrossRefGoogle Scholar
  138. 138.
    Hadigan C, Miller K, Corcoran C, et al. Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 1999; 84: 1932–7PubMedCrossRefGoogle Scholar
  139. 139.
    Noor M, Lo J, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS 2001; 15: 11–8CrossRefGoogle Scholar
  140. 140.
    Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000; 275: 20251–4PubMedCrossRefGoogle Scholar
  141. 141.
    Hadigan C, Meigs JB, Rabe J, et al. Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance. J Clin Endocrinol Metab 2001; 86: 939–43PubMedCrossRefGoogle Scholar
  142. 142.
    Hadigan C, Corcoran C, Basgoz N, et al. Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 2000; 284: 472–7PubMedCrossRefGoogle Scholar
  143. 143.
    Saint-Marc T, Touraine JL. Effects of metformin on insulin resistance and central adiposity in patients receiving effective protease inhibitor therapy. AIDS 1999; 13: 1000–2PubMedCrossRefGoogle Scholar
  144. 144.
    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 body mass index greater than 30. Metabolism 2001; 50: 856–61PubMedCrossRefGoogle Scholar
  145. 145.
    Kay JP, Alemzadeh R, Langley G, et al. Beneficial effects of metformin in normoglycemic morbidly obese adolescents. Metabolism 2001; 50: 1457–61PubMedCrossRefGoogle Scholar
  146. 146.
    Gokel A, Gumurdulu Y, Karakose H, et al. Evaluation of the safety and efficacy of sibutramine, orlistat and metformin in the treatment of obesity. Diabetes Obes Metab 2002; 4: 49–55CrossRefGoogle Scholar
  147. 147.
    Dorella M, Giusto M, Da Tos V, et al. Improvement of insulin sensitivity by metformin treatment does not lower blood pressure if nonobese insulin-resistant hypertensive patients with normal glucose tolerance. J Clin Endocrinol Metab 1996; 81: 1568–74PubMedCrossRefGoogle Scholar
  148. 148.
    Charles MA, Eschwege E, Grandmottet P, et al. Treatment with metformin of non-diabetic men with hypertension, hypertriglyceridemia and central fat distribution: the BIGPRO 1.2 trial. Diabetes Metab Res Rev 2000; 16: 2–7PubMedCrossRefGoogle Scholar
  149. 149.
    Giugliano D, De Rosa N, Di Maro G, et al. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 1993; 16: 1387–90PubMedCrossRefGoogle Scholar
  150. 150.
    Mannucci E, Ognibene A, Cremasco F, et al. Effect of metformin on glucagon-like peptide (GLP-1) and leptin levels in obese non-diabetic subjects. Diabetes Care 2001; 24: 489–94PubMedCrossRefGoogle Scholar
  151. 151.
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221–31PubMedCrossRefGoogle Scholar
  152. 152.
    Lin HZ, Yang SQ, Chuckaree C, et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000; 6: 998–1003PubMedCrossRefGoogle Scholar
  153. 153.
    Marchesini G, Brizi M, Bianchi G, et al. Metformin in nonalcoholic steatohepatitis. Lancet 2001; 358: 893–4PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Diabetes & Metabolic Disease CenterChristiana CareWilmingtonUSA
  2. 2.Section of EndocrinologyYale University School of MedicineNew Haven, TMP 534USA

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