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Diabetes and Vascular Disease Research
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What's this?

Metformin therapy and clinical uses

John HB Scarpello

Department of Diabetes and Endocrinology, University Hospital of North Staffordshire NHS Trust, Stoke-on-Trent, UK.

Harry CS Howlett

CM Care Division, Merck Serono, Bedfont, UK.

Metformin is now established as a first-line antidiabetic therapy for the management of type 2 diabetes. Its early use in treatment algorithms is supported by lack of weight gain, low risk of hypoglycaemia and its mode of action to counter insulin resistance. The drug's anti-atherosclerotic and cardioprotective effects have recently been confirmed in prospective and retrospective studies, and appear to reflect a collection of glucose-independent effects on the vascular endothelium, suppressant effects on glycation, oxidative stress and formation of adhesion molecules, stimulation of fibrinolysis and favourable effects on the lipid profile. Although avoidance of troublesome gastrointestinal tolerability issues requires careful dose titration, the risk of serious adverse events is considered low provided that contra-indications (especially with respect to renal function) are observed. As many of its actions go beyond glucose lowering, emerging evidence indicates potential benefits in other insulin-resistant states and possibly tumour suppression.

Key Words: cardiovascular protection • insulin resistance • metformin • type 2 diabetes

References

  • 1. Giannarelli R Aragona M, Coppelli A, Del Prato S. Reducing insulin resistance with metformin: the evidence today. Diabetes Metab 2003;29:6S28–6S35.[Medline] [Order article via Infotrieve]
  • 2. Hundal RS Krssak M, Dufour S et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000;49:2063–9.[Abstract/Free Full Text]
  • 3. Johnson AB Webster JM, Sum CF et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metabolism 1993;42:1217–22.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 4. Tiikkainen M Hakkinen AM, Korsheninnikova E, Nyman T, Makimattila S, Yki-Jarvinen H. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 2004;53:2169–76.[Abstract/Free Full Text]
  • 5. Riccio A Del Prato S, Vigili de Kreutzenberg S, Tiengo A. Glucose and lipid metabolism in non-insulin-dependent diabetes. Effect of metformin. Diabetes Metab 1991;17:180–4.[Web of Science]
  • 6. Ferner RE Rawlins MD, Alberti KGMM. Impaired B-cell responses improve when fasting blood glucose concentrate is reduced in non-insulin-dependent diabetes. Quat J Med 1988;250:137–46.
  • 7. 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;43:920–8.[Abstract]
  • 8. Zhou G Myers R, Li Y et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167–74.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 9. Shu Y Sheardown SA, Brown C et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007;117:1422–31.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 10. Lindsay JR Duffy NA, McKillop AM et al. Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabet Med 2005;22:654–7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 11. Sinha Roy R, Bergeron R, Zhu L et al. Metformin is a GLP-1 secretagogue, not a dipeptidyl peptidase-4 inhibitor. Diabetologia 2007;50 (suppl 1):S284.
  • 12. Garber AJ Duncan TG, Goodman AM, Mills DJ, Rohlf LJ. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997;103:491–7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 13. Grant PJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 1996;19:64–6.[Abstract]
  • 14. Scarpello JHB. Optimal dosing strategies for maximising the clinical response to metformin in type 2 diabetes. Br J Diabetes Vasc Dis 2001;1:28–36.[Abstract/Free Full Text]
  • 15. Fujioka K Brazg RL, Raz I et al. Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Diabetes Obes Metab 2005;7:28–39.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 16. UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 17. Stratton IM Holman RR. The cardioprotective effects of metformin may not be dose-dependent. Diabet Med 2003;20(suppl 2):A55.
  • 18. Campbell IW Howlett CH. Worldwide experience of metformin as an effective glucose-lowering agent: a meta-analysis. Diabetes Metab Rev 1995;11 (suppl 1):S57–S62.[Web of Science][Medline] [Order article via Infotrieve]
  • 19. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;:CD002966.
  • 20. Chiasson JL Naditch L The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes. Diabetes Care 2001;24:989–94.[Abstract/Free Full Text]
  • 21. Hoffmann J Spengler M Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients: the Essen-II Study. Am J Med 1997;103:483–90.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 22. Holman RR Cull CA, Turner CR. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (UK Prospective Diabetes Study 44). Diabetes Care 1999;22:960–4.[Abstract]
  • 23. Goldstein BJ Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007;30:1979–87.[Abstract/Free Full Text]
  • 24. Schweizer A Couturier A, Foley JE, Dejager S. Comparison between vildagliptin and metformin to sustain reductions in HbA(1C) over 1 year in drug-naíve patients with type 2 diabetes. Diabet Med 2007;24:955–61.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 25. Pavo I Jermendy G, Varkonyi TT et al. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. J Clin Endocrinol Metab 2003;88:1637–45.[Abstract/Free Full Text]
  • 26. Kahn SE Haffner SM, Heise MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427–43.[Abstract/Free Full Text]
  • 27. Nathan DM. Thiazolidinediones for initial treatment of type 2 diabetes? N Engl J Med 2006;355:2477–80.[Free Full Text]
  • 28. Marre M Howlett H, Lehert P, Allavoine T. Improved glycaemic control with metformin-glibenclamide combined tablet therapy (Glucovance®) in Type 2 diabetic patients inadequately controlled on metformin. Diabet Med 2002;19:673–80.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 29. Feinglos M Dailey G, Cefalu W et al. Effect on glycemic control of the addition of 2.5 mg glipizide GITS to metformin in patients with T2DM. Diabetes Res Clin Pract 2005;68:167–75.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 30. Charpentier G Fleury F, Kabir M, Vaur L, Halimi S. Improved glycaemic control by addition of glimepiride to metformin monotherapy in type 2 diabetic patients. Diabet Med 2001;18:828–34.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 31. DeFronzo RA Goodman MA. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 1995;333:541–9.[Abstract/Free Full Text]
  • 32. Blonde L Rosenstock J, Mooradian AD, Piper BA, Henry D. Glyburide/metformin combination product is safe and efficacious in patients with type 2 diabetes failing sulphonylurea therapy. Diabetes Obes Metab 2002;4:368–75.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 33. Goldstein BJ Pans M, Rubin JC. Multicenter, randomized, doublemasked, parallel-group assessment of simultaneous glipizide/metformin as second-line pharmacologic treatment for patients with type 2 diabetes mellitus that is inadequately controlled by a sulphonylurea. Clin Ther 2003;25:890–903.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 34. Hermann LS Schersten B, Melander A. Antihyperglycaemic efficacy, response prediction and dose-response relations of treatment with metformin and sulphonylurea, alone and in primary combination. Diabet Med 1994;11:953–60.[Web of Science][Medline] [Order article via Infotrieve]
  • 35. Marre M Van Gaal L, Usadel KH, Ball M, Whatmough I, Guitard C. Nateglinide improves glycaemic control when added to metformin monotherapy: results of a randomized trial with type 2 diabetes patients. Diabetes Obes Metab 2002;4:177–86.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 36. Charbonnel B Schernthaner G, Brunetti P et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia 2005;48:1093–104.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 37. Fonseca V Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000;283:1695–702.[Abstract/Free Full Text]
  • 38. Einhorn D Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. 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;22:1395–409.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 39. Gomez-Perez FJ, Fanghanel-Salmon G, Antonio Barbosa J et al. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes. Diabetes Metab Res Rev 2002;18:127–34.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 40. Bailey CJ Bagdonas A, Rubes J et al. Rosiglitazone/metformin fixeddose combination compared with uptitrated metformin alone in type 2 diabetes mellitus: a 24-week, multicenter, randomized, doubleblind, parallel-group study. Clin Ther 2005;27:1548–61.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 41. Weissman P Goldstein BJ, Rosenstock J et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Curr Med Res Opin 2005;21:2029–35.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 42. Umpierrez G Issa M, Vlajnic A. Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial. Curr Med Res Opin 2006;22:751–9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 43. Garber A Klein E, Bruce S, Sankoh S, Mohideen P. Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2006;8:156–63.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 44. Perez A Spanheimer R, Khan M. Glycaemic control in patients with type 2 diabetes: the effects of pioglitazone vs. glyburide in a 3-year randomised, double-blind trial. Diabetologia 2006;49(suppl 1):490 (Abstract 0807).
  • 45. Derosa G Gaddi AV, Piccinni MN et al. Differential effect of glimepiride and rosiglitazone on metabolic control of type 2 diabetic patients treated with metformin: a randomized, double-blind, clinical trial. Diabetes Obes Metab 2006;8:197–205.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 46. Phillips P Karrasch J, Scott R, Wilson D, Moses R. Acarbose improves glycemic control in overweight type 2 diabetic patients insufficiently treated with metformin. Diabetes Care 2003;26:269–73.[Abstract/Free Full Text]
  • 47. Bayraktar M Van Thiel DH, Adalar N. A comparison of acarbose versus metformin as an adjuvant therapy in sulphonylurea-treated NIDDM patients. Diabetes Care 1996;19:252–4.[Abstract]
  • 48. Chiasson JL Josse RG, Hunt JA et al. The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus. A multicenter controlled clinical trial. Ann Intern Med 1994;121:928–35.[Abstract/Free Full Text]
  • 49. Hanefeld M Brunetti P, Schernthaner GH, Matthews DR, Charbonnel BH. One-year glycemic control with a sulphonylurea plus pioglitazone versus a sulphonylurea plus metformin in patients with type 2 diabetes. Diabetes Care 2004;27:141–7.[Abstract/Free Full Text]
  • 50. Home PD Jones NP, Pocock SJ et al. Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabet Med 2007;24:626–34.[CrossRef][Medline] [Order article via Infotrieve]
  • 51. Poon T Nelson P, Shen L et al. Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a doseranging study. Diabetes Technol Ther 2005;7:467–77.[CrossRef][Medline] [Order article via Infotrieve]
  • 52. Kendall DM Riddle MC, Rosenstock J et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulphonylurea. Diabetes Care 2005;28:1083–91.[Abstract/Free Full Text]
  • 53. Riddle MC Henry RR, Poon TH et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev 2006;22:483–91.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 54. Ratner RE Maggs D, Nielsen LL et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in overweight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab 2006;8:419–28.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 55. Blonde L Klein EJ, Han J et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab 2006;8:436–47.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 56. Fineman MS Bicsak TA, Shen LZ et al. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulphonylurea treatment in patients with type 2 diabetes. Diabetes Care 2003;26:2370–7.[Abstract/Free Full Text]
  • 57. Heine RJ Van Gaal LF, Johns D et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 2005;143:559–69.[Abstract/Free Full Text]
  • 58. DeFronzo RA Ratner RE, Han J, Kim DD, Fineman MS, Baron DA. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28:1092–100.[Abstract/Free Full Text]
  • 59. Einglos MN Saad MF, Pi-Sunyer FX, An B, Santiago O. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med 2005;22:1016–23.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 60. Nauck MA Hompesch M, Filipczak R, Le TD, Zdravkovic M, Gumprecht J. Five weeks of treatment with the GLP-1 analogue liraglutide improves glycaemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes 2006;114:417–23.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 61. Ahren B Pacini G, Foley JE, Schweizer A. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care 2005;28:1936–40.[Abstract/Free Full Text]
  • 62. Bosi E Camisasca RP, Collober C, Rochotte E, Garber JA. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007;30:890–5.[Abstract/Free Full Text]
  • 63. Charbonnel B Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638–43.[Abstract/Free Full Text]
  • 64. Hermansen K Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007;9:733–45.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 65. Nauck MA Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulphonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, doubleblind, non-inferiority trial. Diabetes Obes Metab 2007;9:194–205.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 66. Brazg R Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab 2007;9:186–93.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 67. Yki-Jarvinen H, Ryysy L, Nikkila K et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1999;130:389–96.[Abstract/Free Full Text]
  • 68. Ryysy L Yki-Jarvinen H. Improvement of glycemic control by 1 year of insulin therapy leads to a sustained decrease in E-selectin concentrations in type 2 diabetes. Diabetes Care 2001;24:549–54.[Abstract/Free Full Text]
  • 69. Golay A. Metformin and body weight. Int J Obes 2008;32:61–72.[CrossRef][Web of Science]
  • 70. Donnelly LA Doney AS, Hattersley AT, Morris AD, Pearson RE. The effect of obesity on glycaemic response to metformin or sulphonylureas in Type 2 diabetes. Diabet Med 2006;23:128–33.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 71. Garber A Marre M, Blonde L et al. Influence of initial hyperglycaemia, weight and age on the blood glucose lowering efficacy and incidence of hypoglycaemic symptoms with a single-tablet metformin-glibenclamide therapy (Glucovance®) in type 2 diabetes. Diabetes Obes Metab 2003;5:171–9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 72. Josephkutty S Potter MJ. Comparison of tolbutamide and metformin in elderly diabetic patients. Diabet Med 1990;7:510–14.[Web of Science][Medline] [Order article via Infotrieve]
  • 73. Jones KL Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002;25:89–94.[Abstract/Free Full Text]
  • 74. Gottschalk M Danne T, Vlajnic A, Cara FJ. Glimepiride versus metformin as monotherapy in pediatric patients with type 2 diabetes: a randomized, single-blind comparative study. Diabetes Care 2007;30:790–4.[Abstract/Free Full Text]
  • 75. UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylurea or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 76. UKPDS Correspondence. Lancet 1998;352:1932–4.[Web of Science][Medline] [Order article via Infotrieve]
  • 77. UKPDS Group. UK Prospective Diabetes Study 6. Complications in newly-diagnosed type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Res 1990;13:1–11.[Medline] [Order article via Infotrieve]
  • 78. Kao J Tobis J, McClelland RL et al. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol 2004;93:1347–50.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 79. Johnson JA Majumdar SR, Simpson SH, Toth LE. Decreased mortality associated with the use of metformin compared with sulphonylurea monotherapy in type 2 diabetes. Diabetes Care 2002;25:2244–8.[Abstract/Free Full Text]
  • 80. Johnson JA Simpson SH, Toth EL, Majumdar RS. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with type 2 diabetes. Diabet Med 2005;22:497–502.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 81. Eurich DT Majumdar SR, McAlister FA, Tsuyuki RT, Johnson AJ. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005;28:2345–51.[Abstract/Free Full Text]
  • 82. Evans JM Ogston SA, Emslie-Smith A, Morris A. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulphonylureas and metformin. Diabetologia 2006;49:930–6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 83. Sgambato S Varricchio M, Tesauro P, Passariello N, Carbone L. L'utilisation de la metformin dans la cardiopathie ischemique. Clin Ter 1980;94:77–85.[Medline] [Order article via Infotrieve]
  • 84. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–18.[CrossRef][Medline] [Order article via Infotrieve]
  • 85. Libby P Plutzky J Diabetic macrovascular disease: the glucose paradox? Circulation 2002;106:2760–3.[Free Full Text]
  • 86. Despres JP. Potential contribution of metformin to the management of cardiovascular disease risk in patients with abdominal obesity, the metabolic syndrome and type 2 diabetes. Diabetes Metab 2003;29:6S53–6S61.[Medline] [Order article via Infotrieve]
  • 87. Nagi DK Yudkin SJ. 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;16:621–9.[Abstract]
  • 88. Kurukulasuriya R Banerji MA, Chaiken R, Lebovitz H. Selective decrease in visceral fat is associated with weight loss during metformin treatment in African Americans with type 2 diabetes. Diabetes 1999;48(suppl):A315.
  • 89. Grant PJ. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab 2003;29:6S44–6S52.[Medline] [Order article via Infotrieve]
  • 90. Gregorio F Ambrosi F, Manfrini S et al. Poorly controlled elderly Type 2 diabetic patients: the effects of increasing sulphonylurea dosages or adding metformin. Diabet Med 1999;16:1016–24.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 91. Grant PJ. Metformin reduces circulating factor VII concentrations in patients with type 2 diabetes mellitus. Thromb Haemost 1998;80:209–10.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 92. Standeven KF Ariens RA, Whitaker P, Ashcroft AE, Weisel JW, Grant JP. The effect of dimethylbiguanide on thrombin activity, FXIII activation, fibrin polymerization, and fibrin clot formation. Diabetes 2002;51:189–97.[Abstract/Free Full Text]
  • 93. Beisswenger PJ Howell SK, O'Dell RM, Wood ME, Touchette AD, Szwergold BS. Alpha-Dicarbonyls increase in the postprandial period and reflect the degree of hyperglycemia. Diabetes Care 2001;24:726–32.[Abstract/Free Full Text]
  • 94. Beisswenger P Ruggiero-Lopez D. Metformin inhibition of glycation processes. Diabetes Metab 2003;29:6S95–6S103.[Medline] [Order article via Infotrieve]
  • 95. Beisswenger PJ, Howell SK, Ruggiero-Lopez D, Szwergold BS, Weirnsperger N. Triazepinone is a marker for metformin-methylglyoxal condensation in type 2 diabetes. 63rd Scientific sessions of the American Diabetes Association, New Orleans, USA, June 13–17 2003, abstract 473–P.
  • 96. Beisswenger PJ Howell SK, Touchette AD, Lal S, Szwergold SB. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes 1999;48:198–202.[Abstract]
  • 97. Backlund T Palojoki E, Saraste A et al. Sustained cardiomyocyte apoptosis and left ventricular remodelling after myocardial infarction in experimental diabetes. Diabetologia 2004;47:325–30.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 98. James TN. Complex causes of fatal myocardial infarction. Circulation 1997;96:1696–700.[Abstract/Free Full Text]
  • 99. Pavloviç D, Kociç R, Kociç G et al. Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes. Diabetes Obes Metab 2000;2:251–6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 100. Mamputu JC Wiernsperger NF, Renier G. Antiatherogenic properties of metformin: the experimental evidence. Diabetes Metab 2003;29:6S71–6S76.[Medline] [Order article via Infotrieve]
  • 101. Wiernsperger NF Bouskela E Microcirculation in insulin resistance and diabetes: more than just a complication. Diabetes Metab 2003;29:6S77–6S87.[Medline] [Order article via Infotrieve]
  • 102. Jadhav S Ferrell W, Greer IA, Petrie JR, Cobbe SM, Sattar N. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2006;48:956–63.[Abstract/Free Full Text]
  • 103. Nathan DM Buse JB, Davidson MB et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711–21.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 104. Carter D Howlett HCS, Wiernsperger NF, Bailey CJ. Differential effects of metformin on bile salt absorption from the jejunum and ileum. Diabetes, Obesity Metab 2003;5:120–5.[CrossRef]
  • 105. Scarpello JH Hodgson E, Howlett CH. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med 1998;15:651–6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 106. Cusi K DeFronzo AR. Metformin: a review of its metabolic effects. Diabetes Rev 1998;6:89–131.
  • 107. Howlett H Davidson J New prolonged-release metformin improves gastrointestinal tolerability. Br J Diabetes Vasc Dis 2004;4:273–7.[Abstract/Free Full Text]
  • 108. Blonde L Dailey GE, Jabbour SA, Reasner CA, Mills JD. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin 2004;20:565–72.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 109. Feher MD Al-Mrayat M, Brake J, Leong KS. Tolerability of prolonged-release metformin (Glucophage® SR) in individuals intolerant to standard metformin – results from four UK centres. Br J Diabetes Vasc Dis 2007;7:225–8.[Abstract/Free Full Text]
  • 110. Howlett HCS Bailey JC. A risk benefit assessment of metformin in type 2 diabetes mellitus. Drug Safety 1999;20:489–503.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 111. Lalau JD Race MJ. Lactic acidosis in metformin therapy: searching for a link with metformin in reports of ‘metformin-associated lactic acidosis’. Diabetes Obes Metab 2000;2:1–7.[Web of Science][Medline] [Order article via Infotrieve]
  • 112. Lalau JD Race MJ. Lactic acidosis in metformin therapy. Drugs 1999;58(suppl 1):55–60.
  • 113. Cryer DR Nicholas SP, Henry DH, Mills DJ, Stadel VB. Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. Diabetes Care 2005;28:539–43.[Abstract/Free Full Text]
  • 114. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Cochrane Database Syst Rev 2006 Jan 25;(1):CD002967.
  • 115. Sirtori CR Pasik C Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res 1994;30:187–228.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 116. Wright AD Cull CA, Macleod KM, Holman RR. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulphonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complications 2006;20:395–401.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 117. Sulkin TV Bosman D, Krentz JA. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997;20:925–8.[Abstract]
  • 118. Emslie-Smith AM, Boyle DI, Evans JM, Sullivan F, Morris AD. Contraindications to metformin therapy in patients with type 2 diabetes – a population-based study of adherence to prescribing guidelines. Diabet Med 2001;18:483–8.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 119. Mlekusch W Exner M, Sabeti S et al. Serum creatinine predicts mortality in patients with peripheral artery disease: influence of diabetes and hypertension. Atherosclerosis 2004;175:361–7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 120. Tahrani AA Scarpello JH, Hanna FWF. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ 2007;335:8–12.[Free Full Text]
  • 121. Rachmani R Slavachevski I, Levi Z, Zadok B, Kedar Y, Ravid M. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 2002;13:428–33.[CrossRef][Medline] [Order article via Infotrieve]
  • 122. Connolly V Kesson MC. Metformin treatment in NIDDM patients with mild renal impairment. Postgrad Med J 1996;72:352–4.[Abstract/Free Full Text]
  • 123. Jones GC Macklin JP, Alexander DW. Contraindications to the use of metformin. BMJ 2003;326:4–5.[Free Full Text]
  • 124. Holstein A Stumvoll M Contraindications can damage your health – is metformin a case in point? Diabetologia 2005;48:2454–9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 125. Nag S Bilous R, Kelly W, Jones S, Roper N, Connolly V. All-cause and cardiovascular mortality in diabetic subjects increases significantly with reduced estimated glomerular filtration rate (eGFR): 10 years' data from the South Tees Diabetes Mortality study. Diabet Med 2007;24:10–17.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 126. New JP O'Donoghue DJ, Middleton RJ et al. Time to move from serum creatinine to eGFR. Diabet Med 2006;23:1047–9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 127. Warren RE Strachan MW, Wild S, McKnight AJ. Introducing estimated glomerular filtration rate (eGFR) into clinical practice in the UK: implications for the use of metformin. Diabet Med 2007;24:494–7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 128. Shaw JS Wilmot RL, Kilpatrick SE. Establishing pragmatic estimated GFR thresholds to guide metformin prescribing. Diabet Med 2007;24:1160–3.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 129. South West Thames Institute for Renal Research. Chronic Kidney Disease Guidelines for Primary Care. Available at http://www. swtirr.org.uk/st_helier_renal_guidelines_gp_jan_06.pdf (last accessed October 2007).
  • 130. 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.[Abstract/Free Full Text]
  • 131. Ramachandran A Snehalatha C, Mary S et al. 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;49:289–97.[CrossRef][Medline] [Order article via Infotrieve]
  • 132. Wenying Y Lixiang L, Jinwu Q, Guangwei L, Zhiqing Y, Xiaoren P. The preventive effect of acarbose and metformin on the IGT population from becoming diabetes mellitus: a 3-year multicentral prospective study. Chin J Endocrinol Metab 2001;17:131–4.
  • 133. Lord JM, Flight IHK, Norman RJ. Insulin sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford:(Update software).
  • 134. Balen AH Rutherford JA. Managing anovulatory infertility and polycystic ovary syndrome. BMJ 2007;335:663–6.[Free Full Text]
  • 135. Guideline CG11 Fertility, available at http://guidance.nice.org.uk/CG11/niceguidance/pdf/English (last accessed October 2007).
  • 136. American Association of Clinical Endocrinologists. Position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Available at www.aace.com/pub/pdf/guidelines/PCOS positionstatement.pdf (last accessed October 2007).
  • 137. Gill HK Wu YG. Non-alcoholic fatty liver disease and the metabolic syndrome: effects of weight loss and a review of popular diets. Are low carbohydrate diets the answer? World J Gastroenterol 2006;12:345–53.[Web of Science][Medline] [Order article via Infotrieve]
  • 138. Portincasa P Grattagliano I, Palmieri VO, Palasciano G. The emerging problem of nonalcoholic steatohepatitis (NASH). Rom J Gastroenterol 2005;14:43–51.[Medline] [Order article via Infotrieve]
  • 139. Sheth SG Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997;126:137–45.[Abstract/Free Full Text]
  • 140. Nair S Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004;20:23–8.[Web of Science][Medline] [Order article via Infotrieve]
  • 141. Duseja A Murlidharan R, Bhansali A et al. Assessment of insulin resistance and effect of metformin in nonalcoholic steatohepatitis – a preliminary report. Indian J Gastroenterol 2004;23:12–15.[Medline] [Order article via Infotrieve]
  • 142. Marchesini G Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001;358:893–4.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 143. Blaszyk H Ferrentino N, Forsell S et al. A pilot study of metformin as treatment for nonalcoholic steatohepatitis. Gastroenterology 2005;128(suppl 2):A-769. [Poster M1699]
  • 144. Schwimmer JB Middleton MS, Deutsch R, Lavine EJ. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2005;21:871–9.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 145. Sweet DE. Metabolic complications of antiretroviral therapy. Top HIV Med 2005;13:70–4.[Medline] [Order article via Infotrieve]
  • 146. Milinkovic A Martinez E Current perspectives on HIV-associated lipodystrophy syndrome. J Antimicrob Chemother 2005;56:6–9.[Abstract/Free Full Text]
  • 147. Echavez M Horstman W Relationship between lipoatrophy and quality of life. AIDS Read 2005;15:369–75.[Medline] [Order article via Infotrieve]
  • 148. 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;86:939–43.[Abstract/Free Full Text]
  • 149. Hadigan C Rabe J, Grinspoon S. Sustained benefits of metformin therapy on markers of cardiovascular risk in human immunodeficiency virus-infected patients with fat redistribution and insulin resistance. J Clin Endocrinol Metab 2002;87:4611–15.[Abstract/Free Full Text]
  • 150. Hadigan C Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA 2000;284:472–7.[Abstract/Free Full Text]
  • 151. Hardie DG. The AMP-activated protein kinase pathway – new players upstream and downstream. J Cell Sci 2004;117:5479–87.[Abstract/Free Full Text]
  • 152. Greenberg AS Obin SM. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006;83:461S–465S.[Abstract/Free Full Text]
  • 153. Shaw RJ Lamia KA, Vasquez D et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005;310:1642–6.[Abstract/Free Full Text]
  • 154. Zakikhani M Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006;66:10269–73.[Abstract/Free Full Text]
  • 155. Evans JM Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330:1304–05.[Free Full Text]
  • 156. Bowker SL Majumdar SR, Veugelers P, Johnson AJ. Increased cancer-related mortality for patients with type 2 diabetes who use sulphonylureas or insulin. Diabetes Care 2006;29:254–8.[Abstract/Free Full Text]
  • 157. Clinical Guidelines Task Force, International Diabetes Federation. 2005 Global Guideline for Type 2 Diabetes. Available at www.idf.org (last accessed October 2007).
  • 158. Asian-Pacific Type 2 Diabetes Policy Group. Type 2 diabetes: practical targets and treatments Fourth edition www.diabetes.com.au/pdf/Diabetes_TreatmentTargets_FINAL.pdf (last accessed October 2007).
  • 159. Alberti KG Zimmet P, Shaw J. International Diabetes Federation: a consensus on Type 2 diabetes prevention. Diabet Med 2007;24:451–63.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 160. Nathan DM Davidson MB, DeFronzo RA et al. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care 2007;30:753–9.[Free Full Text]

Diabetes and Vascular Disease Research, Vol. 5, No. 3, 157-167 (2008)
DOI: 10.3132/dvdr.2008.027
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