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Drug Safety

, Volume 33, Issue 9, pp 727–740 | Cite as

Lactic Acidosis Induced by Metformin

Incidence, Management and Prevention
  • Jean-Daniel Lalau
Review Article

Abstract

Lactic acidosis associated with metformin treatment is a rare but important adverse event, and unravelling the problem is critical. First, this potential event still influences treatment strategies in type 2 diabetes mellitus, particularly in the many patients at risk of kidney failure, in those presenting contraindications to metformin and in the elderly. Second, the relationship between metformin and lactic acidosis is complex, since use of the drug may be causal, co-responsible or coincidental. The present review is divided into three parts, dealing with the incidence, management and prevention of lactic acidosis occurring during metformin treatment. In terms of incidence, the objective of this article is to counter the conventional view of the link between metformin and lactic acidosis, according to which metformin-associated lactic acidosis is rare but is still associated with a high rate of mortality. In fact, the direct metformin-related mortality is close to zero and metformin may even be protective in cases of very severe lactic acidosis unrelated to the drug. Metformin has also inherited a negative class effect, since the early biguanide, phenformin, was associated with more frequent and sometimes fatal lactic acidosis. In the second part of this review, the objective is to identify the most efficient patient management methods based on our knowledge of how metformin acts on glucose/lactate metabolism and how lactic acidosis may occur (at the organ and cellular levels) during metformin treatment. The liver appears to be a key organ for both the antidiabetic effect of metformin and the development of lactic acidosis; the latter is attributed to mitochondrial impairment and subsequent adenosine triphosphate depletion, acceleration of the glycolytic flux, increased glucose uptake and the generation of lactate, which effluxes into the circulation rather than being oxidized further. Haemodialysis should systematically be performed in severe forms of lactic acidosis, since it provides both symptomatic and aetiological treatment (by eliminating lactate and metformin). In the third part of the review (prevention), the objective is to examine the list of contraindications to metformin (primarily related to renal and cardiovascular function). Diabetes is above all a vascular disease and metformin is a vascular drug with antidiabetic properties. Given the importance of the liver in lactate clearance, we suggest focusing on the severity of and prognosis for liver disease; renal dysfunction is only a prerequisite for metformin accumulation, which may only be dangerous per se when associated with liver failure. Lastly, in view of metformin’s impressive overall effectiveness profile, it would be paradoxical to deny the majority of patients with long-established diabetes access to metformin because of the high prevalence of contraindications. The implications of these contraindications are discussed.

Keywords

Metformin Lactic Acidosis Metformin Treatment Phenformin Lactate Clearance 
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

No funding was received for the preparation of this review. Jean-Daniel Lalau has been a compensated speaker for Boehringer-Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Sanofi-aventis and Takeda.

References

  1. 1.
    Chan N, Brain H, Feher M. Metformin-associated lactic acidosis: a rare or very rare clinical entity? Diabetic Med 1999 Apr; 16(4): 273–81PubMedCrossRefGoogle Scholar
  2. 2.
    Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 2004 Jul; 27(7): 1791–3PubMedCrossRefGoogle Scholar
  3. 3.
    Cohen R, Woods H. The clinical presentations and classifications of lactic acidosis. In: Cohen R, HF Woods, editors. Clinical and biochemical aspects of lactic acidosis. Boston (MA): Blackwell Scientific Publications, 1976: 40–52Google Scholar
  4. 4.
    Luft D, Deichsel G, Schmulling R, et al. Definition of clinically relevant lactic acidosis in patients with internal diseases. Am J Clin Pathol 1983 Oct; 80(4): 484–9PubMedGoogle Scholar
  5. 5.
    Arieff A. Pathogenesis of lactic acidosis. Diabetes Metab Rev 1989 Dec; 5(8): 637–49PubMedCrossRefGoogle Scholar
  6. 6.
    Stacpoole P. Lactic acidosis. Endocrinol Metab Clin North Am 1993; 22: 221–45PubMedGoogle Scholar
  7. 7.
    Sterne J. Pharmacology and mode of action of hypoglycaemic guanidine derivatives. In: Campbell IW, editor. Oral hypoglycaemic agents. London: Academic Press, 1969: 193–245Google Scholar
  8. 8.
    Kreisberg R, Pennington L, Boshell B. Lactate turnover and gluconeogenesis in obesity: effect of phenformin. Diabetes 1970 Jan; 19(1): 64–9PubMedGoogle Scholar
  9. 9.
    Searle G, Siperstein M. Lactic acidosis associated with phenformin therapy: evidence that inhibited lactate oxidation is the causative factor. Diabetes 1975 Aug; 24(8): 741–5PubMedCrossRefGoogle Scholar
  10. 10.
    Natrass M, Todd P, Hinks L, et al. Comparative effects of phenformin, metformin and glibenclamide in metabolic rhythms in maturity-onset diabetes. Diabetologia 1977 Apr; 13(2): 145–52CrossRefGoogle Scholar
  11. 11.
    Oates N, Shah R, Idle J, et al. Genetic polymorphism of phenformin 4-hydroxylation. Clin Pharmacol Ther 1982 Jul; 32(1): 81–9PubMedCrossRefGoogle Scholar
  12. 12.
    Williams R, Palmer J. Farewell to phenformin for treating diabetes mellitus. Ann Intern Med 1975 Oct; 83(4): 567–8PubMedGoogle Scholar
  13. 13.
    Cryer DR, Mills DJ, Nicholas SP, et al. Comparative outcomes study of metformin intervention versus conventional approach. Diabetes Care 2005 Mar; 28(3): 539–43PubMedCrossRefGoogle Scholar
  14. 14.
    Salpeter SR, Geryber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010 Jan; (1): CD002967Google Scholar
  15. 15.
    Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med 2007 Sept; 147(6): 386–99PubMedGoogle Scholar
  16. 16.
    Bodmer M, Jick SS, Meier C, et al. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycaemia. Diabetes Care 2008 Nov; 31(11): 2086–91PubMedCrossRefGoogle Scholar
  17. 17.
    Brown JB, Pedula K, Barzilay J, et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care 1998 Oct; 21(10): 1659–63PubMedCrossRefGoogle Scholar
  18. 18.
    Fulop M, Hoberman H. Phenformin-associated metabolic acidosis. Diabetes 1976 Apr; 25(4): 292–6PubMedCrossRefGoogle Scholar
  19. 19.
    Lalau J, Race J. Lactic acidosis in metformin therapy: searching for a link with metformin in reports of ‘metformin-associated lactic acidosis’. Diabetes Obes Metab 2001 Jun; 3(3): 195–201PubMedCrossRefGoogle Scholar
  20. 20.
    Lalau J, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 1995 June; 18(6): 779–84PubMedCrossRefGoogle Scholar
  21. 21.
    Lalau J, Race J, Brinquin L. Lactic acidosis in metformin therapy: relationship between plasma metformin concentration and renal function [letter]. Diabetes Care 1998 Aug; 21(8): 1366–7PubMedCrossRefGoogle Scholar
  22. 22.
    Lalau J, Race J. Lactic acidosis in metformin-treated patients: prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999 Apr; 20(4): 377–84PubMedCrossRefGoogle Scholar
  23. 23.
    Lalau J, Race J. Metformin and lactic acidosis in diabetic humans. Diabetes Obes Metab 2000 Jun; 2(3): 131–7PubMedCrossRefGoogle Scholar
  24. 24.
    Lacroix C, Danger P, Wojciechowski F. Microassay of plasma and erythrocyte metformin by high performance liquid chromatography [in French]. Ann Biol Clin (Paris) 1991; 49(2): 98–101Google Scholar
  25. 25.
    Ahmad S, Beckett M. Recovery from pH 6.38: lactic acidosis complicated by hypothermia. Emerg Med 2002 Mar; 19(2): 169–71CrossRefGoogle Scholar
  26. 26.
    Lalau J, Lacroix C. Measurement of metformin concentration in erythrocytes: clinical implications. Diabetes Obes Metab 2003 Mar; 5(2): 92–8CrossRefGoogle Scholar
  27. 27.
    Robert F, Fendri S, Hary L, et al. Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects. Diabetes Metab 2003 Jun; 29(3): 279–83PubMedCrossRefGoogle Scholar
  28. 28.
    Stades AME, Heikens JT, Erkelens DW, et al. Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 2004 Feb; 255(2): 179–87PubMedCrossRefGoogle Scholar
  29. 29.
    Leverve X. Lactic acidosis: a new insight? Minerva Anestesiol 1999 May; 65(5): 205–9PubMedGoogle Scholar
  30. 30.
    Maran A, Cranston I, Lomas J, et al. Protection by lactate of cerebral function during hypoglycemia. Lancet 1994 Jan; I: 16–20CrossRefGoogle Scholar
  31. 31.
    Vincent J. Lactate levels in critically ill patients. Acta Anaesthesiol Scand 1995; 39 Suppl. 107: 261–6CrossRefGoogle Scholar
  32. 32.
    Veneman T, Mitrakou A, Mokan M, et al. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes 1994 Nov; 43(11): 1311–7PubMedCrossRefGoogle Scholar
  33. 33.
    King P, Parkin H, McDonald IAB, et al. The effect of intravenous lactate on cerebral function during hypoglycemia. Diabet Med 1997 Jan; 14(1): 19–28PubMedCrossRefGoogle Scholar
  34. 34.
    King P, Kong M, Parkin H, et al. Intravenous lactate prevents cerebral dysfunction during hypoglycemia in insulin-dependent diabetes mellitus. Clin Sci 1998 Feb; 94(2): 157–63PubMedGoogle Scholar
  35. 35.
    Cusi K, Consoli A, DeFronzo R. Metabolic effects of metformin on glucose and lactate in non insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996 Nov; 96(11): 4059–67CrossRefGoogle Scholar
  36. 36.
    Wiernsperger N, Bayley C. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs 1999; 58 Suppl. 1: 31–9PubMedCrossRefGoogle Scholar
  37. 37.
    Wilcock C, Bayley C. Sites of metformin-stimulated metabolism. Biochem Pharmacol 1990 Jun; 39(11): 1831–4PubMedCrossRefGoogle Scholar
  38. 38.
    Bailey C, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol 1992 Apr; 105(4): 1009–15PubMedCrossRefGoogle Scholar
  39. 39.
    Radziuk J, Zhang Z, Wiernsperger N, et al. Effects of metformin on lactate uptake and gluconeogenesis in the perfused rat liver. Diabetes 1997 Sep; 46(4): 1406–13PubMedCrossRefGoogle Scholar
  40. 40.
    Leverve X, Guigas B, Detaille D, et al. Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. Diabetes Metab 2003 Sep; 29 (4 Pt 2): 6S88–94PubMedCrossRefGoogle Scholar
  41. 41.
    Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000 Jun; 348 (Pt 3): 607–14PubMedCrossRefGoogle Scholar
  42. 42.
    Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001 Oct; 108(8): 1167–74PubMedGoogle Scholar
  43. 43.
    Foretz M, Leclerc J, Hebrard S, Viollet B. Metformin inhibits hepatic gluconeogenesis through an AMPK-independent mechanism [abstract no. 1507]. 68th Scientific Sessions of the American Diabetic Association; 2008 Jun 6–10; San Francisco (CA), A423Google Scholar
  44. 44.
    Wang DS, Jonker JW, Kato Y, et al. Involvement of organic cation transporter 1 in the hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 2002; 63(4): 844–8Google Scholar
  45. 45.
    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 Feb; 117(2): 1422–31PubMedCrossRefGoogle Scholar
  46. 46.
    Wang DS, Kusuhara H, Kato Y, et al. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 2003 Apr; 63(4): 844–8PubMedCrossRefGoogle Scholar
  47. 47.
    Dykens JA, Jamieson J, Marroquin L, et al. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol 2008; 233: 203–10PubMedCrossRefGoogle Scholar
  48. 48.
    Wilcock C, Wyre N, Bailey C. Subcellular distribution of metformin in rat liver. J Pharm Pharmacol 1991 Jun; 43(6): 442–4PubMedCrossRefGoogle Scholar
  49. 49.
    Wilcock C, Bayley C. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1994 Jan; 24(1): 49–57PubMedCrossRefGoogle Scholar
  50. 50.
    Lalau J, Andrejak M, Morinière P, et al. Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 1989 Jun; 24(6): 683–93Google Scholar
  51. 51.
    Lalau J, Masmoudi K. Unexpected recovery from prolonged hypoglycaemic coma: a protective role of metformin [letter]? Intens Care Med 2005 Mar; 31(3): 493CrossRefGoogle Scholar
  52. 52.
    Assan R, Heuclin C, Ganeval D, et al. Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 1977 May; 13(3): 211–7PubMedCrossRefGoogle Scholar
  53. 53.
    Lalau J, Mourlhon C, Bergeret A, et al. Consequences of metformin intoxication [letter]. Diabetes Care 1998 Nov; 21(11): 2036–7PubMedCrossRefGoogle Scholar
  54. 54.
    European prescribing information for Glucophage®. Lyon: Merck Serono, 2005Google Scholar
  55. 55.
    Holstein A, Stumvoll M. Contraindications can damage your health: is metformin a case in point? Diabetologia 2005 Dec; 48(12): 2454–9PubMedCrossRefGoogle Scholar
  56. 56.
    Fontana L. Modulating human aging and age-associated diseases. Biochim Biophys Acta 2009 Oct; 1790(10): 1133–8PubMedCrossRefGoogle Scholar
  57. 57.
    Tahrani AA, Varughese GI, Scarpello JH, et al. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ 2007 Sept; 335: 508–12PubMedCrossRefGoogle Scholar
  58. 58.
    Gjedde S, Christiansen A, Pedersen S, et al. Survival following a metformin overdose of 63 g: a case report. Pharmacol Toxicol 2003 Aug; 93(2): 98–9PubMedCrossRefGoogle Scholar
  59. 59.
    Knaus WA, Wagner DP, Draper EA, et al. The APACHE III prognostic system: risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991 Dec; 100(6): 1619–36PubMedCrossRefGoogle Scholar
  60. 60.
    Nyirenda MJ, Sandeep T, Grant I, et al. Severe acidosis in patients taking metformin: rapid reversal and survival despite high APACHE score. Diabet Med 2006 Apr; 23(4): 432–5PubMedCrossRefGoogle Scholar
  61. 61.
    Dell’Aglio D, Perino LJ, Kazzi Z, et al. Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Ann Emerg Med 2009 Dec; 54(6): 818–23PubMedCrossRefGoogle Scholar
  62. 62.
    Gras V, Bouffandeau B, Montravers P, et al. Effect of metformin on survival rate in experimental sepsis. Diabetes Metab 2006 Apr; 32(2): 147–50PubMedCrossRefGoogle Scholar
  63. 63.
    Bouskela E, Wiensperger N. Effects of metformin on hemorrhagic shock, blood volume and ischemia/reperfusion on nondiabetic hamsters. J Vasc Med Biol 1993; 4: 41–6Google Scholar
  64. 64.
    Wiernsperger N. 50 years later: is metformin a vascular drug with antidiabetic properties? Br J Vasc Dis 2007 Sept/Oct; 7(5): 204–10CrossRefGoogle Scholar
  65. 65.
    Chan JCN, Davidons JA. Survival benefits of metformin in high-risk populations. In: Bailey CJ, Campbell IW, Chan JCN et al., editors. Metformin: the gold standard. Chichester: Wiley, 2007: 125–34Google Scholar
  66. 66.
    Scarpello JHB, Howlett HCS. Metformin therapy and clinical uses. Diabetes Vasc Dis Res 2008 Sept; 5(3): 157–67CrossRefGoogle Scholar
  67. 67.
    Sirtori C, Franceschini G, Gianfranceschi G et al. Metformin improves peripheral vascular flow in non hyperlipidemic patients with arterial disease. J Cardiovasc Pharmacol 1984 Sep/Oct; 6(5): 914–23PubMedCrossRefGoogle Scholar
  68. 68.
    Group UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998 Sept; II: 854–65Google Scholar
  69. 69.
    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 Jun; 93(11): 1347–50PubMedCrossRefGoogle Scholar
  70. 70.
    Sgambato S, Varrichio M, Tesauro P, et al. The use of metformin in ischemic cardiopathy. Clin Ther 1980 Jul; 94(1): 77–85Google Scholar
  71. 71.
    Eurich DT, Tsuyuki RT, Majundar SR, et al. Improved clinical outcome associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005 Oct; 28(10): 2345–51PubMedCrossRefGoogle Scholar
  72. 72.
    Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005 Feb; 111(5): 583–90PubMedCrossRefGoogle Scholar
  73. 73.
    Evans JMM, Ogston SA, Emslie-Smith A, et al. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006 May; 49(5): 930–6PubMedCrossRefGoogle Scholar
  74. 74.
    Montanari G, Bondioli A, Rizzato G, et al. Treatment with low dose metformin in patients with peripheral vascular disease. Pharmacol Res 1992 Jan; 25(1): 63–73PubMedCrossRefGoogle Scholar
  75. 75.
    Kakkar AK, Besterman WH, Lefer DJ. Preconditioning of the diabetic myocardium with acute metformin treatment. J Am Coll Cardiol 2004; 3: 1116–21Google Scholar
  76. 76.
    Weil M, Afifi A. Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation 1970 Jun; 41(6): 989–1001PubMedCrossRefGoogle Scholar
  77. 77.
    Cady Jr L, Weil M, Afifi A, et al. Quantisation of severity of critical illness with special reference to blood lactate. Crit Care Med 1973 Mar/Apr; 1(2): 75–80PubMedCrossRefGoogle Scholar
  78. 78.
    Batandier C, Guigas B, Detaille D, et al. The ROS production induced by a reverse-electron flux at respiratory complex 1 is hampered by metformin. J Bioenerg Biomembr 2006 Feb; 38(1): 33–42PubMedCrossRefGoogle Scholar
  79. 79.
    Detaille D, Guigas B, Chauvin C, et al. Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005 Jul; 54(7): 2179–87PubMedCrossRefGoogle Scholar
  80. 80.
    Arieff A, Gertz E, Park R, et al. Lactic acidosis and the cardiovascular system in the dog. Clin Sci 1983 Jun; 64(6): 573–80PubMedGoogle Scholar
  81. 81.
    Scheen A. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996 May; 30(5): 359–71PubMedCrossRefGoogle Scholar
  82. 82.
    Lalau J, Race J, Andreeli F, et al. Metformin retention independent of renal failure in intestinal occlusion. Diabetes Metab 2001 Feb; 27(1): 24–8PubMedGoogle Scholar
  83. 83.
    Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999 Mar; 130(6): 461–70PubMedGoogle Scholar
  84. 84.
    Warren RE, Strachan MWJ, Wild S, et al. Introducing estimated glomerular filtration rate (eGFR) into clinical practice in the UK: implications for the use of metformin. Diabet Med 2007 May; 24(5): 494–7PubMedCrossRefGoogle Scholar
  85. 85.
    Shaw JS, Wilmot RL, Kilpatrick ES. Establishing pragmatic estimated GFR thresholds to guide metformin prescribing. Diabet Med 2007 Oct; 24(10): 1160–3PubMedCrossRefGoogle Scholar
  86. 86.
    Lalau J, Vermersch A, Hary L, et al. Type 2 diabetes in the elderly: an assessment of metformin. Int J Clin Pharmacol Ther Toxicol 1990 Aug; 28(8): 329–32PubMedGoogle Scholar
  87. 87.
    Rachmani R, Slavachevski I, Levi Z, et al. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 2002 Oct; 13(7): 428–33PubMedCrossRefGoogle Scholar
  88. 88.
    Johnson JA, Majumdar SR, Simpson SH, et al. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 2002 Dec; 25(12): 2244–8PubMedCrossRefGoogle Scholar
  89. 89.
    Cohen R. Role of the liver and the kidney in acid-base regulation and its disorders. Br J Anesthesiol 1991 Aug; 67(2): 154–64CrossRefGoogle Scholar
  90. 90.
    Seidowsky A, Nseir S, Houdret N, et al. Metformin-associated lactic acidosis: a prognosis and therapeutic study. Crit Care Med 2009 Jul; 37(7): 2191–6PubMedCrossRefGoogle Scholar
  91. 91.
    Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973 Aug; 60(8): 646–9PubMedCrossRefGoogle Scholar
  92. 92.
    Emslie-Smith AM, Boyle DI, Evans JM, et al. Contraindications to metformin therapy in patients with type 2 diabetes: a population-based study of adherence to prescribing guidelines. Diabetic Med 2001 Jun; 18(6): 483–8PubMedCrossRefGoogle Scholar
  93. 93.
    Holstein A, Nahrwold D, Hinze S, et al. Contraindications to metformin are largely discarded. Diabetic Med 1999 Aug; 16(8): 692–6PubMedCrossRefGoogle Scholar
  94. 94.
    Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. Evidence suggests that it is time to amend the list. BMJ 2003 Apr; 326: 4–5PubMedCrossRefGoogle Scholar
  95. 95.
    McCormack J, Johns K, Tildesley H. Metformin’s contraindications should be contraindicated. CAMJ 2005 Aug; 173(5): 502–4CrossRefGoogle Scholar
  96. 96.
    Prikis M, Mesler EL, Hood VL, et al. When a friend can become an enemy! Recognition and management of metformin-associated lactic acidosis. Kidney Int 2007 Nov; 72(9): 1157–60PubMedCrossRefGoogle Scholar
  97. 97.
    Golay A. Metformin and body weight. Int J Obes 2008 Jan; 32(1): 61–72CrossRefGoogle Scholar
  98. 98.
    El-Mir MY, Detaille D, R-Villanueva G, et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 2008; 34(1): 77–87PubMedCrossRefGoogle Scholar
  99. 99.
    Libby G, Alessi DR, Donnelly LA, et al. New users of metformin are at low risk of incident cancer. Diabetes Care 2009 Sept; 32(9): 1620–5PubMedCrossRefGoogle Scholar
  100. 100.
    Zhen D, Chen Y, Tang X. Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complications. Epub 2009 Jul 21Google Scholar
  101. 101.
    Amiel SA, Dixon T, Mann R, et al. Hypoglycaemia in type 2 diabetes. Diabet Med 2008 Mar; 25(3): 245–54PubMedCrossRefGoogle Scholar
  102. 102.
    Mitri J, Hamdy O. Diabetes medications and body weight. Expert Opin Drug Saf 2009 Sep; 8(5): 573–84PubMedCrossRefGoogle Scholar
  103. 103.
    Patel RR. Thiazolidinediones and congestive heart failure: a judicious balance of risks and benefits. Cardiol Rev 2009 May–Jun; 17(3): 132–5PubMedCrossRefGoogle Scholar
  104. 104.
    Habib ZA, Havstad SL, Wells K, et al. Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2010 Feb; 95(2): 592–600PubMedCrossRefGoogle Scholar
  105. 105.
    Monami M, Balzi D, Lamanna C, et al. Are sulphonylureas all the same? A cohort study on cardiovascular and cancer-related mortality. Diabetes Metab Res Rev 2007 Sep; 23(6): 479–84PubMedCrossRefGoogle Scholar
  106. 106.
    Draznin B. Mitogenic action of insulin: friend, foe or ‘frenemy’? Diabetologia 2010 Feb; 53(2): 229–33PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2010

Authors and Affiliations

  1. 1.Service d’Endocrinologie-NutritionHôpital SudAmiens, Cedex 1France

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