Lactic acidosis induced by metformin: Incidence, management and prevention

Drug Safety

Volumn 33, Issue 9, 2010, Pages 727-740

  Lalau, Jean Daniel ^a  

^a AMIENS UNIVERSITY HOSPITAL   (France)

Author keywords

Lactic acidosis, drug induced; Lactic acidosis, epidemiology; Lactic acidosis, management; Lactic acidosis, prevention; Metformin, adverse reactions.

Indexed keywords

METFORMIN; PHENFORMIN;

CAUSAL ATTRIBUTION; DRUG CONTRAINDICATION; HEMODIALYSIS; HIGH RISK PATIENT; HUMAN; INCIDENCE; KIDNEY DYSFUNCTION; KIDNEY FAILURE; LACTIC ACIDOSIS; LIVER DISEASE; MORTALITY; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; RARE DISEASE; REVIEW;

ACIDOSIS, LACTIC; ANIMALS; DIABETES MELLITUS, TYPE 2; HUMANS; HYPOGLYCEMIC AGENTS; INCIDENCE; METFORMIN; RISK FACTORS;

EID: 77955566180     PISSN: 01145916     EISSN: 11791942     Source Type: Journal    
DOI: 10.2165/11536790-000000000-00000     Document Type: Review

References (106)

1. Chan N, Brain H, Feher M. Metformin-associated lacticacidosis: a rare or very rare clinical entity? Diabetic Med 1999 Apr; 16 (4): 273-281
2. Misbin RI. The phantom of lactic acidosis due to metfor-min in patients with diabetes. Diabetes Care 2004 Jul; 27 (7): 1791-1793
3. Cohen R, Woods H. The clinical presentations and classi-fications of lactic acidosis. In: Cohen R, HF Woods, editors. Clinical and biochemical aspects of lactic acidosis. Boston (MA): Blackwell Scientific Publications, 1976: 40-52
4. Luft D, Deichsel G, Schmulling R, et al. Definition ofclinically relevant lactic acidosis in patients with internal diseases. Am J Clin Pathol 1983 Oct; 80 (4): 484-489
5. Arieff A. Pathogenesis of lactic acidosis. Diabetes MetabRev 1989 Dec; 5 (8): 637-649
6. Stacpoole P. Lactic acidosis. Endocrinol Metab Clin NorthAm 1993; 22: 221-245
7. Sterne J. Pharmacology and mode of action of hypogly-caemic guanidine derivatives. In: Campbell IW, editor. Oral hypoglycaemic agents. London: Academic Press, 1969: 193-245
8. Kreisberg R, Pennington L, Boshell B. Lactate turnoverand gluconeogenesis in obesity: effect of phenformin. Diabetes 1970 Jan; 19 (1): 64-69
9. Searle G, Siperstein M. Lactic acidosis associated withphenformin therapy: evidence that inhibited lactate oxidation is the causative factor. Diabetes 1975 Aug; 24 (8): 741-745
10. Natrass M, Todd P, Hinks L, et al. Comparative effects of phenformin, metformin and glibenclamide in metabolicrhythms in maturity-onset diabetes. Diabetologia 1977 Apr; 13 (2): 145-152
11. Oates N, Shah R, Idle J, et al. Genetic polymorphism ofphenformin 4-hydroxylation. Clin Pharmacol Ther 1982 Jul; 32 (1): 81-89
12. Williams R, Palmer J. Farewell to phenformin for treatingdiabetes mellitus. Ann Intern Med 1975 Oct; 83 (4): 567-568
13. Cryer DR, Mills DJ, Nicholas SP, et al. Comparative out-comes study of metformin intervention versus conventional approach. Diabetes Care 2005 Mar; 28 (3): 539-543
14. Salpeter SR, Geryber E, Pasternak GA, et al. Risk of fataland nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010 Jan; (1): CD002967
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): 386-399
16. Bodmer M, Jick SS, Meier C, et al. Metformin, sulfony-lureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycaemia. Diabetes Care 2008 Nov; 31 (11): 2086-2091
17. Brown JB, Pedula K, Barzilay J, et al. Lactic acidosisrates in type 2 diabetes. Diabetes Care 1998 Oct; 21 (10): 1659-1663
18. Fulop M, Hoberman H. Phenformin-associated metabolicacidosis. Diabetes 1976 Apr; 25 (4): 292-296
19. Lalau J, Race J. Lactic acidosis in metformin therapy:searching for a link with metformin in reports of 'met-formin-associated lactic acidosis'. Diabetes Obes Metab 2001 Jun; 3 (3): 195-201
20. Lalau J, Lacroix C, Compagnon P, et al. Role of metforminaccumulation in metformin-associated lactic acidosis. Diabetes Care 1995 June; 18 (6): 779-784
21. Lalau J, Race J, Brinquin L. Lactic acidosis in metformintherapy: relationship between plasma metformin concentration and renal function [letter]. Diabetes Care 1998 Aug; 21 (8): 1366-1367
22. Lalau J, Race J. Lactic acidosis in metformin-treatedpatients: prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999 Apr; 20 (4): 377-384
23. Lalau J, Race J. Metformin and lactic acidosis in diabetichumans. Diabetes Obes Metab 2000 Jun; 2 (3): 131-137
24. Lacroix C, Danger P, Wojciechowski F. Microassay ofplasma and erythrocyte metformin by high performance liquid chromatography [in French]. Ann Biol Clin (Paris) 1991; 49 (2): 98-101
25. Ahmad S, Beckett M. Recovery from pH 6.38: lacticacidosis complicated by hypothermia. Emerg Med 2002 Mar; 19 (2): 169-171
26. Lalau J, Lacroix C. Measurement of metformin con-centration in erythrocytes: clinical implications. Diabetes Obes Metab 2003 Mar; 5 (2): 92-98
27. Robert F, Fendri S, Hary L, et al. Kinetics of plasma anderythrocyte metformin after acute administration in healthy subjects. Diabetes Metab 2003 Jun; 29 (3): 279-283
28. Stades AME, Heikens JT, Erkelens DW, et al. Metforminand lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 2004 Feb; 255 (2): 179-187
29. Leverve X. Lactic acidosis: a new insight? Minerva Anes-tesiol 1999 May; 65 (5): 205-209
30. Maran A, Cranston I, Lomas J, et al. Protection by lactateof cerebral function during hypoglycemia. Lancet 1994 Jan; I: 16-20
31. Vincent J. Lactate levels in critically ill patients. Acta An-aesthesiol Scand 1995; 39 Suppl. 107: 261-266
32. Veneman T, Mitrakou A, Mokan M, et al. Effect of hyper-ketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes 1994 Nov; 43 (11): 1311-1317
33. King P, Parkin H, McDonald IAB, et al. The effect of intra-venous lactate on cerebral function during hypoglycemia. Diabet Med 1997 Jan; 14 (1): 19-28
34. King P, Kong M, Parkin H, et al. Intravenous lactate pre-vents cerebral dysfunction during hypoglycemia in insulin-dependent diabetes mellitus. Clin Sci 1998 Feb; 94 (2): 157-163
35. Cusi K, Consoli A, DeFronzo R. Metabolic effects ofmetformin onglucose and lactatein non insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996 Nov; 96 (11): 4059-4067
36. Wiernsperger N, Bayley C. The antihyperglycaemic effectof metformin: therapeutic and cellular mechanisms. Drugs 1999; 58 Suppl. 1: 31-39
37. Wilcock C, Bayley C. Sites of metformin-stimulated me-tabolism. Biochem Pharmacol 1990 Jun; 39 (11): 1831-1834
38. Bailey C, Wilcock C, Day C. Effect of metformin on glu-cose metabolism in the splanchnic bed. Br J Pharmacol 1992 Apr; 105 (4): 1009-1015
39. Radziuk J, Zhang Z, Wiernsperger N, et al. Effects ofmetformin on lactate uptake and gluconeogenesis in the perfused rat liver. Diabetes 1997 Sep; 46 (4): 1406-1413
40. Leverve X, Guigas B, Detaille D, et al. Mitochondrial me-tabolism and type-2 diabetes: a specific target of metfor-min. Diabetes Metab 2003 Sep; 29 (4 Pt 2): 6S88-94
41. Owen MR, Doran E, Halestrap AP. Evidence that met-formin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Bio-chem J 2000 Jun; 348 (Pt 3): 607-614
42. Zhou G, Myers R, Li Y, et al. Role of AMP-activatedprotein kinase in mechanism of metformin action. J Clin Invest 2001 Oct; 108 (8): 1167-1174
43. Foretz M, Leclerc J, Hebrard S, Viollet B. Metformin inhibitshepatic gluconeogenesis through an AMPK-independent mechanism [abstract no. 1507]. 68th Scientific Sessions of the American Diabetic Association; 2008 Jun 6-10; San Francisco (CA), A423
44. Wang DS, Jonker JW, Kato Y, et al. Involvement of or-ganic cation transporter 1 in the hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 2002; 63 (4): 844-848
45. Shu Y, Sheardown SA, Brown C, et al. Effect of geneticvariation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007 Feb; 117 (2): 1422-1431
46. Wang DS, Kusuhara H, Kato Y, et al. Involvement oforganic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 2003 Apr; 63 (4): 844-848
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: 203-210
48. Wilcock C, Wyre N, Bailey C. Subcellular distribution ofmetformin in rat liver. J Pharm Pharmacol 1991 Jun; 43 (6): 442-444
49. Wilcock C, Bayley C. Accumulation of metformin by tis-sues of the normal and diabetic mouse. Xenobiotica 1994 Jan; 24 (1): 49-57
50. Lalau J, Andrejak M, Moriniere P, et al. Hemodialysis inthe treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 1989 Jun; 24 (6): 683-693
51. Lalau J, Masmoudi K. Unexpected recovery from pro-longed hypoglycaemic coma: a protective role of metformin [letter]? Intens Care Med 2005 Mar; 31 (3): 493
52. Assan R, Heuclin C, Ganeval D, et al. Metformin-inducedlactic acidosis in the presence of acute renal failure. Dia-betologia 1977 May; 13 (3): 211-217
53. Lalau J, Mourlhon C, Bergeret A, et al. Consequences ofmetformin intoxication [letter]. Diabetes Care 1998 Nov; 21 (11): 2036-2037
54. European prescribing information for Glucophage®. Lyon:Merck Serono, 2005
55. Holstein A, Stumvoll M. Contraindications can damageyour health: is metformin a case in point? Diabetologia 2005 Dec; 48 (12): 2454-2459
56. Fontana L. Modulating human aging and age-associateddiseases. Biochim Biophys Acta 2009 Oct; 1790 (10): 1133-1138
57. Tahrani AA, Varughese GI, Scarpello JH, et al. Metfor-min, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ 2007 Sept; 335: 508-512
58. Gjedde S, Christiansen A, Pedersen S, et al. Survival fol-lowing a metformin overdose of 63 g: a case report. Pharmacol Toxicol 2003 Aug; 93 (2): 98-99
59. Knaus WA, Wagner DP, Draper EA, et al. The APACHEIII prognostic system: risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991 Dec; 100 (6): 1619-1636
60. Nyirenda MJ, Sandeep T, Grant I, et al. Severe acidosis inpatients taking metformin: rapid reversal and survival despite high APACHE score. Diabet Med 2006 Apr; 23 (4): 432-435
61. Dell'Aglio D, Perino LJ, Kazzi Z, et al. Acute metforminoverdose: 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): 818-823
62. Gras V, Bouffandeau B, Montravers P, et al. Effect ofmetformin on survival rate in experimental sepsis. Diabetes Metab 2006 Apr; 32 (2): 147-150
63. Bouskela E, Wiensperger N. Effects of metformin on he-morrhagic shock, blood volume and ischemia/reperfusion on nondiabetic hamsters. J Vasc Med Biol 1993; 4: 41-46
64. Wiernsperger N. 50 years later: is metformin a vasculardrug with antidiabetic properties? Br J Vasc Dis 2007 Sept/Oct; 7 (5): 204-210
65. Chan JCN, Davidons JA. Survival benefits of metformin inhigh-risk populations. In: Bailey CJ, Campbell IW, ChanJCN et al., editors. Metformin: the gold standard. Chi-chester: Wiley, 2007: 125-134
66. Scarpello JHB, Howlett HCS. Metformin therapy andclinical uses. Diabetes Vasc Dis Res 2008 Sept; 5 (3): 157-167
67. Sirtori C, Franceschini G, Gianfranceschi G et al. Metforminimproves peripheral vascular flow in non hyperlipidemic patients with arterial disease. J Cardiovasc Pharmacol 1984 Sep/Oct; 6 (5): 914-923
68. Group UKPDS. Effect of intensive blood-glucose controlwith metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998 Sept; II: 854-865
69. Kao J, Tobis J, McClelland RL, et al. Relation of metfor-min treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol 2004 Jun; 93 (11): 1347-1350
70. Sgambato S, Varrichio M, Tesauro P, et al. The use ofmetformin in ischemic cardiopathy. Clin Ther 1980 Jul; 94 (1): 77-85
71. Eurich DT, Tsuyuki RT, Majundar SR, et al. Improvedclinical outcome associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005 Oct; 28 (10): 2345-2351
72. Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinedi-ones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005 Feb; 111 (5): 583-590
73. Evans JMM, Ogston SA, Emslie-Smith A, et al. Risk ofmortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006 May; 49 (5): 930-936
74. Montanari G, Bondioli A, Rizzato G, et al. Treatment withlow dose metformin in patients with peripheral vascular disease. Pharmacol Res 1992 Jan; 25 (1): 63-73
75. Kakkar AK, Besterman WH, Lefer DJ. Preconditioning ofthe diabetic myocardium with acute metformin treatment. J Am Coll Cardiol 2004; 3: 1116-1121
76. Weil M, Afifi A. Experimental and clinical studies on lac-tate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation 1970 Jun; 41 (6): 989-1001
77. Cady Jr L, Weil M, Afifi A, et al. Quantisation of severityof critical illness with special reference to blood lactate. Crit Care Med 1973 Mar/Apr; 1 (2): 75-80
78. Batandier C, Guigas B, Detaille D, et al. The ROS pro-duction induced by a reverse-electron flux at respiratory complex 1 is hampered by metformin. J Bioenerg Bio-membr 2006 Feb; 38 (1): 33-42
79. Detaille D, Guigas B, Chauvin C, et al. Metformin preventshigh-glucose- induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005 Jul; 54 (7): 2179-2187
80. Arieff A, Gertz E, Park R, et al. Lactic acidosis and thecardiovascular system in the dog. Clin Sci 1983 Jun; 64 (6): 573-580
81. Scheen A. Clinical pharmacokinetics of metformin. ClinPharmacokinet 1996 May; 30 (5): 359-371
82. Lalau J, Race J, Andreeli F, et al. Metformin retentionindependent of renal failure in intestinal occlusion. Diabetes Metab 2001 Feb; 27 (1): 24-28
83. Levey AS, Bosch JP, Lewis JB, et al. A more accuratemethod 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): 461-470
84. Warren RE, Strachan MWJ, Wild S, et al. Introducing es-timated glomerular filtration rate (eGFR) into clinical practice in the UK: implications for the use of metformin. Diabet Med 2007 May; 24 (5): 494-497
85. Shaw JS, Wilmot RL, Kilpatrick ES. Establishing prag-matic estimated GFR thresholds to guide metformin prescribing. Diabet Med 2007 Oct; 24 (10): 1160-1163
86. Lalau J, Vermersch A, Hary L, et al. Type 2 diabetes in theelderly: an assessment of metformin. Int J Clin Pharmacol Ther Toxicol 1990 Aug; 28 (8): 329-332
87. Rachmani R, Slavachevski I, Levi Z, et al. Metformin inpatients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 2002 Oct; 13 (7): 428-433
88. Johnson JA, Majumdar SR, Simpson SH, et al. Decreasedmortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 2002 Dec; 25 (12): 2244-2248
89. Cohen R. Role of the liver and the kidney in acid-baseregulation and its disorders. Br J Anesthesiol 1991 Aug; 67 (2): 154-164
90. Seidowsky A, Nseir S, Houdret N, et al. Metformin-asso-ciated lactic acidosis: a prognosis and therapeutic study. Crit Care Med 2009 Jul; 37 (7): 2191-2196
91. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transec-tion of the oesophagus for bleeding oesophageal varices. Br J Surg 1973 Aug; 60 (8): 646-649
92. Emslie-Smith AM, Boyle DI, Evans JM, et al. Contra-indications to metformin therapy in patients with type 2 diabetes: a population-based study of adherence to prescribing guidelines. Diabetic Med 2001 Jun; 18 (6): 483-488
93. Holstein A, Nahrwold D, Hinze S, et al. Contraindicationsto metformin are largely discarded. Diabetic Med 1999 Aug; 16 (8): 692-696
94. Jones GC, Macklin JP, Alexander WD. Contraindicationsto the use of metformin. Evidence suggests that it is time to amend the list. BMJ 2003 Apr; 326: 4-5
95. McCormack J, Johns K, Tildesley H. Metformin's contra-indications should be contraindicated. CAMJ 2005 Aug; 173 (5): 502-504
96. Prikis M, Mesler EL, Hood VL, et al. When a friend canbecome an enemy! Recognition and management of met-formin-associated lactic acidosis. Kidney Int 2007 Nov; 72 (9): 1157-1160
97. Golay A. Metformin and body weight. Int J Obes 2008 Jan;32 (1): 61-72
98. El-Mir MY, Detaille D, R-Villanueva G, et al. Neuroprotec-tive role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 2008; 34 (1): 77-87
99. Libby G, Alessi DR, Donnelly LA, et al. New users ofmetformin are at low risk of incident cancer. Diabetes Care 2009 Sept; 32 (9): 1620-1625
100. Zhen D, Chen Y, Tang X. Metformin reverses the deleter-ious effects of high glucose on osteoblast function. J Diabetes Complications. Epub 2009 Jul 21
101. Amiel SA, Dixon T, Mann R, et al. Hypoglycaemia in type2 diabetes. Diabet Med 2008 Mar; 25 (3): 245-254
102. Mitri J, Hamdy O. Diabetes medications and body weight.Expert Opin Drug Saf 2009 Sep; 8 (5): 573-584
103. Patel RR. Thiazolidinediones and congestive heart failure:a judicious balance of risks and benefits. Cardiol Rev 2009 May-Jun; 17 (3): 132-135
104. Habib ZA, Havstad SL, Wells K, et al. Thiazolidinedioneuse and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2010 Feb; 95 (2): 592-600
105. Monami M, Balzi D, Lamanna C, et al. Are sulphonylureasall the same? A cohort study on cardiovascular and cancer-related mortality. Diabetes Metab Res Rev 2007 Sep; 23 (6): 479-484
106. Draznin B. Mitogenic action of insulin: friend, foe or'frenemy'? Diabetologia 2010 Feb; 53 (2): 229-233