Metformin revisited: A critical review of the benefit-risk balance in at-risk patients with type 2 diabetes

Diabetes and Metabolism

Volumn 39, Issue 3, 2013, Pages 179-190

  Scheen, A J ^a   Paquot, N ^a  

^a UNIVERSITY OF LIÈGE   (Belgium)

Author keywords

Coronary artery disease; Elderly; Heart failure; Lactic acidosis; Metformin; Renal insufficiency; Type 2 diabetes

Indexed keywords

GLIBENCLAMIDE; GLICLAZIDE; GLIMEPIRIDE; GLIPIZIDE; INSULIN; INSULIN SENSITIZING AGENT; METFORMIN; REPAGLINIDE; SULFONYLUREA; THIAZOLIDINE DERIVATIVE; TOLBUTAMIDE;

ACUTE CORONARY SYNDROME; AGING; CHRONIC KIDNEY DISEASE; CHRONIC RESPIRATORY FAILURE; CLINICAL ASSESSMENT; CLINICAL PRACTICE; COMORBIDITY; CONGESTIVE HEART FAILURE; CORONARY ARTERY DISEASE; CREATININE CLEARANCE; DISEASE REGISTRY; DISEASE SEVERITY; GLOMERULUS FILTRATION RATE; HEART INFARCTION; HUMAN; INSULIN SENSITIVITY; KIDNEY CLEARANCE; KIDNEY DYSFUNCTION; LACTIC ACIDOSIS; LIVER DYSFUNCTION; MEDLINE; MORTALITY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; OBSERVATIONAL STUDY; PHYSICIAN; PRESCRIPTION; PREVALENCE; REVIEW; RISK BENEFIT ANALYSIS; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; TREATMENT CONTRAINDICATION;

DIABETES MELLITUS, TYPE 2; HUMANS; HYPOGLYCEMIC AGENTS; METFORMIN;

EID: 84878753448     PISSN: 12623636     EISSN: 18781780     Source Type: Journal    
DOI: 10.1016/j.diabet.2013.02.006     Document Type: Review

References (97)

1. Consoli A., Gomis R., Halimi S., Home P.D., Mehnert H., Strojek K., et al. Initiating oral glucose-lowering therapy with metformin in type 2 diabetic patients: an evidence-based strategy to reduce the burden of late-developing diabetes complications. Diabetes Metab 2004, 30:509-516.
2. Bennett W.L., Maruthur N.M., Singh S., Segal J.B., Wilson L.M., Chatterjee R., et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 2011, 154:602-613.
3. Inzucchi S.E., Bergenstal R.M., Buse J.B., Diamant M., Ferrannini E., Nauck M., et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012, 55:1577-1596.
4. Viollet B., Guigas B., Sanz Garcia N., Leclerc J., Foretz M., Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012, 122:253-270.
5. Miller R.A., Chu Q., Xie J., Foretz M., Viollet B., Birnbaum M.J. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013, 494:256-260.
6. Bailey C.J., Turner R.C. Metformin. N Engl J Med 1996, 334:574-579.
7. Kirpichnikov D., McFarlane S.I., Sowers J.R. Metformin: an update. Ann Intern Med 2002, 137:25-33.
8. Lalau J.D. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf 2010, 33:727-740.
9. Scheen A.J. Metformin and lactic acidosis. Acta Clin Belg 2011, 66:329-331.
10. UK 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, 352:854-865.
11. Holman R.R., Paul S.K., Bethel M.A., Matthews D.R., Neil H.A. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008, 359:1577-1589.
12. Howlett H.C., Bailey C.J. A risk-benefit assessment of metformin in type 2 diabetes mellitus. Drug Saf 1999, 20:489-503.
13. Boussageon R., Supper I., Bejan-Angoulvant T., Kellou N., Cucherat M., Boissel J.P., et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012, 9:e1001204.
14. Klachko D., Whaley-Connell A. Use of metformin in patients with kidney and cardiovascular diseases. Cardiorenal Med 2011, 1:87-95.
15. Salpeter S.R., Greyber E., Pasternak G.A., Salpeter Posthumous E.E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010, [Epub 2010/01/22: CD002967].
16. Emslie-Smith A.M., Boyle D.I., Evans J.M., Sullivan F., Morris A.D. Contraindications to metformin therapy in patients with Type 2 diabetes - a population-based study of adherence to prescribing guidelines. Diabet Med 2001, 18:483-488.
17. Sulkin T.V., Bosman D., Krentz A.J. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997, 20:925-928.
18. Holstein A., Nahrwold D., Hinze S., Egberts E.H. Contra-indications to metformin therapy are largely disregarded. Diabet Med 1999, 16:692-696.
19. Legrand D., Scheen A.J. Cumul de facteurs de risque et interactions médicamenteuses aboutissant à une acidose lactique sévère. Therapie 2008, 63:69-70.
20. Roussel R., Travert F., Pasquet B., Wilson P.W., Smith S.C., Goto S., et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 2010, 170:1892-1899.
21. Fisman E.Z., Tenenbaum A., Benderly M., Goldbourt U., Behar S., Motro M. Antihyperglycemic treatment in diabetics with coronary disease: increased metformin-associated mortality over a 5-year follow-up. Cardiology 1999, 91:195-202.
22. Schramm T.K., Gislason G.H., Vaag A., Rasmussen J.N., Folke F., Hansen M.L., et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J 2011, 32:1900-1908.
23. Pantalone K.M., Kattan M.W., Yu C., Wells B.J., Arrigain S., Jain A., et al. Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab 2012, 14:803-809.
24. Hong J., Zhang Y., Lai S., Lv A., Su Q., Dong Y., et al. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2012, [Epub 2012/12/12, still on line].
25. Frye R.L., August P., Brooks M.M., Hardison R.M., Kelsey S.F., MacGregor J.M., et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009, 360:2503-2515.
26. Kao J., Tobis J., McClelland R.L., Heaton M.R., Davis B.R., Holmes D.R., et al. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol 2004, 93:1347-1350. [A5].
27. McGuire D.K., Newby L.K., Bhapkar M.V., Moliterno D.J., Hochman J.S., Klein W.W., et al. Association of diabetes mellitus and glycemic control strategies with clinical outcomes after acute coronary syndromes. Am Heart J 2004, 147:246-252.
28. Inzucchi S.E., Masoudi F.A., Wang Y., Kosiborod M., Foody J.M., Setaro J.F., et al. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: insights from the National Heart Care Project. Diabetes Care 2005, 28:1680-1689.
29. Horsdal H.T., Johnsen S.P., Sondergaard F., Rungby J. Type of preadmission glucose-lowering treatment and prognosis among patients hospitalised with myocardial infarction: a nationwide follow-up study. Diabetologia 2008, 51:567-574.
30. Jorgensen C.H., Gislason G.H., Andersson C., Ahlehoff O., Charlot M., Schramm T.K., et al. Effects of oral glucose-lowering drugs on long-term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention--a retrospective nationwide cohort study. Cardiovasc Diabetol 2010, 9:54.
31. Jorgensen C.H., Gislason G.H., Bretler D., Sorensen R., Norgaard M.L., Hansen M.L., et al. Glyburide increases risk in patients with diabetes mellitus after emergent percutaneous intervention for myocardial infarction - a nationwide study. Int J Cardiol 2011, 152:327-331.
32. Mellbin L.G., Malmberg K., Norhammar A., Wedel H., Ryden L. Prognostic implications of glucose-lowering treatment in patients with acute myocardial infarction and diabetes: experiences from an extended follow-up of the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Study. Diabetologia 2011, 54:1308-1317.
33. Zhao J.L., Fan C.M., Yang Y.J., You S.J., Gao X., Zhou Q., et al. Chronic pretreatment of metformin is associated with the reduction of the No-reflow phenomenon in patients with diabetes mellitus after primary angioplasty for acute myocardial infarction. Cardiovasc Ther 2013, 31:60-64.
34. El Messaoudi S., Rongen G.A., de Boer R.A., Riksen N.P. The cardioprotective effects of metformin. Curr Opin Lipidol 2011, 22:445-453.
35. Lexis C.P., van der Horst I.C., Lipsic E., van der Harst P., van der Horst-Schrivers A.N., Wolffenbuttel B.H., et al. Metformin in non-diabetic patients presenting with ST elevation myocardial infarction: rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial. Cardiovasc Drugs Ther 2012, 26:417-426.
36. Masoudi F.A., Wang Y., Inzucchi S.E., Setaro J.F., Havranek E.P., Foody J.M., et al. Metformin and thiazolidinedione use in Medicare patients with heart failure. JAMA 2003, 290:81-85.
37. Eurich D.T., McAlister F.A., Blackburn D.F., Majumdar S.R., Tsuyuki R.T., Varney J., et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007, 335:497.
38. Papanas N., Maltezos E., Mikhailidis D.P. Metformin and heart failure: never say never again. Expert Opin Pharmacother 2012, 13:1-8.
39. Masoudi F.A., Inzucchi S.E., Wang Y., Havranek E.P., Foody J.M., Krumholz H.M. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005, 111:583-590.
40. Eurich D.T., Majumdar S.R., McAlister F.A., Tsuyuki R.T., Johnson J.A. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005, 28:2345-2351.
41. Andersson C., Olesen J.B., Hansen P.R., Weeke P., Norgaard M.L., Jorgensen C.H., et al. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. Diabetologia 2010, 53:2546-2553.
42. MacDonald M.R., Eurich D.T., Majumdar S.R., Lewsey J.D., Bhagra S., Jhund P.S., et al. Treatment of type 2 diabetes and outcomes in patients with heart failure: a nested case-control study from the U.K. general practice research database. Diabetes Care 2010, 33:1213-1218.
43. Aguilar D., Chan W., Bozkurt B., Ramasubbu K., Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail 2011, 4:53-58.
44. Eurich D.T., Tsuyuki R.T., Majumdar S.R., McAlister F.A., Lewanczuk R., Shibata M.C., et al. Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality. Trials 2009, 10:12.
45. Tahrani A.A., Varughese G.I., Scarpello J.H., Hanna F.W. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated?. BMJ 2007, 335:508-512.
46. Boyd A., Nawarskas J. Metformin use in decompensated heart failure. Cardiol Rev 2008, 16:269-272.
47. Scheen A.J. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996, 30:359-371.
48. Graham G.G., Punt J., Arora M., Day R.O., Doogue M.P., Duong J.K., et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011, 50:81-98.
49. Sambol N.C., Chiang J., Lin E.T., Goodman A.M., Liu C.Y., Benet L.Z., et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol 1995, 35:1094-1102.
50. Harrower A.D. Pharmacokinetics of oral antihyperglycaemic agents in patients with renal insufficiency. Clin Pharmacokinet 1996, 31:111-119.
51. Scheen A.J. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin Drug Metab Toxicol 2013, [Epub ahead of print].
52. Koro C.E., Lee B.H., Bowlin S.J. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin Ther 2009, 31:2608-2617.
53. Meyers J.L., Candrilli S.D., Kovacs B. Type 2 diabetes mellitus and renal impairment in a large outpatient electronic medical records database: rates of diagnosis and antihyperglycemic medication dose adjustment. Postgrad Med 2011, 123:133-143.
54. American Diabetes Association Standards of medical care in diabetes - 2011. Diabetes Care 2011, 34(Suppl. 1):S11-S61.
55. Ekstrom N., Schioler L., Svensson A.M., Eeg-Olofsson K., Miao Jonasson J., Zethelius B., et al. Effectiveness and safety of metformin in 51,675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open 2012, 2(4). [doi:pii: e001076. 10.1136/bmjopen-2012-001076].
56. Nkontchou G., Cosson E., Aout M., Mahmoudi A., Bourcier V., Charif I., et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab 2011, 96:2601-2608.
57. Popov V.B., Lim J.K. Impact of insulin-sensitizing agents on risk for liver cancer and liver-related death in diabetic patients with compensated hepatitis C cirrhosis. J Clin Endocrinol Metab 2011, 96:2398-2400.
58. Brackett C.C. Clarifying metformin's role and risks in liver dysfunction. J Am Pharm Assoc (2003) 2010, 50:407-410.
59. Rakoski M.O., Singal A.G., Rogers M.A., Conjeevaram H. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2010, 32:1211-1221.
60. Mazza A., Fruci B., Garinis G.A., Giuliano S., Malaguarnera R., Belfiore A. The role of metformin in the management of NAFLD. Exp Diabetes Res 2012, 2012:716404.
61. Barbero-Becerra V.J., Santiago-Hernandez J.J., Villegas-Lopez F.A., Mendez-Sanchez N., Uribe M., Chavez-Tapia N.C. Mechanisms involved in the protective effects of metformin against nonalcoholic fatty liver disease. Curr Med Chem 2012, 19:2918-2923.
62. Nadeau K.J., Ehlers L.B., Zeitler P.S., Love-Osborne K. Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr Diabetes 2009, 10:5-13.
63. Nobili V., Manco M., Ciampalini P., Alisi A., Devito R., Bugianesi E., et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther 2008, 30:1168-1176.
64. Williamson R.M., Price J.F., Glancy S., Perry E., Nee L.D., Hayes P.C., et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 2011, 34:1139-1144.
65. Bugianesi E., Gentilcore E., Manini R., Natale S., Vanni E., Villanova N., et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005, 100:1082-1090.
66. Tiikkainen M., Hakkinen A.M., 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, 53:2169-2176.
67. Musso G., Cassader M., Rosina F., Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012, 55:885-904.
68. Chalasani N., Younossi Z., Lavine J.E., Diehl A.M., Brunt E.M., Cusi K., et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012, 142:1592-1609.
69. Park C.S., Bang B.R., Kwon H.S., Moon K.A., Kim T.B., Lee K.Y., et al. Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem Pharmacol 2012, 84:1660-1670.
70. Neumiller J.J., Setter S.M. Pharmacologic management of the older patient with type 2 diabetes mellitus. Am J Geriatr Pharmacother 2009, 7:324-342.
71. Lalau J.D., Vermersch A., Hary L., Andrejak M., Isnard F., Quichaud J. Type 2 diabetes in the elderly: an assessment of metformin (metformin in the elderly). Int J Clin Pharmacol Ther Toxicol 1990, 28:329-332.
72. Ito H., Ohno Y., Yamauchi T., Kawabata Y., Ikegami H. Efficacy and safety of metformin for treatment of type 2 diabetes in elderly Japanese patients. Geriatr Gerontol Int 2011, 11:55-62.
73. Kosmalski M., Drozdowska A., Sliwinska A., Drzewoski J. Inappropriate metformin prescribing in elderly type 2 diabetes mellitus (T2DM) patients. Adv Med Sci 2012, 57:65-70.
74. Tzoulaki I., Molokhia M., Curcin V., Little M.P., Millett C.J., Ng A., et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 2009, 339:b4731.
75. Holstein A., Stumvoll M. Contraindications can damage your health - is metformin a case in point?. Diabetologia 2005, 48:2454-2459.
76. Ryden L., Standl E., Bartnik M., Van den Berghe G., Betteridge J., de Boer M.J., et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The task force on diabetes and cardiovascular diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007, 28:88-136.
77. Kooy A., de Jager J., Lehert P., Bets D., Wulffele M.G., Donker A.J., et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009, 169:616-625.
78. Anfossi G., Russo I., Bonomo K., Trovati M. The cardiovascular effects of metformin: further reasons to consider an old drug as a cornerstone in the therapy of type 2 diabetes mellitus. Curr Vasc Pharmacol 2010, 8:327-337.
79. Yeh C.H., Chen T.P., Wang Y.C., Lin Y.M., Fang S.W. AMP-activated protein kinase activation during cardioplegia-induced hypoxia/reoxygenation injury attenuates cardiomyocytic apoptosis via reduction of endoplasmic reticulum stress. Mediators Inflamm 2010, 2010:130636.
80. Calvert J.W., Gundewar S., Jha S., Greer J.J., Bestermann W.H., Tian R., et al. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 2008, 57:696-705.
81. Whittington H.J., Hall A.R., McLaughlin C.P., Hausenloy D.J., Yellon D.M., Mocanu M.M. Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon. Cardiovasc Drugs Ther 2013, 27:5-16.
82. National Kidney Foundation KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012, 60:850-886.
83. Lipska K.J., Bailey C.J., Inzucchi S.E. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011, 34:1431-1437.
84. Philbrick A.M., Ernst M.E., McDanel D.L., Ross M.B., Moores K.G. Metformin use in renal dysfunction: is a serum creatinine threshold appropriate?. Am J Health Syst Pharm 2009, 66:2017-2023.
85. Vasisht K.P., Chen S.C., Peng Y., Bakris G.L. Limitations of metformin use in patients with kidney disease: are they warranted?. Diabetes Obes Metab 2010, 12:1079-1083.
86. Pongwecharak J., Tengmeesri N., Malanusorn N., Panthong M., Pawangkapin N. Prescribing metformin in type 2 diabetes with a contraindication: prevalence and outcome. Pharm World Sci 2009, 31:481-486.
87. Kennedy L., Herman W.H. Renal status among patients using metformin in a primary care setting. Diabetes Care 2005, 28:922-924.
88. Nye H.J., Herrington W.G. Metformin: the safest hypoglycaemic agent in chronic kidney disease?. Nephron Clin Pract 2011, 118:c380-c383.
89. Pilmore H.L. Review: metformin: potential benefits and use in chronic kidney disease. Nephrology (Carlton) 2010, 15:412-418.
90. del Pozo-Fernandez C., Pardo-Ruiz C., Sanchez-Botella C., Blanes-Castaner V., Lopez-Menchero R., Gisbert-Selles C., et al. Discrepancies among consensus documents, guidelines, clinical practice and the legal framework for the treatment of type 2 diabetes mellitus patients. Nefrologia 2012, 32:367-373.
91. Eurich D.T., Majumdar S.R., McAlister F.A., Tsuyuki R.T., Johnson J.A. Levels of evidence needed for changing indications, contraindications, and food and drug administration labeling: the case of metformin. Arch Intern Med 2011, 171:1042-1043. [Author reply 3].
92. Rocha A., Almeida M., Santos J., Carvalho A. Metformin in patients with chronic kidney disease: strengths and weaknesses. J Nephrol 2013, 26:55-60.
93. Scheen A.J. DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab 2012, 38:89-101.
94. Paolisso G., Monami M., Marfella R., Rizzo M.R., Mannucci E. Dipeptidyl peptidase-4 inhibitors in the elderly: more benefits or risks?. Adv Ther 2012, 29:218-233.
95. Cayea D., Boyd C., Durso S.C. Individualising therapy for older adults with diabetes mellitus. Drugs Aging 2007, 24:851-863.
96. Beck E., Scheen A.J. Quels bénéfices anti-tumoraux attendre de la metformine?. Ann Endocrinol (Paris) 2013, [sous presse].
97. Noto H., Goto A., Tsujimoto T., Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. Plos One 2012, 7:e33411.