Metformin: an old but still the best treatment for type 2 diabetes

Diabetology & Metabolic Syndrome

Marilia Brito Gomes¹  Lilian Beatriz Aguayo Rojas¹ 

[1] Department of Medicine, Diabetes Unit, State University of Rio de Janeiro, Av 28 setembro 77, Rio de Janeiro CEP20555-030, Brazil

关键词: Resistance;    Insulin;    Diabetes mellitus;    Metformin;   

Others  :  814718
DOI  :  10.1186/1758-5996-5-6

 received in 2012-12-12, accepted in 2013-02-05,  发布年份 2013

【 摘 要 】

The management of T2DM requires aggressive treatment to achieve glycemic and cardiovascular risk factor goals. In this setting, metformin, an old and widely accepted first line agent, stands out not only for its antihyperglycemic properties but also for its effects beyond glycemic control such as improvements in endothelial dysfunction, hemostasis and oxidative stress, insulin resistance, lipid profiles, and fat redistribution. These properties may have contributed to the decrease of adverse cardiovascular outcomes otherwise not attributable to metformin’s mere antihyperglycemic effects. Several other classes of oral antidiabetic agents have been recently launched, introducing the need to evaluate the role of metformin as initial therapy and in combination with these newer drugs. There is increasing evidence from in vivo and in vitro studies supporting its anti-proliferative role in cancer and possibly a neuroprotective effect. Metformin’s negligible risk of hypoglycemia in monotherapy and few drug interactions of clinical relevance give this drug a high safety profile. The tolerability of metformin may be improved by using an appropiate dose titration, starting with low doses, so that side-effects can be minimized or by switching to an extended release form. We reviewed the role of metformin in the treatment of patients with type 2 diabetes and describe the additional benefits beyond its glycemic effect. We also discuss its potential role for a variety of insulin resistant and pre-diabetic states, obesity, metabolic abnormalities associated with HIV disease, gestational diabetes, cancer, and neuroprotection.

【 授权许可】

   
2013 Rojas and Gomes.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Godarzi MO, Brier-Ash M: Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab 2005, 5:654-665.
• [2]Shaw RJ, Lamia KA, Vasquez D: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005, 310:1642-1646.
• [3]El-Mir MY, Nogueira V, Fontaine E: Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000, 275:223-228.
• [4]Wild S, Roglic G, Green A, Sicree R, King H: Global prevalence of diabetes. Estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27:1047-1053.
• [5]Guillies C, Abram KR, Lambert PC, Cooper NJ, Sutton AJ: Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ 2007, 334:299.
• [6]Petersen J, Mc Guire D: Impaired glucose tolerance and impaired fasting glucose – a review of diagnosis, clinical implications and management. Diabetes Vasc Dis Res 2005, 2(1):9-15.
• [7]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.
• [8]Diabetes Prevention Program Research Group: Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care 2003, 26(4):977-980.
• [9]Ramachandran A, Snehalatha C, Mukesh M: Indian diabetes prevention programme (IDPP). 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, 49:289-297.
• [10]Yang W, Lin L, Qi J: 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, 17:131-134.
• [11]Diabetes Prevention Program Research Group: 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009, 374(9702):1677-1686.
• [12]Ramachandran A, Snehalatha C, Vijay V: Low risk threshold for acquired diabetogenic factors in Asian Indians. Diab Res Clin Pract 2004, 65:189-195.
• [13]Pan XR, Li GW, Hu YH: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: The Da Qing IGT and Diabetes Study. Diabetes Care 1997, 20:537-544.
• [14]Salpeter SR, Buckley NS, Kahn JA: Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med 2008, 121:149-157.
• [15]Lily M, Godwin M: Treating prediabetes with metformin systematic review and meta-analysis. Can Fam Physician 2009, 55:363-369.
• [16]American Diabetes Association: Summary of revisions to the 2011 clinical practice recommendations. Diabetes Care 2011, 34(Suppl 1):S3.
• [17]Rodbard HW, Jellinger PS, Davidson JA: Statement by an American association of clinical endocrinologists/American college of endocrinology consensus panel on type 2 diabetes mellitus. An algorithm for glycemic control. Endocr Pract 2009, 15(6):540-559.
• [18]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(9131):854-865.
• [19]Ito H, Ishida H, Takeuchi Y: Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus. Nutr Metab 2010, 7:83. BioMed Central Full Text
• [20]Turner RC, Cull CA, Frighi V, Holman RR: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999, 281:2005-2012.
• [21]Gerich J, Raskin P, Jean-Louis L: PRESERVE-beta: two-year efficacy and safety of initial combination therapy with nateglinide or glyburide plus metformin. Diabetes Care 2005, 28:2093-2099.
• [22]Phung OJ, Scholle JM, Talwar M, Coleman CI: Effect of noninsulin Antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 2010, 303(14):1410-1418.
• [23]Charbonnel B, Shernthaner G, Brunetti P: Long-term efficacy and tolerability of add-on piogçitazone therapy to faliling monotherapy compared with addition of glicazide or metformin in patients with type 2 diabetes. Diabetologia 2005, 48:1093-1104.
• [24]Hanefeld M, Brunetti P, Schhernthaner GH: One year glycemic control with sulphonylurea plus pioglitazone versus sulphonylurea plus metformin in patients with type 2 diabetes. Diabetes Care 2004, 27:141-147.
• [25]González-Ortiza M, Guerrero-Romero J, Violante-Ortiz R: Efficacy of glimepiride/metformin combination versus glibenclamide/metformin in patients with uncontrolled type 2 diabetes mellitus. J Diabetes Complications 2009, 23:376-379.
• [26]Johnson JA, Majumdar SR, Simpson SH: Decreased mortality associated with the use of metformin compared with sulfonylurea Monotherapy in type 2 diabetes. Diabetes Care 2002, 25:2244-2248.
• [27]Evans JM, Ogston SA, Emslie-Smith A, Morris AD: Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006, 49:930-936.
• [28]Giugliano D, Quatraro A, Consoli G: Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol 1993, 44:107-112.
• [29]Lund SS, Tarnow L, Frandsen M: Combining insulin with metformin or an insulin secretagogue in non-obese patients with type 2 diabetes: 12 month, randomised, double blind trial. BJ 2009, 339:b4324.
• [30]Vella S, Buetow L, Royle P: The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia 2010, 53(5):809-820.
• [31]Abdelghaffar S, Attia AM: Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. Cochrane Database Syst Rev 2009, (Issue 1):CD006691.
• [32]Bailey CJ, Bagdonas A, Rubes J: Rosiglitazone-metformin fixed-dose combination compared with uptritrated metformin alone in type diabetes mellitus:a 24 week, multicenter, randomized, double-blind, parallel-group study. Clin Ther 2005, 27:1548-1561.
• [33]Retnakaran R, Qi Y, Harris SB, Hanley AJ, Zinman B: Changes over time in glycemic control, insulin sensitivity, and beta-cell function in response to low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance. Diabetes Care 2011, 34(7):1601-1604.
• [34]Scheen AJ: ADOPT study: which first-line glucose-lowering oral medication in type 2 diabetes? Rev Med Liege 2007, 62(1):48-52.
• [35]Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M: Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther 2009, 85:513-519.
• [36]List JF, Woo V, Morales E, Tang W, Fiedorek FT: Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009, 32:650-657.
• [37]Scheen AJ, de Magalhanes AC, Salvatore T: Reduction of the acute bioavailability of metformin by the α glycosidase inhibitor acarbose in normal man. Eur J Clin Invest 1994, 24(Suppl3):50-54.
• [38]Rosenstok J, Brown A, Fischer J: Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes. Diabetes Care 1998, 21:2050-2055.
• [39]Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL: Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2008, (2):CD006739.
• [40]Mannucci E, Ognibene A, Cremasco F: Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care 2001, 24:489-494.
• [41]DeFronzo RA, Hissa MN, Garber AJ, for Saxagliptin Study Group: The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009, 32(9):1649-1655.
• [42]Deacon CF, Mannucci E, Ahrén B: Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis. Diabetes Obes Metab 2012, 14(8):762-767.
• [43]Charles B, Norris R, Xiao X, Hague W: Population pharmacokinetics of metformin in late pregnancy. Ther Drug Monit 2006, 28:67-72.
• [44]Gutzin SJ, Kozer E, Magee LA, Feig DS, Koren G: The safety of oral hypoglycemic agents in the first trimester of pregnancy. a meta-analysis. Can J Clin Pharmacol 2003, 10:179-183.
• [45]Gilbert C, Valois M, Koren G: Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril 2006, 86:658-663.
• [46]Rowan JA, Hague WM, Gao W, Battin MR, Moore MP: MiG trial investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008, 358:2003-2015.
• [47]Moore LE, Briery CM, Clokey D: Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. J Reprod Med 2007, 52:1011-1015.
• [48]Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM: Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 2011, 34:2279-2284.
• [49]Wiegand S, Maikowski U, Blankenstein O, Bierbermann H, Tarnow P, Grutes A: Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity- a problem that is no longer restrited to minority groups. Eur J Endocrinol 2004, 151:199-206.
• [50]Pinhas-Hamiel O, Zeitler P: Clinical presentation and treatment of type 2 diabetes in children. Pediatr Diabetes 2007, 8(Suppl. 9):16-27.
• [51]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.
• [52]Gottschalk M, Danne T, Vlajnic A, Cara J: Glimepiride Versus Metformin as Monotherapy in Pediatric Patients With Type 2 Diabetes.A randomized, single-blind comparative study. DiabetesCare 2007, 30:790-794.
• [53]Gungor N, Thompson T, Sutton-Tyrrell K, Janosky J, Arslanian S: Early signs of cardiovascular disease in youth with obesityand type 2 diabetes. Diabetes Care 2005, 28(5):1219-1221.
• [54]Freedman DS, Khan LK, Dietz WH, Srinivasan SR, Berenson GS: Relationship of childhood obesity to coronary heart disease risk factors in adulthood: the Bogalusa Heart Study. Pediatrics 2001, 108(3):712-718.
• [55]Rashid M, Roberts EA: Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000, 30:48-53.
• [56]Targher G, Bertolini L, Poli F: Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005, 54:3541-3546.
• [57]Carnethon MR, Gidding SS, Nehgme R, Sidney S: Cardiorespiratory fitness in young adulthood and the development of cardiovascular disease risk factors. JAMA 2003, 290:3092-3100.
• [58]Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C: Prevalence of fatty liver in children and adolescents. Pediatrics 2006, 118:1388-1393.
• [59]Reinehr T, Kiess W, Kappellen T, Andler W: Insulin sensitivity among obese children and adolescents, according to degree of weight loss. Pediatrics 2004, 114:1569-1573.
• [60]Tock L, Dˆamaso A, de Piano A, Carnier J: Long-TermEffects of metformin and lifestyle modification on nonalcoholic fatty liver disease obese adolescents. J Obes 2010, 831901:6. Article ID 831901
• [61]Burgert TS, Duran EJ, Goldberg-Gell R, Dziura J, Yeckel CW, Katz S, Tamborlane WV, Caprio S: Short-term metabolic and cardiovascular effects of metformin in markedly obese adolescents with normal glucose tolerance. Pediatr Diabetes 2008, 9:567-576.
• [62]Park M, Kinra S, Ward K, White B, Viner R: Metformin for obesity in children and adolescents: a systematic review. Diabetes Care 2009, 32:1743-1745.
• [63]Cole CR, Foody JM, Blackstone EH, Lauer MS: Heart rate recovery after submaximal exercise testing asa predictor of mortality in a cardiovascularly healthy cohort. Ann Intern Med 2000, 132:552-555.
• [64]Lind L, Andren B: Heart rate recovery after exercise is related to the insulin resistance syndrome and heart rate variability in elderly men. Am Heart J 2002, 144:666-672.
• [65]Nadeau KJ, Ehlers LB, Zeitler PS, Love-Osborne K: Treatment of nonalcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr Diabetes 2009, 10:5-13.
• [66]Oude Luttikhuis H, Baur L, Jansen H, Shrewsbury VA, O’Malley C, Stolk RP, Summerbell CD: Interventions for treating obesity in children. Cochrane Database Syst Rev 2009, (1):CD001872.
• [67]Kannel WB, McGee DL: Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care 1979, 2:120-126.
• [68]Wingard DL, Barrett-Connor E: Heart disease and diabetes. 2nd edition. Washington, D.C: GPO; 1995:429-48. [NationalDiabetes Data Group. Diabetes in America] NIH publication no.95-1468
• [69]Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998, 339:229-234.
• [70]Krempf M, Parhofer KG, Steg G: National Cholesterol Education Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).Third Report of the NationalCholesterol Education Program (NCEP) Expert Panel on Detection. Circulation 2002, 106:3143-3421.
• [71]Bulugahapitiya U, Siyambalapitiya S, Sithole J, Idris I: Is diabetes a coronary risk equivalent? Systematic review and meta-analysis. Diabet Med 2009, 26:142-148.
• [72]Sgambato S, Varricchio M, Tesauro P, Passariello N, Carbone L: Use of metformin in ischemic cardiopathy. Clin Ther 1980, 94:77-85.
• [73]Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA: 10-year follow up of intensive glucose control in type 2 diabetes. N Engl J Med 2008, 359:1577-1589.
• [74]Kao J, Tobis J, Mc Clelland RL: Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol 2004, 93:1347-1350.
• [75]Kooy A, de Jager J, Lehert P: 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.
• [76]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. J Am Coll Cardiol 2006, 48:956-963.
• [77]Boussageon R, Supper I, Bejan-Angoulvant T: Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012, 9(4):e1001204.
• [78]MacDonald MR, Petrie MC, Hawkins NM: Diabetes, left ventricular systolic dysfunction, and chronic heart failure. Eur Heart J 2008, 10:1224-1240.
• [79]Hulisz DT, Bonfiglio MF, Murray RD: Metformin-associated lactic acidosis. J Am Board Fam Pract 1998, 11:233-236.
• [80]Food and Drug Administration. Product label approval: metformin. 2006. http://packageinserts.bms.com/pi/piglucophage.pdf webcite
• [81]Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM: Thiazolinediones, metformin, and outcomes in older patients with diabetes and heart failure. Circulation 2005, 111:583-590.
• [82]Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA: Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005, 28:2345-2351.
• [83]Papanas N, Maltezos E, Mikhailidis DP: Metformin and heart failure: never say never again. Expert Opin Pharmacother 2012, 1:1-8.
• [84]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, 13:428-433.
• [85]Shah DD, Fonarow GC, Horwich TB: Metformin Therapy and Outcomes in Patients With Advanced Systolic Heart Failure and Diabetes. J Card Fail 2010, 16(3):200-206.
• [86]Isoda K, Young J, Zirlik A: Metformin inhibits Proinflammatory Responses and Nuclear Factor ĸß in Human Vascular Wall Cells. Arterioscler Thromb Vasc Biol 2006, 26:611-617.
• [87]The Diabetes Prevention Program Research Group Intensive: Lifestyle Intervention or Metformin on Inflammation and Coagulation in Participants With Impaired Glucose Tolerance. Diabetes 2005, 54(5):1566-1572.
• [88]De Jager J, Kooy A, Lehert P: Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med 2004, 256:1-14.
• [89]Mather KJ, Verma S, Anderson TJ: Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 2001, 37(5):1344-1350.
• [90]Vitale C, Mercuro G, Cornoldi A, Fini M: Metformin improves endothelial function in patients with metabolic syndrome. J Intern Med 2005, 258:250-256.
• [91]Grant PJ: Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab 2003, 29(6S):44-52.
• [92]Standeven KF, Ariens RA, Whitaker P: The effect of dimethylbiguanide on thrombin activity, FXIII activation, fibrin polymerization, and fibrin clot formation. Diabetes 2002, 51:189-197.
• [93]Charles MA, Morange P, Eschwege E: Effect of weight change and metformin on fibrinolysis and the von Willebrand factor in obese nondiabetic subjects: the BIGPRO1 Study. Biguanides and the Prevention of the Risk of Obesity. Diabetes Care 1998, 21:1967-1972.
• [94]Wu RR, Zhao JP, Jin H: Lifestyle Intervention and Metformin for Treatment of Antipsychotic-Induced Weight Gain A Randomized Controlled Trial. JAMA 2008, 299(2):185-193.
• [95]Glueck CJ, Fontaine RN, Wang P: Metformin reduces weight, centripetalobesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism 2001, 50:856-861.
• [96]Kusaka I, Nagasaka S, Horie H, Ishibashi S: Metformin, but not pioglitazone, decreases postchallenge plasma ghrelin levels in type 2 diabetic patients: a possible role in weight stability? Diabetes Obes Metab 2008, 10:1039-1046.
• [97]Hadigan C, Corcoran C, Basgoz N: Metformin in the Treatment of HIV Lipodystrophy Syndrome A Randomized Controlled Trial. JAMA 2000, 284:472-477.
• [98]Sheth S, Larson L: The efficacy and safety of insulin-sensitizing drugs in HIV-associated lipodystrophy syndrome: a meta-analysis of randomized trials. BMC Infect Dis 2010, 10:183. BioMed Central Full Text
• [99]Bailey CJ, Turner RC: Metformin. N Engl J Med 1996, 334:574-579.
• [100]Faure P, Rossini E, Wiernsperger N: An insulin sensitizer improves the free radical defense system potential and insulin sensitivity in high fructose-fed rats. Diabetes 1999, 48:353-357.
• [101]Beisswenger P, Rugiero-Lopez D: Metformin inhibition of glycation processes. Diabetes Metab 2003, 29(6S):95-103.
• [102]Anedda A, Rial E, Gonzalez Barroso : Metformin induces oxidative stress in white adipocytes and raises uncoupling proten levels. J Endocrinol 2008, 199:33-40.
• [103]Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, Jin H, He Y, Gu Q, Xun X: Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes 2012, 61(1):217-228.
• [104]Kahn SE, Haffner SM, Heise MA: Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. N Engl J Med 2006, 355:2427-2443.
• [105]Desilets AR, Dhakal-Karki S, Dunican KC: Role of metformin for weight management in patients without type 2 diabetes. Ann Pharmacother 2008, 42:817-826.
• [106]Eleftheriadou I, Grigoropoulou P, Katsilambros N, Tentolouris N: The effects of medications used for the management of diabetes and obesity on postprandial lipid metabolism. Curr Diabetes Rev 2008, 4:340-356.
• [107]Wulffelé MG, Kooy A, Lehert P, Bets D, Donker A, Stehouwer C: Does metformin decrease blood pressure in patients with type 2 diabetes intensively treated with insulin? Diabet Med 2005, 22:907.
• [108]Tack CJ, Smits P, Willemsen JJ, Lenders JW, Thien T, Lutterman JA: Effects of insulin on vascular tone and sympathetic nervous system in NIDDM. Diabetes 1996, 45:15-22.
• [109]Sechi LA, Bartoli E: Molecular mechanisms of insulin resistance in arterial hypertension. Blood Press Suppl 1996, 1:47-54.
• [110]Granberry MC, Fonseca VA: Cardiovascular risk factors associated with insulin resistance: effects of oral antidiabetic agents. Am J Cardiovasc Drugs 2005, 5:201-209.
• [111]Fontbonne A, Diouf I, Baccara-Dinet M, Eschwege E, Charles A: Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper-body obese subjects with mild glucose anomalies: a post-hoc analysis of the BIGPRO1 trial. Diabetes Metab 2009, 35:385-391.
• [112]Vigersky R, Filmore-Nassar A, Allan R: Thyrotropin Suppression by Metformin. J Clin Endocrinol Metab 2006, 91:225-227.
• [113]Capelli C, Rotondi M, Pirola I, Agosti B, Gandossi E: TSH-lowering effect of metformin in type 2 diabetic patients differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients. Diabetes Care 2009, 32:1589-1590.
• [114]Triant VA, Lee H, Hadigan C, Grinspoon SK: Increased acute myocardial infarction rates and cardiovascular risk factors among patients with HIV disease. J Clin Endocrinol Metab 2007, 92:2506-2512.
• [115]Kinlaw WB, Marsh B: Adiponectin and HIV-lipodystrophy:taking HAART. Endocrinology 2004, 145:484-486.
• [116]Moyle GJ, Sabin CA, Cartledge J: A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. Acquir Immune Defic Syndr 2006, 20:2043-2050.
• [117]Behrens G, Dejam A, Schmidt H: Impaired glucose tolerance, b cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. Acquir Immune Defic Syndr 1999, 13:F63-F70.
• [118]Kohli R, Shevitz A, Gorbach S, Wanke C: A randomized placebo-controlled trial of metformin for the treatment of HIV lipodystrophy. HIV Med 2007, 8:420-426.
• [119]van Wijk , de Koning E, Castro M: Comparison of Rosiglitazone and Metformin for treating HIV Lipodistrophy. Ann Inter Med 2005, 143:337-346.
• [120]Spasic MR, Callaerts P, Norga KK: AMP-Activated Protein Kinase (AMPK) Molecular Crossroad for Metabolic Control and Survival of Neurons. Neuroscientist 2009, 15(4):309-316.
• [121]Culmsee C, Monnig J, Kemp BE, Mattson MP: AMPactivated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J Mol Neurosci 2001, 17:45-58.
• [122]Santomauro Júnior AC, Ugolini MR, Santomauro AT, Souto RP: Metformina e AMPK: Um Antigo Fármaco e Uma Nova Enzima no Contexto da Síndrome Metabólica. Arq Bras Endocrinol Metabol 2008, 52(1):120-125.
• [123]El-Mir MY, Detaille D, Villanueva G: Neuroprotective Role of Antidiabetic Drug Metformin Against Apoptotic Cell Death in Primary Cortical Neurons. J Mol Neurosci 2008, 34(1):77-87.
• [124]Andersen JK: Oxidative stress in neurodegeneration: Cause or consequence? Nat Med 2004, 10:S18-S25.
• [125]Kroemer G, Reed JC: Mitochondrial control of cell death. Nat Med 2000, 6:513-519.
• [126]Detaille D, Guigas B, Chauvin C: Metformin prevents high glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005, 54:2179-2187.
• [127]Plum L, Schubert M, Bruning JC: The role of insulin receptor signaling in the brain. Trends Endocrinol Metab 2005, 16:59-65.
• [128]van der Heide LP, Ramakers GM, Smidt MP: Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 2006, 79:205-221.
• [129]Gupta A, Bisht B, Dey CS: Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like change. Neuropharmacology 2011, 60:910-920.
• [130]Selkoe DJ: The cell biology of ßamyloid precursor protein and presenilin in Alzheimer’s disease. Trends Cell Biol 1998, 8:447-453.
• [131]Chen Y, Zhoua K, Wanga R, Liua Y: Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. PNAS 2009, 106(10):3907-3912.
• [132]Wang J, Gallagher D, De Vito L: Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 2012, 11:23-35.
• [133]Papanas N, Maltezos E, Mikhailidis DP: Metformin and cancer: licence to heal? Expert Opin Investig Drugs 2010, 19:913-917.
• [134]Larsson SC, Orsini N, Wolk A: Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Canc Ins 2005, 97:1679-1687.
• [135]Li D, Yeung SJ, Hassan MM, Konopleva M, Abbruzzese JL: Anti-diabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009, 137(2):482-488.
• [136]Donadon V, Balbi M, Valent F, Avogaro A: Glycated hemoglobin and antidiabetic strategies as risk factors for hepatocellular carcinoma. World J Gastroenterol 2010, 16(24):3025-3032.
• [137]Libby G, Donnelly LA, Donnan PT: New users of metformin area at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009, 32:1620-1625.
• [138]Landman GW, Kleefstra N, van Hateren KJ: Metformin associated with lower cancer mortality in type 2 diabetes ZODIAC-16. Diabetes Care 2010, 33:322-326.
• [139]Lee JH, Kim TI, Jeon SM: The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer 2011, 12:1-24.
• [140]Inoue M, Iwasaki M, Otami T: Diabetes mellitus and the risk of cancer. Results from a large-scale population-based cohort study. Arch Intern Med 2006, 166:1871-1877.
• [141]Grimberg A, Cohen P: Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis. J Cell Physiol 2000, 183:1-9.
• [142]Smith U, Gale EAU: Cancer and diabetes: are we ready for prime time? Diabetologia 2010, 53:1541-1544.
• [143]Markman B, Atzori F, Perez-Garcia J, Tabernero J, Baselga J: Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol 2010, 21:683-691.
• [144]Kalender A, Selvaraj A, Kim SY: Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPasedependent manner. Cell Metab 2010, 11:390-401.
• [145]Evans J, Donelly L, Emslie A: Metformin and reduced risk of cancer in diabetic patients. BMJ 2005, 330(7503):1304-1305.
• [146]Bodmer M, Meier C, Krähenbühl S: Long-term metformin Use is associated with decreased risk of breast cancer. Diabetes Care 2010, 33:1304-1308.
• [147]Bowker SL, Majumdar SR, Veugelers P, Johnson JA: Increased cancer-related mortality for patients with type 2 diabetes who usesulfonylureas or insulin. Diabetes Care 2006, 29:254-258.
• [148]Ben Sahra I, Laurent K, Loubat A: The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 2008, 27:3576-3586.
• [149]Pollak M: Insulin and insulin-like growth factor signaling in neoplasia. Nat Rev Cancer 2008, 8:915-928.
• [150]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, 66:10269-10273.
• [151]Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA: The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle 2009, 8:88-96.
• [152]Lund SS, Tarnow L, Stehouwer CD: Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol 2008, 158:631-641.
• [153]Thoreen CC, Sabatini DM: AMPK and p53 help cells through lean times. Cell Metab 2005, 1:287-288.
• [154]Zhuang Y, Miskimins W: Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal 2008, 3:18. BioMed Central Full Text
• [155]Pearce EL, Walsh MC, Cejas PJ: Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009, 460:103-107.
• [156]Jiralerspong S, Palla S, Giordano S: Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer. J Clin Oncol 2009, 27:3297-3302.
• [157]Hirsh H, Iliopoulos D, Tsichlis P, Stuh K: Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009, 69(19):7507-7511.
• [158]Scarpello J, Howlett H: Metformin therapy and clinical uses. Diabetes Vasc Dis Res 2008, 5:157-167.
• [159]Rosand J, Friedberg J, Yang J: Fatal phenformin-associated lactic acidosis. Ann Intern Med 1997, 127:170.
• [160]Salpeter SR, Greyber E, Pasternak GA, Salpeter EE: Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010, 1:CD002967.
• [161]Tahrani AA, Varghese GI, Scarpello JH, Hanna FWF: Metformin, heart failure and lactic acidosis: is Metformin absolutely contraindicated? BMJ 2007, 355:508-512.
• [162]Lipska KJ, Bailey CJ, Inzucchi SE: Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011, 34(6):1431-1437.
• [163]Frid A, Sterner GN, Londahl M: Novel assay of metformin levels in patients with type 2 diabetes mellitus and varying levels of renal function. Diabetes Care 2010, 33:1291-1293.
• [164]Metformin LS: Metformin: a review of its pharmacological properties and therapeutic use. Diabetes Metab 1979, 5:233-245.
• [165]Cusi K, DeFronzo RA: Metformin: a review of its metabolic effects. Diabetes Rev 1998, 6:89-131.
• [166]Bauman WA, Shaw S, Jayatilleke E: Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 2000, 23:1227-1231.
• [167]Callaghan TS, Hadden DR, Tomkin GH: Megaloblastic anemia due to vitamin B12 malaborsption associated with long-term metformin treatment. Br Med J 1980, 280:1214-1215.
• [168]Jager J, Kooy A, Lehert P, Wulffelé M: Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomized placebo controlled trial. BMJ 2010, 340:c2181.
• [169]Wei Ting RZ, Szeto CC, Chan M, Ma K: Risk Factors of Vitamin B12 Deficiency in Patients Receiving Metformin. Arch Intern Med 2006, 166:1975-1979.
• [170]Klapholz L, Leitersdorf E, Weinrauch L: Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ 1986, 293:483.
• [171]Desilets DJ, Shorr AF, Moran KA, Holtzmuller KC: Cholestatic jaundice associated with the use of metformin. Am J Gastroenterol 2001, 96:2257-2258.
• [172]Kashyap AS, Kashyap S: Haemolytic anaemia due to metformin. Postgrad Med J 2000, 76:125-126.
• [173]Giugliano D, De Rosa N, Di Maro G: Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 1993, 16:1387-1390.
• [174]United Kingdom Prospective Diabetes Study (UKPDS) Group: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years (UKPDS 13). BMJ 1995, 310:83-88.
• [175]Glucophage® and Glucophage XRproduct information. Bristol-Myers Squibb Company. 2003. Available at: http://www.drugs.com/pro/glucophage.html webcite
• [176]Haupt E, Knick B, Koschinsky T, Liebermeister H, Schneider J, Hirche H: Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabete Metab 1991, 17:224-231.
• [177]Nathan DM, Buse JB, Davidson MB: Management of hyperglycaemiain 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, 49:1711-1721.
• [178]Grant P: The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 1996, 19:64-66.
• [179]Garber AJ, Duncan TG, Goodman AM, Millus DJ, Rohlf JL: Efficacy of metformin in type 2 diabetes: results of a double-blind, placebo-controlled, dose–response trial. Am J Med 1997, 103:491-497.
• [180]Donahue S, Marathe P, Guld T, Meeker J: The phamacokinetics and pharmacodynamics of extended-release metformin tablets vs immediate-release metformin in subjects with type 2 diabetes. Diabetes 2002, 51(Suppl 2):A468.
• [181]Levy J, Cobas RA, Gomes MB: Assessment of efficacy and tolerability of oncedaily extended release metformin in patients with type 2 diabetes mellitus. Diabetol Metab Syndr 2010, 2:16. BioMed Central Full Text
• [182]Raz I, Delaet I, Goyvaerts H: Safety and efficacy of novel extended-release formulation of metformin in patients with type 2 diabetes. Diabetes 2000, 49(Suppl 1):A363.
• [183]Donnelly LA, Morris AD, Pearson ER: Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab 2009, 11:338-342.