Metformin: from mechanisms of action to advanced clinical use
Abstract
Metformin represents the first line of treatment and is the most widely prescribed antihypergycemic drug in type 2 diabetic patients. It can be used as monotherapy or in combination with other oral antihyperglycemic drugs or insulin. Additionally, it is also prescribed in type 1 diabetic patients, it proved to be effective in prediabetes and also provided beneficial effects in other insulin resistant states, for example in polycystic ovary syndrome. Nevertheless, the exact molecular mechanism of its action remains unknown. It was shown that it inhibits liver gluconeogenesis, facilitates glucose uptake into peripheral tissues, such as striated muscle; it also acts in the gut. Besides antihyperglycemic effects, metformin was also shown to possess several beneficial, protective effects, so-called pleiotropic effects: particularly on the cardiovascular system and in cancer patients. Metformin has only few side effects, the most serious being metformin-associated lactic acidosis. The latter appears in rare clinical cases with pre-existing chronic kidney disease or advanced heart failure with tissue hypoperfusion, which consequently represent relative contraindications for metformin use. In the past, metformin treatment was usually discontinued when performing iodine contrast imaging, however recently there is evidence of its safety even in patients with higher stages of chronic kidney disease. All in all, metformin is a drug with a long tradition and a promising future.
Downloads
References
Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm–2016 Executive Summary. Endocr Pract. 2016;22(1):84–113.
International Diabetes Federation Guideline Development G. Global guideline for type 2 diabetes. Diabetes Res Clin Pract. 2014;104(1):1–52.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position state ment of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140–9.
Zaletel J, Ravnik-Oblak M, Zavratnik A, eds. Slovenske smernice za klinično obravnavo sladkorne bolezni tipa 2. 3 ed. Ljubljana: Diabetološko združenje Slovenije; 2016.
Sterne J. Du nouveau dans les antidiabetiques. La NN dimethylamin guanyl guanide. Maroc Med. 1957;36(388):1295–6.
Watanabe CK. Studies in the metabolic changes by administration of guanidine hydrochloride on blood sugar content. J Biol Chem. 1918;33(2):253–65.
Bailey CJ, Day C. Metformin: its botanical background. Practical Diabetes Int. 2004;21(3):115–7.
Misbin RI. Te phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care. 2004;27(7):1791–3.
Liu C, Wu D, Zheng X, Li P, Li L. Efcacy and safety of metformin for patients with type 1 diabetes mellitus: a meta-analysis. Diabetes Technol Ter. 2015;17(2):142–8.
Ludvigsson J. Te latest pharmacotherapy options for type 1 diabetes. Expert Opin Pharmacother. 2014;15(1):37–49.
Palomba S, Falbo A, Zullo F, Orio F, Jr. Evidence-based and potential benefts of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30(1):1–50.
Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):6.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854–65.
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(15):1577–89.
Boussageon R, Supper I, Bejan-Angoulvant T, Kellou N, Cucherat M, Boissel JP, et al. Reappraisal of metformin efcacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med. 2012;9(4):e1001204.
Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13(3):221–8.
Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996;30(5):359–71.
Ali S, Fonseca V. Overview of metformin: special focus on metformin extended release. Expert Opin Pharmacother. 2012;13(12):1797–805.
Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, et al. Te Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies. Diabetes Care. 2016;39(2):198–205.
Detaille D, Guigas B, Leverve X, Wiernsperger N, Devos P. Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function. Biochem Pharmacol. 2002;63(7):1259–72.
Dresser MJ, Leabman MK, Giacomini KM. Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci. 2001 90(4):397–421.
Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24(1):49–57.
Hacker K, Maas R, Kornhuber J, Fromm MF, Zolk O. Substrate-Dependent Inhibition of the Human Organic Cation Transporter OCT2: A Comparison of Metformin with Experimental Substrates. PLoS One. 2015;10(9):e0136451.
Dujic T, Causevic A, Bego T, Malenica M, Velija-Asimi Z, Pearson ER, et al. Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes. Diabet Med. 2015;33(4):511–4.
Ornik V, Ferk P. Raznolikost v farmakološkem odzivu na zdravljenje z metforminom. Zdrav Vestn. 2013;82(7):487–96.
Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49(12):2063–9.
Song R. Mechanism of Metformin: A Tale of Two Sites. Diabetes Care. 2016;39(2):187–9.
Hardie DG. Neither LKB1 nor AMPK are the direct targets of metformin. Gastroenterology. 2006;131(3):973; author reply 4–5.
Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J. 2015;471(3):307–22.
Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251–62.
Foretz M, Viollet B. Regulation of hepatic metabolism by AMPK. J Hepatol. 2011;54(4):827–9.
Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10(3):143–56.
Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013,494(7436):256–60.
Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542–6.
Turban S, Stretton C, Drouin O, Green CJ, Watson ML, Gray A, et al. Defning the contribution of AMP-activated protein kinase (AMPK) and protein kinase C (PKC) in regulation of glucose uptake by metformin in skeletal muscle cells. J Biol Chem. 2012;287(24):20088–99.
Kristensen JM, Treebak JT, Schjerling P, Goodyear L, Wojtaszewski JF. Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle. Am J Physiol Endocrinol Metab. 2014;306(10):E1099–109.
Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology. 2011;152(12):4610–9.
Lindsay JR, Duffy NA, McKillop AM, Ardill J, O’Harte FP, Flatt PR, et al. Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabet Med. 2005;22(5):654–7.
Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014;80(19):5935–43.
Professional Practice Committee for the Standards of Medical Care in Diabetes-2016. Diabetes Care. 2016;39 Suppl 1:S107–8.
DeFronzo RA, Goodman AM. Efcacy of metformin in patients with non-insulin-dependent diabetes mellitus. Te Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541–9.
Hemmingsen B, Christensen LL, Wetterslev J, Vaag A, Gluud C, Lund SS, et al. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. BMJ. 2012;344:e1771.
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE, Sitagliptin 036 Study G. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30(8):1979–87.
Nwosu BU, Maranda L, Cullen K, Greenman L, Fleshman J, McShea N, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Metformin Terapy in Overweight/Obese Youth with Type 1 Diabetes. PLoS One. 2015;10(9):e0137525.
Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR. Te use of metformin in type 1 diabetes: a systematic review of efcacy. Diabetologia. 2010;53(5):809–20.
Canadian Diabetes Association Clinical Practice Guidelines Expert C, McGibbon A, Richardson C, Hernandez C, Dornan J. Pharmacotherapy in type 1 diabetes. Can J Diabetes. 2013;37 Suppl 1:S56–60.
Charles B, Norris R, Xiao X, Hague W. Population pharmacokinetics of metformin in late pregnancy. Ter Drug Monit. 2006;28(1):67–72.
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(10):2279–84.
Petersen JL, McGuire DK. Impaired glucose tolerance and impaired fasting glucose—a review of diagnosis, clinical implications and management. Diab Vasc Dis Res. 2005;2(1):9–15.
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.
Lily M, Godwin M. Treating prediabetes with metformin: systematic review and meta-analysis. Can Fam Physician. 2009;55(4):363–9.
Košir R, Meden-Vrtovec H. Vloga metformina pri obravnavi bolnic s sindromom policističnih jajčnikov. Zdrav Vestn. 2009;78(3):137–41.
Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2010;(1):CD003053.
Bromage DI, Yellon DM. Te pleiotropic effects of metformin: time for prospective studies. Cardiovasc Diabetol. 2015;14:109.
Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med. 2014;2(6):57.
Pulito C, Donzelli S, Muti P, Puzzo L, Strano S, Blandino G. microRNAs and cancer metabolism reprogramming: the paradigm of metformin. Ann Transl Med. 2014;2(6):58.
Gosmanova EO, Canada RB, Mangold TA, Rawls WN, Wall BM. Effect of metformin-containing antidiabetic regimens on all-cause mortality in veterans with type 2 diabetes mellitus. Am J Med Sci. 2008;336(3):241–7.
Romualdi D, Costantini B, Selvaggi L, Giuliani M, Cristello F, Macri F, et al. Metformin improves endothelial function in normoinsulinemic PCOS patients: a new prospective. Hum Reprod. 2008;23(9):2127–33.
de Jager J, Kooy A, Schalkwijk C, van der Kolk J, Lehert P, Bets D, et al. Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. J Intern Med. 2014;275(1):59–70.
Forouzandeh F, Salazar G, Patrushev N, Xiong S, Hilenski L, Fei B, et al. Metformin beyond diabetes: pleiotropic benefts of metformin in attenuation of atherosclerosis. J Am Heart Assoc. 2014;3(6):e001202.
Wulffele MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT. Te effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004;256(1):1–14.
Grant PJ. Benefcial effects of metformin on haemostasis and vascular function in man. Diabetes Metab. 2003;29(4 Pt 2):6S44–52.
Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Tromb Vasc Biol. 2006;26(3):611–7.
Carter AM, Bennett CE, Bostock JA, Grant PJ. Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with Type 2 diabetes mellitus. Diabet Med. 2005;22(9):1282–4.
Beisswenger P, Ruggiero-Lopez D. Metformin inhibition of glycation processes. Diabetes Metab. 2003;29(4 Pt 2):6S95–103.
Fontbonne A, Diouf I, Baccara-Dinet M, Eschwege E, Charles MA. 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(5):385–91.
Papanas N, Maltezos E, Mikhailidis DP. Metformin and heart failure: never say never again. Expert Opin Pharmacother. 2012;13(1):1–8.
Inoue M, Iwasaki M, Otani T, Sasazuki S, Noda M, Tsugane S. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med. 2006;166(17):1871–7.
Dankner R, Boffetta P, Balicer RD, Boker LK, Sadeh M, Berlin A, et al. Time-Dependent Risk of Cancer Afer a Diabetes Diagnosis in a Cohort of 2.3 Million Adults. Am J Epidemiol. 2016;183(12):1098–106.
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–5.
Smith U, Gale EA. Cancer and diabetes: are we ready for prime time? Diabetologia. 2010;53(8):1541–4.
Bao B, Azmi AS, Ali S, Zaiem F, Sarkar FH. Metformin may function as anti-cancer agent via targeting cancer stem cells: the potential biological signifcance of tumor-associated miRNAs in breast and pancreatic cancers. Ann Transl Med. 2014;2(6):59.
Cioce M, Valerio M, Casadei L, Pulito C, Sacconi A, Mori F, et al. Metformin-induced metabolic reprogramming of chemoresistant ALDHbright breast cancer cells. Oncotarget. 2014;5(12):4129–43.
Li W, Yuan Y, Huang L, Qiao M, Zhang Y. Metformin alters the expression profles of microRNAs in human pancreatic cancer cells. Diabetes Res Clin Pract. 2012;96(2):187–95.
Wang Y, Dai W, Chu X, Yang B, Zhao M, Sun Y. Metformin inhibits lung cancer cells proliferation through repressing microRNA-222. Biotechnol Lett. 2013;35(12):2013–9.
Amin S, Mhango G, Lin J, Aronson A, Wisnivesky J, Boffetta P, et al. Metformin Improves Survival in Patients with Pancreatic Ductal Adenocarcinoma and Pre-Existing Diabetes: A Propensity Score Analysis. Am J Gastroenterol. 2016;111(9):1350–7.
Chlebowski RT, McTiernan A, Aragaki AK, Rohan T, Wactawski-Wende J, Ipp E, et al. Metformin and breast cancer incidence in postmenopausal diabetic women in the Women’s Health Initiative (WHI). J Clin Oncol. 2011;29(12):1503–4.
Jacob L, Kostev K, Rathmann W, Kalder M. Impact of metformin on metastases in patients with breast cancer and type 2 diabetes. J Diabetes Complications. 2016;30(6):1056–9.
Liu F, Yan L, Wang Z, Lu Y, Chu Y, Li X, et al. Metformin therapy and risk of colorectal adenomas and colorectal cancer in type 2 diabetes mellitus patients: A systematic review and meta-analysis. Oncotarget. 2016;8(9):16017–16026.
Rosato V, Tavani A, Gracia-Lavedan E, Guino E, Castano-Vinyals G, Villanueva CM, et al. Type 2 Diabetes, Antidiabetic Medications, and Colorectal Cancer Risk: Two Case-Control Studies from Italy and Spain. Front Oncol. 2016;6:210.
Lee JH, Kim TI, Jeon SM, Hong SP, Cheon JH, Kim WH. Te effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer. 2012;131(3):752–9.
Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, et al. Metformin Use Is Associated With Better Survival of Breast Cancer Patients With Diabetes: A Meta-Analysis. Oncologist. 2015;20(11):1236–44.
Lee SH, Yoon SH, Lee HS, Chung MJ, Park JY, Park SW, et al. Can metformin change the prognosis of pancreatic cancer? Retrospective study for pancreatic cancer patients with pre-existing diabetes mellitus type 2. Dig Liver Dis. 2016;48(4):435–40.
Cantoria MJ, Boros LG, Meuillet EJ. Contextual inhibition of fatty acid synthesis by metformin involves glucose-derived acetyl-CoA and cholesterol in pancreatic tumor cells. Metabolomics. 2014;10(1):91–104.
Hamieh L, McKay RR, Lin X, Moreira RB, Simantov R, Choueiri TK. Effect of Metformin Use on Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma. Clin Genitourin Cancer. 2016. In press.
Tseng CH. Use of metformin and risk of kidney cancer in patients with type 2 diabetes. Eur J Cancer. 2016;52:19–25.
Hankinson SJ, Fam M, Patel NN. A review for clinicians: Prostate cancer and the antineoplastic properties of metformin. Urol Oncol. 2017;35(1):21–9.
Akinyeke T, Matsumura S, Wang X, Wu Y, Schalfer ED, Saxena A, et al. Metformin targets c-MYC oncogene to prevent prostate cancer. Carcinogenesis. 2013;34(12):2823–32.
Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388–93.
Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305(16):1659–68.
Cappelli C, Rotondi M, Pirola I, Agosti B, Formenti A, Zarra E, et al. Tyreotropin levels in diabetic patients on metformin treatment. Eur J Endocrinol. 2012;167(2):261–5.
Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, et al. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY). 2011;3(2):148–57.
Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cocheme HM, Noori T, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153(1):228–39.
Chung MM, Chen YL, Pei D, Cheng YC, Sun B, Nicol CJ, et al. Te neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent. Biochim Biophys Acta. 2015;1852(5):720–31.
Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014;9(6):e100379.
Buvat DR. Use of metformin is a cause of vitamin B12 defciency.Am Fam Physician. 2004;69(2):264; author reply 264, 266.
Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin.Diabetes Care. 2013;36(10):2981–7.
Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care. 2008;31(11):2086–91.
DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. 2016;65(2):20–9.
Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309–19.
Miles JM, Rule AD, Borlaug BA. Use of metformin in diseases of aging. Curr Diab Rep. 2014;14(6):490.
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;(4):CD002967.
Ekstrom N, Schioler L, Svensson AM, 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).
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia 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). Diabetes Care. 2012;35(6):1364–79.
Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014;312(24):2668–75.
Inzucchi SE, Masoudi FA, McGuire DK. Metformin in heart failure. Diabetes Care. 2007;30(12):e129.
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(10):2345–51.
Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, et al. Te risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta Diabetol. 2009;46(2):145–54.
Roussel R, Travert F, Pasquet B, Wilson PW, Smith SC, Jr, Goto S, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170(21):1892–9.
Goldberg T, Kroehl ME, Suddarth KH, Trinkley KE. Variations in Metformin Prescribing for Type 2 Diabetes. J Am Board Fam Med. 2015;28(6):777–84.
Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002;25(12):2244–8.
Scheen AJ, Paquot N. Metformin revisited: a critical review of the beneft-risk balance in at-risk patients with type 2 diabetes. Diabetes Metab. 2013;39(3):179–90.
Popov VB, Lim JK. 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(8):2398–400.
Neumiller JJ, Setter SM. Pharmacologic management of the older patient with type 2 diabetes mellitus. Am J Geriatr Pharmacother. 2009;7(6):324–42.
Tomsen H, Webb J, Contrast Media. Safety Issues and ESUR Guidelines. Heidelberg: Springer; 014.
The Author transfers to the Publisher (Zdravniški vestnik/Slovenian Medical Journal) all economic copyrights following form Article 22 of the Slovene Copyright and Related Rights Act (ZASP), including the right of reproduction, the right of distribution, the rental right, the right of public performance, the right of public transmission, the right of public communication by means of phonograms and videograms, the right of public presentation, the right of broadcasting, the right of rebroadcasting, the right of secondary broadcasting, the right of communication to the public, the right of transformation, the right of audiovisual adaptation and all other rights of the author according to ZASP.
The aforementioned rights are transferred non-exclusively, for an unlimited number of editions, for the term of the statutory
The Author can make use of his work himself or transfer subjective rights to others only after 3 months from date of first publishing in the journal Zdravniški vestnik/Slovenian Medical Journal.
The Publisher (Zdravniški vestnik/Slovenian Medical Journal) has the right to transfer the rights, acquired parties without explicit consent of the Author.
The Author consents that the Article be published under the Creative Commons BY-NC 4.0 (attribution-non-commercial) or comparable licence.
