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Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Review Article

Metformin: Up to Date

Author(s): Silvia Sciannimanico, Franco Grimaldi, Fabio Vescini, Giovanni De Pergola , Massimo Iacoviello, Brunella Licchelli , Edoardo Guastamacchia , Vito A. Giagulli and Vincenzo Triggiani *

Volume 20, Issue 2, 2020

Page: [172 - 181] Pages: 10

DOI: 10.2174/1871530319666190507125847

Price: $65

Abstract

Background: Metformin is an oral hypoglycemic agent extensively used as first-line therapy for type 2 diabetes. It improves hyperglycemia by suppressing hepatic glucose production and increasing glucose uptake in muscles. Metformin improves insulin sensitivity and shows a beneficial effect on weight control. Besides its metabolic positive effects, Metformin has direct effects on inflammation and can have immunomodulatory and antineoplastic properties.

Aim: The aim of this narrative review was to summarize the up-to-date evidence from the current literature about the metabolic and non-metabolic effects of Metformin.

Methods: We reviewed the current literature dealing with different effects and properties of Metformin and current recommendations about the use of this drug. We identified keywords and MeSH terms in Pubmed and the terms Metformin and type 2 diabetes, type 1 diabetes, pregnancy, heart failure, PCOS, etc, were searched, selecting only significant original articles and review in English, in particular of the last five years.

Conclusion: Even if many new effective hypoglycemic agents have been launched in the market in the last few years, Metformin would always keep a place in the treatment of type 2 diabetes and its comorbidities because of its multiple positive effects and low cost.

Keywords: Metformin, type 2 diabetes, type 1 diabetes, insulin resistance, polycystic ovary syndrome, heart failure.

Graphical Abstract
[1]
Walker, R.S.; Linton, A.L. Phenethyldiguanide: a dangerous side-effect. BMJ, 1959, 2(5158), 1005-1006.
[http://dx.doi.org/10.1136/bmj.2.5158.1005] [PMID: 13842538]
[2]
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.
[http://dx.doi.org/10.1016/S0140-6736(98)07037-8] [PMID: 9742977]
[3]
DeFronzo, R.A.; Stonehouse, A.H.; Han, J.; Wintle, M.E. Relationship of baseline HbA1c and efficacy of current glucose-lowering therapies: a meta-analysis of randomized clinical trials. Diabet. Med., 2010, 27(3), 309-317.
[http://dx.doi.org/10.1111/j.1464-5491.2010.02941.x] [PMID: 20536494]
[4]
Garber, A.J.; Duncan, T.G.; Goodman, A.M.; Mills, D.J.; Rohlf, J.L. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am. J. Med., 1997, 103(6), 491-497.
[http://dx.doi.org/10.1016/S0002-9343(97)00254-4] [PMID: 9428832]
[5]
Kahn, S.E.; Haffner, S.M.; Heise, M.A.; Herman, W.H.; Holman, R.R.; Jones, N.P.; Kravitz, B.G.; Lachin, J.M.; O’Neill, M.C.; Zinman, B.; Viberti, G. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med., 2006, 355(23), 2427-2443.
[http://dx.doi.org/10.1056/NEJMoa066224] [PMID: 17145742]
[6]
Inzucchi, S.E.; Lipska, K.J.; Mayo, H.; Bailey, C.J.; McGuire, D.K. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA, 2014, 312(24), 2668-2675.
[http://dx.doi.org/10.1001/jama.2014.15298] [PMID: 25536258]
[7]
Salpeter, S.R.; Greyber, E.; Pasternack, G.A.; Salpeter, E.E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst. Rev, 2010, 4, CD002967.
[http://dx.doi.org/10.1002/14651858.CD002967.pub3]
[8]
Connelly, P.J.; Lonergan, M.; Soto-Pedre, E.; Donnelly, L.; Zhou, K.; Pearson, E.R. Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: A GoDarts study. Diabetes Obes. Metab., 2017, 19(11), 1579-1586.
[http://dx.doi.org/10.1111/dom.12978] [PMID: 28432751]
[9]
De Broe, M.E.; Kajbaf, F.; Lalau, J.D. Renoprotective Effects of Metformin. Nephron, 2018, 138(4), 261-274.
[http://dx.doi.org/10.1159/000481951] [PMID: 29241197]
[10]
de Jager, J.; Kooy, A.; Lehert, P.; Wulffelé, M.G.; van der Kolk, J.; Bets, D.; Verburg, J.; Donker, A.J.; Stehouwer, C.D. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ, 2010, 340, c2181.
[http://dx.doi.org/10.1136/bmj.c2181] [PMID: 20488910]
[11]
Aroda, V.R.; Edelstein, S.L.; Goldberg, R.B.; Knowler, W.C.; Marcovina, S.M.; Orchard, T.J.; Bray, G.A.; Schade, D.S.; Temprosa, M.G.; White, N.H.; Crandall, J.P. Long term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J. Clin. Endocrinol. Metab., 2016, 101(4), 1754-1761.
[http://dx.doi.org/10.1210/jc.2015-3754] [PMID: 26900641]
[12]
Doemcq, J.P.; Prutsky, G.; Wang, Z.; Elraiyah, T.; Brito, J.P.; Mauck, K.; Lababidi, M.H.; Leppin, A.; Fidahussein, S.; Prokop, L.J.; Montori, V.M.; Murad, M.H. Drugs commonly associated with weight change: a systematic review and meta-analysis. Syst. Rev., 2012, 29, 1-44.
[13]
Vella, S.; Buetow, L.; Royle, P.; Livingstone, S.; Colhoun, H.M.; Petrie, J.R. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia, 2010, 53(5), 809-820.
[http://dx.doi.org/10.1007/s00125-009-1636-9] [PMID: 20057994]
[14]
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 1998, 352(9131), 837-853.
[http://dx.doi.org/10.1016/S0140-6736(98)07019-6] [PMID: 9742976]
[15]
Wang, D.S.; Jonker, J.W.; Kato, Y.; Kusuhara, H.; Schinkel, A.H.; Sugiyama, Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther., 2002, 302(2), 510-515.
[http://dx.doi.org/10.1124/jpet.102.034140] [PMID: 12130709]
[16]
Owen, M.R.; Doran, E.; Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J., 2000, 348(Pt 3), 607-614.
[http://dx.doi.org/10.1042/bj3480607] [PMID: 10839993]
[17]
El-Mir, M.Y.; Nogueira, V.; Fontaine, E.; Avéret, N.; Rigoulet, M.; Leverve, X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem., 2000, 275(1), 223-228.
[http://dx.doi.org/10.1074/jbc.275.1.223] [PMID: 10617608]
[18]
Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M.F.; Goodyear, L.J.; Moller, D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 2001, 108(8), 1167-1174.
[http://dx.doi.org/10.1172/JCI13505] [PMID: 11602624]
[19]
Zhang, C.S.; Li, M.; Ma, T.; Zong, Y.; Cui, J.; Feng, J.W.; Wu, Y.Q.; Lin, S.Y.; Lin, S.C. Metformin activates AMPK through the lysosomal pathway. Cell Metab., 2016, 24(4), 521-522.
[http://dx.doi.org/10.1016/j.cmet.2016.09.003] [PMID: 27732831]
[20]
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(7436), 256-260.
[http://dx.doi.org/10.1038/nature11808] [PMID: 23292513]
[21]
Fullerton, M.D.; Galic, S.; Marcinko, K.; Sikkema, S.; Pulinilkunnil, T.; Chen, Z.P.; O’Neill, H.M.; Ford, R.J.; Palanivel, R.; O’Brien, M.; Hardie, D.G.; Macaulay, S.L.; Schertzer, J.D.; Dyck, J.R.; van Denderen, B.J.; Kemp, B.E.; Steinberg, G.R. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med., 2013, 19(12), 1649-1654.
[http://dx.doi.org/10.1038/nm.3372] [PMID: 24185692]
[22]
McCreight, L.J.; Bailey, C.J.; Pearson, E.R. Metformin and the gastrointestinal tract. Diabetologia, 2016, 59(3), 426-435.
[http://dx.doi.org/10.1007/s00125-015-3844-9] [PMID: 26780750]
[23]
DeFronzo, R.A.; Buse, J.B.; Kim, T.; Burns, C.; Skare, S.; Baron, A.; Fineman, M. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia, 2016, 59(8), 1645-1654.
[http://dx.doi.org/10.1007/s00125-016-3992-6] [PMID: 27216492]
[24]
Forslund, K.; Hildebrand, F.; Nielsen, T.; Falony, G.; Le Chatelier, E.; Sunagawa, S.; Prifti, E.; Vieira-Silva, S.; Gudmundsdottir, V.; Pedersen, H.K.; Arumugam, M.; Kristiansen, K.; Voigt, A.Y.; Vestergaard, H.; Hercog, R.; Costea, P.I.; Kultima, J.R.; Li, J.; Jørgensen, T.; Levenez, F.; Dore, J.; Nielsen, H.B.; Brunak, S.; Raes, J.; Hansen, T.; Wang, J.; Ehrlich, S.D.; Bork, P.; Pedersen, O. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature, 2015, 528(7581), 262-266.
[http://dx.doi.org/10.1038/nature15766] [PMID: 26633628]
[25]
Pedersen, H.K.; Gudmundsdottir, V.; Nielsen, H.B.; Hyotylainen, T.; Nielsen, T.; Jensen, B.A.; Forslund, K.; Hildebrand, F.; Prifti, E.; Falony, G.; Le Chatelier, E.; Levenez, F.; Doré, J.; Mattila, I.; Plichta, D.R.; Pöhö, P.; Hellgren, L.I.; Arumugam, M.; Sunagawa, S.; Vieira-Silva, S.; Jørgensen, T.; Holm, J.B.; Trošt, K.; Kristiansen, K.; Brix, S.; Raes, J.; Wang, J.; Hansen, T.; Bork, P.; Brunak, S.; Oresic, M.; Ehrlich, S.D.; Pedersen, O. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature, 2016, 535(7612), 376-381.
[http://dx.doi.org/10.1038/nature18646] [PMID: 27409811]
[26]
Perry, R.J.; Peng, L.; Barry, N.A.; Cline, G.W.; Zhang, D.; Cardone, R.L.; Petersen, K.F.; Kibbey, R.G.; Goodman, A.L.; Shulman, G.I. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature, 2016, 534(7606), 213-217.
[http://dx.doi.org/10.1038/nature18309] [PMID: 27279214]
[27]
Cubeddu, L.X.; Bönisch, H.; Göthert, M.; Molderings, G.; Racké, K.; Ramadori, G.; Miller, K.J.; Schwörer, H. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn Schmiedebergs Arch. Pharmacol., 2000, 361(1), 85-91.
[http://dx.doi.org/10.1007/s002109900152] [PMID: 10651152]
[28]
The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care, 1999, 22(4), 623-634.
[http://dx.doi.org/10.2337/diacare.22.4.623] [PMID: 10189543]
[29]
Knowler, W.C.; Fowler, S.E.; Hamman, R.F.; Christophi, C.A.; Hoffman, H.J.; Brenneman, A.T.; Brown-Friday, J.O.; Goldberg, R.; Venditti, E.; Nathan, D.M. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet, 2009, 374(9702), 1677-1686.
[http://dx.doi.org/10.1016/S0140-6736(09)61457-4] [PMID: 19878986]
[30]
Knowler, W.C.; Barrett-Connor, E.; Fowler, S.E.; Hamman, R.F.; Lachin, J.M.; Walker, E.A.; Nathan, D.M. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med., 2002, 346(6), 393-403.
[http://dx.doi.org/10.1056/NEJMoa012512] [PMID: 11832527]
[31]
Lachin, J.M.; Christophi, C.A.; Edelstein, S.L.; Ehrmann, D.A.; Hamman, R.F.; Kahn, S.E.; Knowler, W.C.; Nathan, D.M. Factors associated with diabetes onset during metformin versus placebo therapy in the diabetes prevention program. Diabetes, 2007, 56(4), 1153-1159.
[http://dx.doi.org/10.2337/db06-0918] [PMID: 17395752]
[32]
HbA1c as a predictor of diabetes and as an outcome in the diabetes prevention program: a randomized clinical trial. Diabetes Care, 2015, 38(1), 51-58.
[http://dx.doi.org/10.2337/dc14-0886] [PMID: 25336746]
[33]
Lund, S.S.; Tarnow, L.; Astrup, A.S.; Hovind, P.; Jacobsen, P.K.; Alibegovic, A.C.; Parving, I.; Pietraszek, L.; Frandsen, M.; Rossing, P.; Parving, H.H.; Vaag, A.A. Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. PLoS One, 2008, 3(10)e3363
[http://dx.doi.org/10.1371/journal.pone.0003363] [PMID: 18852875]
[34]
Meng, H.; Zhang, A.; Liang, Y.; Hao, J.; Zhang, X.; Lu, J. Effect of metformin on glycaemic control in patients with type 1 diabetes: A meta-analysis of randomized controlled trials. Diabetes Metab. Res. Rev., 2018, 34(4)e2983
[http://dx.doi.org/10.1002/dmrr.2983] [PMID: 29351716]
[35]
American Diabetes Association Standards of Medical Care in Diabetes-2018. Diabetes Care, 2018, 41(Suppl 1)
[36]
Petrie, J.R.; Chaturvedi, N.; Ford, I.; Brouwers, M.C.G.J.; Greenlaw, N.; Tillin, T.; Hramiak, I.; Hughes, A.D.; Jenkins, A.J.; Klein, B.E.K.; Klein, R.; Ooi, T.C.; Rossing, P.; Stehouwer, C.D.A.; Sattar, N.; Colhoun, H.M. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol., 2017, 5(8), 597-609.
[http://dx.doi.org/10.1016/S2213-8587(17)30194-8] [PMID: 28615149]
[37]
Jankowska, E.A.; Biel, B.; Majda, J.; Szklarska, A.; Lopuszanska, M.; Medras, M.; Anker, S.D.; Banasiak, W.; Poole-Wilson, P.A.; Ponikowski, P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation, 2006, 114(17), 1829-1837.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.649426] [PMID: 17030678]
[38]
Arcopinto, M.; Salzano, A.; Bossone, E.; Ferrara, F.; Bobbio, E.; Sirico, D.; Vriz, O.; De Vincentiis, C.; Matarazzo, M.; Saldamarco, L.; Saccà, F.; Napoli, R.; Iacoviello, M.; Triggiani, V.; Isidori, A.M.; Vigorito, C.; Isgaard, J.; Cittadini, A. Multiple hormone deficiencies in chronic heart failure. Int. J. Cardiol., 2015, 184, 421-423.
[http://dx.doi.org/10.1016/j.ijcard.2015.02.055] [PMID: 25755056]
[39]
Bossone, E.; Arcopinto, M.; Iacoviello, M.; Triggiani, V.; Cacciatore, F.; Maiello, C.; Limongelli, G.; Masarone, D.; Perticone, F.; Sciacqua, A.; Perrone-Filardi, P.; Mancini, A.; Volterrani, M.; Vriz, O.; Castello, R.; Passantino, A.; Campo, M.; Modesti, P.A.; De Giorgi, A.; Monte, I.; Puzzo, A.; Ballotta, A.; Caliendo, L.; D’Assante, R.; Marra, A.M.; Salzano, A.; Suzuki, T.; Cittadini, A. Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry. Intern. Emerg. Med., 2018, 13(5), 661-671.
[http://dx.doi.org/10.1007/s11739-018-1844-8] [PMID: 29619769]
[40]
Iacoviello, M.; Triggiani, V. Editorial (Hot Topic: Introduction to the Special Issue: Relevance of Endocrine and Metabolic Disorders in Heart Failure: From Pathophysiology to Therapeutic Approach). Endocr. Metab. Immune Disord. Drug Targets, 2013, 13(1), 2-3.
[http://dx.doi.org/10.2174/1871530311313010002]
[41]
Triggiani, V.; Iacoviello, M. Thyroid disorders in chronic heart failure: from prognostic set-up to therapeutic management. Endocr. Metab. Immune Disord. Drug Targets, 2013, 13(1), 22-37.
[http://dx.doi.org/10.2174/1871530311313010005] [PMID: 23369135]
[42]
Triggiani, V.; Angelo Giagulli, V.; De Pergola, G.; Licchelli, B.; Guastamacchia, E.; Iacoviello, M. Mechanisms Explaining the Influence of Subclinical Hypothyroidism on the Onset and Progression of Chronic Heart Failure. Endocr. Metab. Immune Disord. Drug Targets, 2016, 16(1), 2-7.
[http://dx.doi.org/10.2174/1871530316666151218151319] [PMID: 26680772]
[43]
Ning, N.; Gao, D.; Triggiani, V.; Iacoviello, M.; Mitchell, J.E.; Ma, R.; Zhang, Y.; Kou, H. Prognostic Role of Hypothyroidism in Heart Failure: A Meta-Analysis. Medicine (Baltimore), 2015, 94(30)e1159
[http://dx.doi.org/10.1097/MD.0000000000001159] [PMID: 26222845]
[44]
Triggiani, V.; Iacoviello, M.; Monzani, F.; Puzzovivo, A.; Guida, P.; Forleo, C.; Ciccone, M.M.; Catanzaro, R.; Tafaro, E.; Licchelli, B.; Giagulli, V.A.; Guastamacchia, E.; Favale, S. Incidence and prevalence of hypothyroidism in patients affected by chronic heart failure: role of amiodarone. Endocr. Metab. Immune Disord. Drug Targets, 2012, 12(1), 86-94.
[http://dx.doi.org/10.2174/187153012799278947] [PMID: 22214334]
[45]
Giagulli, V.A.; Guastamacchia, E.; De Pergola, G.; Iacoviello, M.; Triggiani, V. Testosterone deficiency in male: a risk factor for heart failure. Endocr. Metab. Immune Disord. Drug Targets, 2013, 13(1), 92-99.
[http://dx.doi.org/10.2174/1871530311313010011] [PMID: 23369141]
[46]
Arcopinto, M.; Salzano, A.; Giallauria, F.; Bossone, E.; Isgaard, J.; Marra, A.M.; Bobbio, E.; Vriz, O.; Åberg, D.N.; Masarone, D.; De Paulis, A.; Saldamarco, L.; Vigorito, C.; Formisano, P.; Niola, M.; Perticone, F.; Bonaduce, D.; Saccà, L.; Colao, A.; Cittadini, A. Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study. PLoS One, 2017, 12(1)e0170058
[http://dx.doi.org/10.1371/journal.pone.0170058] [PMID: 28095492]
[47]
Dei Cas, A.; Khan, S.S.; Butler, J.; Mentz, R.J.; Bonow, R.O.; Avogaro, A.; Tschoepe, D.; Doehner, W.; Greene, S.J.; Senni, M.; Gheorghiade, M.; Fonarow, G.C. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail., 2015, 3(2), 136-145.
[http://dx.doi.org/10.1016/j.jchf.2014.08.004] [PMID: 25660838]
[48]
De Pergola, G.; Nardecchia, A.; Giagulli, V.A.; Triggiani, V.; Guastamacchia, E.; Minischetti, M.C.; Silvestris, F. Obesity and heart failure. Endocr. Metab. Immune Disord. Drug Targets, 2013, 13(1), 51-57.
[http://dx.doi.org/10.2174/1871530311313010007] [PMID: 23369137]
[49]
Grande, D.; Terlizzese, P.; Gioia, M.I.; Parisi, G.; Giagulli, V.A.; Triggiani, V.; Iacoviello, M. New frontiers in the therapeutic approach of patients with cardiovascular and endocrine diseases. Endocr. Metab. Immune Disord. Drug Targets, 2019. Epub ahead of print
[http://dx.doi.org/10.2174/1871530319666190101151542] [PMID: 30621568]
[50]
Arcopinto, M.; Salzano, A.; Isgaard, J.; Cittadini, A. Hormone replacement therapy in heart failure. Curr. Opin. Cardiol., 2015, 30(3), 277-284.
[http://dx.doi.org/10.1097/HCO.0000000000000166] [PMID: 25807222]
[51]
Giagulli, V.A.; Moghetti, P.; Kaufman, J.M.; Guastamacchia, E.; Iacoviello, M.; Triggiani, V. Managing erectile dysfunction in heart failure. Endocr. Metab. Immune Disord. Drug Targets, 2013, 13(1), 125-134.
[http://dx.doi.org/10.2174/1871530311313010015] [PMID: 23369145]
[52]
Mudoni, A.; Caccetta, F.; Caroppo, M.; Musio, F.; Accogli, A.; Zacheo, M.D.; Burzo, M.D.; Nuzzo, R.; Nuzzo, V. Lactic acidosis, acute renal failure and heart failure during treatment with metformin: what do we know? G. Ital. Nefrol, 2015, 32(5), ii: gin/32.5.6.
[53]
Fácila, L.; Fabregat-Andrés, Ó.; Bertomeu, V.; Navarro, J.P.; Miñana, G.; García-Blas, S.; Valero, E.; Morell, S.; Sanchis, J.; Núñez, J. Metformin and risk of long-term mortality following an admission for acute heart failure. J. Cardiovasc. Med. (Hagerstown), 2017, 18(2), 69-73.
[http://dx.doi.org/10.2459/JCM.0000000000000420] [PMID: 27341193]
[54]
Crowley, M.J.; Diamantidis, C.J.; McDuffie, J.R.; Cameron, C.B.; Stanifer, J.W.; Mock, C.K.; Wang, X.; Tang, S.; Nagi, A.; Kosinski, A.S.; Williams, J.W., Jr Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review. Ann. Intern. Med., 2017, 166(3), 191-200.
[http://dx.doi.org/10.7326/M16-1901] [PMID: 28055049]
[55]
Evans, J.M.; Doney, A.S.; AlZadjali, M.A.; Ogston, S.A.; Petrie, J.R.; Morris, A.D.; Struthers, A.D.; Wong, A.K.; Lang, C.C. Effect of Metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am. J. Cardiol., 2010, 106(7), 1006-1010.
[http://dx.doi.org/10.1016/j.amjcard.2010.05.031] [PMID: 20854965]
[56]
Cosmi, F.; Cosmi, D. [Metformin and insulin in chronic heart failure: contraindications not contraindicated and indications not indicated G. Ital. Cardiol. (Rome), 2011, 12(12), 796-803.
[PMID: 22158450]
[57]
Wong, A.K.; AlZadjali, M.A.; Choy, A.M.; Lang, C.C. Insulin resistance: a potential new target for therapy in patients with heart failure. Cardiovasc. Ther., 2008, 26(3), 203-213.
[http://dx.doi.org/10.1111/j.1755-5922.2008.00053.x] [PMID: 18786090]
[58]
Pantalone, K.M.; Kattan, M.W.; Yu, C.; Wells, B.J.; Arrigain, S.; Jain, A.; Atreja, A.; Zimmerman, R.S. The 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), 145-154.
[http://dx.doi.org/10.1007/s00592-008-0090-3] [PMID: 19194648]
[59]
Papanas, N.; Maltezos, E.; Mikhailidis, D.P. Metformin and heart failure: never say never again. Expert Opin. Pharmacother., 2012, 13(1), 1-8.
[http://dx.doi.org/10.1517/14656566.2012.638283] [PMID: 22149365]
[60]
Roberts, F.; Ryan, G.J. The safety of metformin in heart failure. Ann. Pharmacother., 2007, 41(4), 642-646.
[http://dx.doi.org/10.1345/aph.1H523] [PMID: 17374622]
[61]
Ponikowski, P.; Voors, A.A.; Anker, S.D.; Bueno, H.; Cleland, J.G.; Coats, A.J.; Falk, V.; González-Juanatey, J.R.; Harjola, V.P.; Jankowska, E.A.; Jessup, M.; Linde, C.; Nihoyannopoulos, P.; Parissis, J.T.; Pieske, B.; Riley, J.P.; Rosano, G.M.; Ruilope, L.M.; Ruschitzka, F.; Rutten, F.H.; van der Meer, P. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail., 2016, 18(8), 891-975.
[http://dx.doi.org/10.1002/ejhf.592] [PMID: 27207191]
[62]
Moiseeva, O.; Deschênes-Simard, X.; St-Germain, E.; Igelmann, S.; Huot, G.; Cadar, A.E.; Bourdeau, V.; Pollak, M.N.; Ferbeyre, G. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell, 2013, 12(3), 489-498.
[http://dx.doi.org/10.1111/acel.12075] [PMID: 23521863]
[63]
Batandier, C.; Guigas, B.; Detaille, D.; El-Mir, M.Y.; Fontaine, E.; Rigoulet, M.; Leverve, X.M. The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin. J. Bioenerg. Biomembr., 2006, 38(1), 33-42.
[http://dx.doi.org/10.1007/s10863-006-9003-8] [PMID: 16732470]
[64]
Jadhav, K.S.; Dungan, C.M.; Williamson, D.L. Metformin limits ceramide-induced senescence in C2C12 myoblasts. Mech. Ageing Dev., 2013, 134(11-12), 548-559.
[http://dx.doi.org/10.1016/j.mad.2013.11.002] [PMID: 24269881]
[65]
Meng, X.; Chu, G.; Yang, Z.; Qiu, P.; Hu, Y.; Chen, X.; Peng, W.; Ye, C.; He, F.F.; Zhang, C. Metformin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury by down-regulating MAD2B. Cell. Physiol. Biochem., 2016, 40(3-4), 477-485.
[http://dx.doi.org/10.1159/000452562] [PMID: 27889750]
[66]
El-Mir, M.Y.; Detaille, D. R-Villanueva, G.; Delgado-Esteban, M.; Guigas, B.; Attia, S.; Fontaine, E.; Almeida, A.; Leverve, X. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J. Mol. Neurosci., 2008, 34(1), 77-87.
[http://dx.doi.org/10.1007/s12031-007-9002-1] [PMID: 18040888]
[67]
Gupta, A.; Bisht, B.; Dey, C.S. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology, 2011, 60(6), 910-920.
[http://dx.doi.org/10.1016/j.neuropharm.2011.01.033] [PMID: 21277873]
[68]
Takahashi, N.; Shibata, R.; Ouchi, N.; Sugimoto, M.; Murohara, T.; Komori, K. Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model. J. Vasc. Surg., 2015, 61(2), 489-496.
[http://dx.doi.org/10.1016/j.jvs.2013.09.061] [PMID: 24993950]
[69]
Wang, C.P.; Lorenzo, C.; Habib, S.L.; Jo, B.; Espinoza, S.E. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J. Diabetes Complications, 2017, 31(4), 679-686.
[http://dx.doi.org/10.1016/j.jdiacomp.2017.01.013] [PMID: 28190681]
[70]
Jadhav, S.; Ferrell, W.; Greer, I.A.; Petrie, J.R.; Cobbe, S.M.; Sattar, N. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study. J. Am. Coll. Cardiol., 2006, 48(5), 956-963.
[http://dx.doi.org/10.1016/j.jacc.2006.04.088] [PMID: 16949486]
[71]
Griffin, S.J.; Leaver, J.K.; Irving, G.J. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia, 2017, 60(9), 1620-1629.
[http://dx.doi.org/10.1007/s00125-017-4337-9] [PMID: 28770324]
[72]
Fiore, V.; Marci, M.; Poggi, A.; Giagulli, V.A.; Licchelli, B.; Iacoviello, M.; Guastamacchia, E.; De Pergola, G.; Triggiani, V. The association between diabetes and depression: a very disabling condition. Endocrine, 2015, 48(1), 14-24.
[http://dx.doi.org/10.1007/s12020-014-0323-x] [PMID: 24927794]
[73]
Guo, M.; Mi, J.; Jiang, Q.M.; Xu, J.M.; Tang, Y.Y.; Tian, G.; Wang, B. Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus. Clin. Exp. Pharmacol. Physiol., 2014, 41(9), 650-656.
[http://dx.doi.org/10.1111/1440-1681.12265] [PMID: 24862430]
[74]
Cheng, C.; Lin, C.H.; Tsai, Y.W.; Tsai, C.J.; Chou, P.H.; Lan, T.H. Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J. Gerontol. A Biol. Sci. Med. Sci., 2014, 69(10), 1299-1305.
[http://dx.doi.org/10.1093/gerona/glu073] [PMID: 24899525]
[75]
Luchsinger, J.A.; Ma, Y.; Christophi, C.A.; Florez, H.; Golden, S.H.; Hazuda, H.; Crandall, J.; Venditti, E.; Watson, K.; Jeffries, S.; Manly, J.J.; Pi-Sunyer, F.X. Metformin, Lifestyle Intervention, and Cognition in the Diabetes Prevention Program Outcomes Study. Diabetes Care, 2017, 40(7), 958-965.
[http://dx.doi.org/10.2337/dc16-2376] [PMID: 28500216]
[76]
Corona, G.; Monami, M.; Rastrelli, G.; Aversa, A.; Sforza, A.; Lenzi, A.; Forti, G.; Mannucci, E.; Maggi, M. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int. J. Androl., 2011, 34(6 Pt 1), 528-540.
[http://dx.doi.org/10.1111/j.1365-2605.2010.01117.x] [PMID: 20969599]
[77]
Corona, G.; Rastrelli, G.; Monami, M.; Saad, F.; Luconi, M.; Lucchese, M.; Facchiano, E.; Sforza, A.; Forti, G.; Mannucci, E.; Maggi, M. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur. J. Endocrinol., 2013, 168(6), 829-843.
[http://dx.doi.org/10.1530/EJE-12-0955] [PMID: 23482592]
[78]
Giagulli, V.A.; Carbone, M.D.; Ramunni, M.I.; Licchelli, B.; De Pergola, G.; Sabbà, C.; Guastamacchia, E.; Triggiani, V. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology, 2015, 3(6), 1094-1103.
[http://dx.doi.org/10.1111/andr.12099] [PMID: 26447645]
[79]
Vasamsetti, S.B.; Karnewar, S.; Kanugula, A.K.; Thatipalli, A.R.; Kumar, J.M.; Kotamraju, S. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes, 2015, 64(6), 2028-2041.
[http://dx.doi.org/10.2337/db14-1225] [PMID: 25552600]
[80]
Cameron, A.R.; Morrison, V.L.; Levin, D.; Mohan, M.; Forteath, C.; Beall, C.; McNeilly, A.D.; Balfour, D.J.; Savinko, T.; Wong, A.K.; Viollet, B.; Sakamoto, K.; Fagerholm, S.C.; Foretz, M.; Lang, C.C.; Rena, G. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ. Res., 2016, 119(5), 652-665.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.308445] [PMID: 27418629]
[81]
Blagih, J.; Coulombe, F.; Vincent, E.E.; Dupuy, F.; Galicia-Vázquez, G.; Yurchenko, E.; Raissi, T.C.; van der Windt, G.J.; Viollet, B.; Pearce, E.L.; Pelletier, J.; Piccirillo, C.A.; Krawczyk, C.M.; Divangahi, M.; Jones, R.G. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity, 2015, 42(1), 41-54.
[http://dx.doi.org/10.1016/j.immuni.2014.12.030] [PMID: 25607458]
[82]
Eikawa, S.; Nishida, M.; Mizukami, S.; Yamazaki, C.; Nakayama, E.; Udono, H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc. Natl. Acad. Sci. USA, 2015, 112(6), 1809-1814.
[http://dx.doi.org/10.1073/pnas.1417636112] [PMID: 25624476]
[83]
Resta, F.; Triggiani, V.; Sabbà, C.; Licchelli, B.; Ghiyasaldin, S.; Liso, A.; Schittulli, F.; Quaranta, M.; Paradiso, A.; Tafaro, E.; Guastamacchia, E. The impact of body mass index and type 2 diabetes on breast cancer: current therapeutic measures of prevention. Curr. Drug Targets Immune Endocr. Metabol. Disord., 2004, 4(4), 327-333.
[http://dx.doi.org/10.2174/1568008043339686] [PMID: 15578984]
[84]
Guastamacchia, E.; Resta, F.; Triggiani, V.; Liso, A.; Licchelli, B.; Ghiyasaldin, S.; Sabbà, C.; Tafaro, E. Evidence for a putative relationship between type 2 diabetes and neoplasia with particular reference to breast cancer: role of hormones, growth factors and specific receptors. Curr. Drug Targets Immune Endocr. Metabol. Disord., 2004, 4(1), 59-66.
[http://dx.doi.org/10.2174/1568008043339965] [PMID: 15032627]
[85]
Guastamacchia, E.; Resta, F.; Mangia, A.; Schittulli, F.; Ciampolillo, A.; Triggiani, V.; Licchelli, B.; Paradiso, A.; Sabbà, C.; Tafaro, E. Breast cancer: biological characteristics in postmenopausal type 2 diabetic women. Identification of therapeutic targets. Curr. Drug Targets Immune Endocr. Metabol. Disord., 2003, 3(3), 205-209.
[http://dx.doi.org/10.2174/1568008033340199] [PMID: 12871027]
[86]
Wheaton, W.W.; Weinberg, S.E.; Hamanaka, R.B.; Soberanes, S.; Sullivan, L.B.; Anso, E.; Glasauer, A.; Dufour, E.; Mutlu, G.M.; Budigner, G.S.; Chandel, N.S. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife, 2014, 3, e02242.
[http://dx.doi.org/10.7554/eLife.02242] [PMID: 24843020]
[87]
Cai, H.; Zhang, Y.; Han, T.K.; Everett, R.S.; Thakker, D.R. Cation-selective transporters are critical to the AMPK-mediated antiproliferative effects of metformin in human breast cancer cells. Int. J. Cancer, 2016, 138(9), 2281-2292.
[http://dx.doi.org/10.1002/ijc.29965] [PMID: 26669511]
[88]
Gonzalez-Angulo, A.M.; Meric-Bernstam, F. Metformin: a therapeutic opportunity in breast cancer. Clin. Cancer Res., 2010, 16(6), 1695-1700.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1805] [PMID: 20215559]
[89]
Bao, B.; Wang, Z.; Ali, S.; Ahmad, A.; Azmi, A.S.; Sarkar, S.H.; Banerjee, S.; Kong, D.; Li, Y.; Thakur, S.; Sarkar, F.H. Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev. Res. (Phila.), 2012, 5(3), 355-364.
[http://dx.doi.org/10.1158/1940-6207.CAPR-11-0299] [PMID: 22086681]
[90]
Ben Sahra, I.; Laurent, K.; Loubat, A.; Giorgetti-Peraldi, S.; Colosetti, P.; Auberger, P.; Tanti, J.F.; Le Marchand-Brustel, Y.; Bost, F. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene, 2008, 27(25), 3576-3586.
[http://dx.doi.org/10.1038/sj.onc.1211024] [PMID: 18212742]
[91]
Decensi, A.; Puntoni, M.; Goodwin, P.; Cazzaniga, M.; Gennari, A.; Bonanni, B.; Gandini, S. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev. Res. (Phila.), 2010, 3(11), 1451-1461.
[http://dx.doi.org/10.1158/1940-6207.CAPR-10-0157] [PMID: 20947488]
[92]
Zhang, P.; Li, H.; Tan, X.; Chen, L.; Wang, S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol., 2013, 37(3), 207-218.
[http://dx.doi.org/10.1016/j.canep.2012.12.009] [PMID: 23352629]
[93]
Wu, L.; Zhu, J.; Prokop, L.J.; Murad, M.H. Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies. Sci. Rep., 2015, 5, 10147.
[http://dx.doi.org/10.1038/srep10147] [PMID: 26076034]
[94]
Tang, G.H.; Satkunam, M.; Pond, G.R.; Steinberg, G.R.; Blandino, G.; Schünemann, H.J.; Muti, P. Association of Metformin with Breast Cancer Incidence and Mortality in Patients with Type II Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis. Cancer Epidemiol. Biomarkers Prev., 2018, 27(6), 627-635.
[http://dx.doi.org/10.1158/1055-9965.EPI-17-0936] [PMID: 29618465]
[95]
Xin, W.X.; Fang, L.; Fang, Q.L.; Zheng, X.W.; Ding, H.Y.; Huang, P. Effect of hypoglycemic agents on survival outcomes of lung cancer patients with diabetes mellitus: A meta-analysis. Medicine (Baltimore), 2018, 97(9)e0035
[http://dx.doi.org/10.1097/MD.0000000000010035] [PMID: 29489653]
[96]
Xin, W.; Fang, L.; Fang, Q.; Zheng, X.; Huang, P. Effects of metformin on survival outcomes of pancreatic cancer patients with diabetes: A meta-analysis. Mol. Clin. Oncol., 2018, 8(3), 483-488.
[PMID: 29468063]
[97]
Xiao, Y.; Zheng, L.; Mei, Z.; Xu, C.; Liu, C.; Chu, X.; Hao, B. The impact of metformin use on survival in prostate cancer: a systematic review and meta-analysis. Oncotarget, 2017, 8(59), 100449-100458.
[http://dx.doi.org/10.18632/oncotarget.22117] [PMID: 29245991]
[98]
Zhou, X.L.; Xue, W.H.; Ding, X.F.; Li, L.F.; Dou, M.M.; Zhang, W.J.; Lv, Z.; Fan, Z.R.; Zhao, J.; Wang, L.X. Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies. Oncotarget, 2017, 8(33), 55622-55631.
[http://dx.doi.org/10.18632/oncotarget.16973] [PMID: 28903449]
[99]
Li, Y.; Hu, L.; Xia, Q.; Yuan, Y.; Mi, Y. The impact of metformin use on survival in kidney cancer patients with diabetes: a meta-analysis. Int. Urol. Nephrol., 2017, 49(6), 975-981.
[http://dx.doi.org/10.1007/s11255-017-1548-4] [PMID: 28271326]
[100]
Zhou, Y.Y.; Zhu, G.Q.; Liu, T.; Zheng, J.N.; Cheng, Z.; Zou, T.T.; Braddock, M.; Fu, S.W.; Zheng, M.H. Systematic Review with Network Meta-Analysis: Antidiabetic Medication and Risk of Hepatocellular Carcinoma. Sci. Rep., 2016, 6, 33743.
[http://dx.doi.org/10.1038/srep33743] [PMID: 27642100]
[101]
Stevens, R.J.; Ali, R.; Bankhead, C.R.; Bethel, M.A.; Cairns, B.J.; Camisasca, R.P.; Crowe, F.L.; Farmer, A.J.; Harrison, S.; Hirst, J.A.; Home, P.; Kahn, S.E.; McLellan, J.H.; Perera, R.; Plüddemann, A.; Ramachandran, A.; Roberts, N.W.; Rose, P.W.; Schweizer, A.; Viberti, G.; Holman, R.R. Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia, 2012, 55(10), 2593-2603.
[http://dx.doi.org/10.1007/s00125-012-2653-7] [PMID: 22875195]
[102]
Gandini, S.; Puntoni, M.; Heckman-Stoddard, B.M.; Dunn, B.K.; Ford, L.; DeCensi, A.; Szabo, E. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev. Res. (Phila.), 2014, 7(9), 867-885.
[http://dx.doi.org/10.1158/1940-6207.CAPR-13-0424] [PMID: 24985407]
[103]
Bonanni, B.; Puntoni, M.; Cazzaniga, M.; Pruneri, G.; Serrano, D.; Guerrieri-Gonzaga, A.; Gennari, A.; Trabacca, M.S.; Galimberti, V.; Veronesi, P.; Johansson, H.; Aristarco, V.; Bassi, F.; Luini, A.; Lazzeroni, M.; Varricchio, C.; Viale, G.; Bruzzi, P.; Decensi, A. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J. Clin. Oncol., 2012, 30(21), 2593-2600.
[http://dx.doi.org/10.1200/JCO.2011.39.3769] [PMID: 22564993]
[104]
Higurashi, T.; Hosono, K.; Takahashi, H.; Komiya, Y.; Umezawa, S.; Sakai, E.; Uchiyama, T.; Taniguchi, L.; Hata, Y.; Uchiyama, S.; Hattori, A.; Nagase, H.; Kessoku, T.; Arimoto, J.; Matsuhashi, N.; Inayama, Y.; Yamanaka, S.; Taguri, M.; Nakajima, A. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol., 2016, 17(4), 475-483.
[http://dx.doi.org/10.1016/S1470-2045(15)00565-3] [PMID: 26947328]
[105]
Mitsuhashi, A.; Kiyokawa, T.; Sato, Y.; Shozu, M. Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer, 2014, 120(19), 2986-2995.
[http://dx.doi.org/10.1002/cncr.28853] [PMID: 24917306]
[106]
Curry, J.; Johnson, J.; Tassone, P.; Vidal, M.D.; Menezes, D.W.; Sprandio, J.; Mollaee, M.; Cotzia, P.; Birbe, R.; Lin, Z.; Gill, K.; Duddy, E.; Zhan, T.; Leiby, B.; Reyzer, M.; Cognetti, D.; Luginbuhl, A.; Tuluc, M.; Martinez-Outschoorn, U. Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial. Laryngoscope, 2017, 127(8), 1808-1815.
[http://dx.doi.org/10.1002/lary.26489] [PMID: 28185288]
[107]
Joshua, A.M.; Zannella, V.E.; Downes, M.R.; Bowes, B.; Hersey, K.; Koritzinsky, M.; Schwab, M.; Hofmann, U.; Evans, A.; van der Kwast, T.; Trachtenberg, J.; Finelli, A.; Fleshner, N.; Sweet, J.; Pollak, M. A pilot ‘window of opportunity’ neoadjuvant study of metformin in localised prostate cancer. Prostate Cancer Prostatic Dis., 2014, 17(3), 252-258.
[http://dx.doi.org/10.1038/pcan.2014.20] [PMID: 24861559]
[108]
Tseng, C.H. Metformin reduces thyroid cancer risk in Taiwanese patients with type 2 diabetes. PLoS One, 2014, 9(10)e109852
[http://dx.doi.org/10.1371/journal.pone.0109852] [PMID: 25303400]
[109]
Cho, Y.Y.; Kang, M.J.; Kim, S.K.; Jung, J.H.; Hahm, J.R.; Kim, T.H.; Nam, J.Y.; Lee, B.W.; Lee, Y.H.; Chung, J.H.; Song, S.O.; Kim, S.W. Protective effect of metformin against thyroid cancer development: a population-based study in Korea. Thyroid, 2018, 28(7), 864-870.
[http://dx.doi.org/10.1089/thy.2017.0550] [PMID: 29808777]
[110]
Lupoli, R.; Di Minno, A.; Tortora, A.; Ambrosino, P.; Lupoli, G.A.; Di Minno, M.N. Effects of treatment with metformin on TSH levels: a meta-analysis of literature studies. J. Clin. Endocrinol. Metab., 2014, 99(1), E143-E148.
[http://dx.doi.org/10.1210/jc.2013-2965] [PMID: 24203069]
[111]
Cappelli, C.; Rotondi, M.; Pirola, I.; Agosti, B.; Gandossi, E.; Valentini, U.; De Martino, E.; Cimino, A.; Chiovato, L.; Agabiti-Rosei, E.; Castellano, M. 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(9), 1589-1590.
[http://dx.doi.org/10.2337/dc09-0273] [PMID: 19502536]
[112]
Cappelli, C.; Rotondi, M.; Pirola, I.; Agosti, B.; Formenti, A.; Zarra, E.; Valentini, U.; Leporati, P.; Chiovato, L.; Castellano, M. Thyreotropin levels in diabetic patients on metformin treatment. Eur. J. Endocrinol., 2012, 167(2), 261-265.
[http://dx.doi.org/10.1530/EJE-12-0225] [PMID: 22645202]
[113]
Tang, T.; Lord, J.M.; Norman, R.J.; Yasmin, E.; Balen, A.H. 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(1)CD003053
[http://dx.doi.org/10.1002/14651858.CD003053.pub4] [PMID: 20091537]
[114]
Hirsch, A.; Hahn, D.; Kempná, P.; Hofer, G.; Nuoffer, J.M.; Mullis, P.E.; Flück, C.E. Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Endocrinology, 2012, 153(9), 4354-4366.
[http://dx.doi.org/10.1210/en.2012-1145] [PMID: 22778212]
[115]
Kurzthaler, D.; Hadziomerovic-Pekic, D.; Wildt, L.; Seeber, B.E. Metformin induces a prompt decrease in LH-stimulated testosterone response in women with PCOS independent of its insulin-sensitizing effects. Reprod. Biol. Endocrinol., 2014, 12, 98.
[http://dx.doi.org/10.1186/1477-7827-12-98] [PMID: 25304843]
[116]
Cosma, M.; Swiglo, B.A.; Flynn, D.N.; Kurtz, D.M.; Labella, M.L.; Mullan, R.J.; Elamin, M.B.; Erwin, P.J.; Montori, V.M. Clinical review: Insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J. Clin. Endocrinol. Metab., 2008, 93(4), 1135-1142.
[http://dx.doi.org/10.1210/jc.2007-2429] [PMID: 18252787]
[117]
Tang, T.; Lord, J.M.; Norman, R.J.; Yasmin, E.; Balen, A.H. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst. Rev., 2012, 5(5)CD003053
[http://dx.doi.org/10.1002/14651858.CD003053.pub5] [PMID: 22592687]
[118]
Naderpoor, N.; Shorakae, S.; de Courten, B.; Misso, M.L.; Moran, L.J.; Teede, H.J. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum. Reprod. Update, 2015, 21(5), 560-574.
[http://dx.doi.org/10.1093/humupd/dmv025] [PMID: 26060208]
[119]
Morley, L.C.; Tang, T.; Yasmin, E.; Norman, R.J.; Balen, A.H. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst. Rev, 2017, 11, CD003053.
[http://dx.doi.org/10.1002/14651858.CD003053.pub6] [PMID: 29183107]
[120]
Zhao, J.; Liu, X.; Zhang, W. The Effect of Metformin Therapy for Preventing Gestational Diabetes Mellitus in Women with Polycystic Ovary Syndrome: A Meta-Analysis. Exp. Clin. Endocrinol. Diabetes, 2018. Epub ahead of print
[http://dx.doi.org/10.1055/a-0603-3394] [PMID: 29890554]
[121]
Cassina, M.; Donà, M.; Di Gianantonio, E.; Litta, P.; Clementi, M. First-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis. Hum. Reprod. Update, 2014, 20(5), 656-669.
[http://dx.doi.org/10.1093/humupd/dmu022] [PMID: 24861556]
[122]
Feng, L.; Lin, X.F.; Wan, Z.H.; Hu, D.; Du, Y.K. Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis. Gynecol. Endocrinol., 2015, 31(11), 833-839.
[http://dx.doi.org/10.3109/09513590.2015.1041906] [PMID: 26440203]
[123]
Rowan, J.A.; Hague, W.M.; Gao, W.; Battin, M.R.; Moore, M.P. Metformin versus insulin for the treatment of gestational diabetes. N. Engl. J. Med., 2008, 358(19), 2003-2015.
[http://dx.doi.org/10.1056/NEJMoa0707193] [PMID: 18463376]
[124]
Balsells, M.; García-Patterson, A.; Solà, I.; Roqué, M.; Gich, I.; Corcoy, R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ, 2015, 350, h102.
[http://dx.doi.org/10.1136/bmj.h102] [PMID: 25609400]
[125]
Polasek, T.M.; Doogue, M.P.; Thynne, T.R.J. Metformin treatment of type 2 diabetes mellitus in pregnancy: update on safety and efficacy. Ther. Adv. Drug Saf., 2018, 9(6), 287-295.
[http://dx.doi.org/10.1177/2042098618769831] [PMID: 29854390]
[126]
Tieu, J.; Coat, S.; Hague, W.; Middleton, P.; Shepherd, E. Oral anti-diabetic agents for women with established diabetes/impaired glucose tolerance or previous gestational diabetes planning pregnancy, or pregnant women with pre-existing diabetes. Cochrane Database Syst. Rev, 2017, 10, CD007724.
[http://dx.doi.org/10.1002/14651858.CD007724.pub3] [PMID: 29045765]
[127]
Butalia, S.; Gutierrez, L.; Lodha, A.; Aitken, E.; Zakariasen, A.; Donovan, L. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis. Diabet. Med., 2017, 34(1), 27-36.
[http://dx.doi.org/10.1111/dme.13150] [PMID: 27150509]
[128]
Lee, H.Y.; Wei, D.; Loeken, M.R. Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy. Diabetes Metab. Res. Rev., 2014, 30(1), 23-30.
[http://dx.doi.org/10.1002/dmrr.2451] [PMID: 23983188]

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