Abstract
Introduction
Metformin, an oral hypoglycemic agent, was introduced in the clinical practice for the treatment of type 2 diabetes mellitus more than a half-century ago. Over the years, several studies demonstrated that diabetic patients treated with metformin have a lower incidence of cancer, raising the hypothesis that the spectrum of clinical applications of the drug could be expanded also to cancer therapy. Following these initial findings, a large number of studies were performed aimed at elucidating the effects of metformin on different types of tumor, at explaining its direct and indirect anti-cancer mechanisms and at identifying the molecular pathways targeted by the drug. Several clinical trials were also performed aimed at evaluating the potential anti-cancer effect of metformin among diabetic and non-diabetic patients affected by different types of cancer. While the results of several clinical studies are encouraging, a considerable number of other investigations do not support a role of metformin as an anti-cancer agent, and highlight variables possibly accounting for discrepancies.
Aim
We hereby review the results of in vitro and in vivo studies addressing the issue of the anti-cancer effects of metformin.
Conclusions
If in vitro data appear solid, the results provided by in vivo studies are somehow controversial. In this view, larger studies are needed to fully elucidate the role of metformin on cancer development and progression, as well as the specific clinical settings in which metformin could become an anti-cancer drug.
References
Bailey CJ, Day C (2004) Metformin: its botanical background. Pract Diab Int 21:115–117
Malek M, Aghili R, Emami Z, Khamseh ME (2013) Risk of cancer in diabetes: the effect of metformin. ISRN Endocrinol 2013:636927
Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, Shulman GI (1998) Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 338:867–872
Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51:2074–2081
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE (1995) Metabolic effects of metformin in noninsulin-dependent diabetes mellitus. N Engl J Med 333:550–554
Pala L, Rotella CM (2014) The “slower” the better. J Endocrinol Invest 37:497–498
Glintborg D, Mumm H, Altinok ML, Richelsen B, Bruun JM, Andersen M (2014) Adiponectin, interleukin-6, monocyte chemoattractant protein-1, and regional fat mass during 12-month randomized treatment with metformin and/or oral contraceptives in polycystic ovary syndrome. J Endocrinol Invest 37:757–764
Ghazeeri G, Abbas HA, Skaff B, Harajly S, Awwad J (2015) Inadequacy of initiating rosuvastatin then metformin on biochemical profile of polycystic ovarian syndrome patients. J Endocrinol Invest [Epub ahead of print]
Vassilatou E (2014) Nonalcoholic fatty liver disease and polycystic ovary syndrome. World J Gastroenterol 20:8351–8363
Esteghamati A, Rezvani S, Khajeh E, Ebadi M, Nakhjavani M, Noshad S (2014) Comparative effects of metformin and pioglitazone on YKL-40 in type 2 diabetes: a randomized clinical trial. J Endocrinol Invest (epub ahead of print)
Cappelli C, Rotondi M, Pirola I, Agosti B, Formenti A, Zarra E, Valentini U, Leporati P, Chiovato L, Castellano M (2012) Thyreotropin levels in diabetic patients on metformin treatment. Eur J Endocrinol 167:261–265
Rotondi M, Cappelli C, Magri F, Botta R, Dionisio R, Iacobello C, De Cata P, Nappi RE, Castellano M, Chiovato L (2011) Thyroidal effect of metformin treatment in patients with polycystic ovary syndrome. Clin Endocrinol (Oxf) 75:378–381
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638
Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo AA, Kurshan N, Mejia W, Santopietro S, Yakar S, Wood TL, LeRoith D (2010) Insulin mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 70:741–751
Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16:1103–1123
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305
Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancerrelated mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258
Bo S, Benso A, Durazzo M, Ghigo E (2012) Does use of metformin protect against cancer in type 2 diabetes mellitus? J Endocrinol Invest 35:231–235
Mei ZB, Zhang ZJ, Liu CY, Liu Y, Cui A, Liang ZL, Wang GH, Cui L (2014) Survival benefits of metformin for colorectal cancer patients with diabetes: a systematic review and meta-analysis. PLoS One 9:e91818
Franciosi M, Lucisano G, Lapice E, Strippoli GF, Pellegrini F, Nicolucci A (2013) Metformin therapy and risk of cancer in patients with type 2 diabetes. PLoS One 8:e71583
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174
Shackelford DB, Shaw RJ (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 9:563–575
El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228
Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its antidiabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348:607–614
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251–262
Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646
Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100:328–341
Hadad S, Iwamoto T, Jordan L, Purdie C, Bray S, Baker L, Jellema G, Deharo S, Hardie DG, Pusztai L, Moulder-Thompson S, Dewar JA, Thompson AM (2011) Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat 128:783–794
Campagnoli C, Pasanisi P, Abbà C, Ambroggio S, Biglia N, Brucato T, Colombero R, Danese S, Donadio M, Venturelli E, Zito G, Berrino F (2012) Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study. Clin Breast Cancer 12:175–182
Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67:10804–10812
Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, Marette A, Kozma SC, Thomas G (2010) Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase dependent manner. Cell Metab 11:390–401
Saeedi R, Parsons HL, Wambolt RB, Paulson K, Sharma V, Dyck JR, Brownsey RW, Allard MF (2008) Metabolic actions of metformin in the heart can occur by AMPK independent mechanisms. Am J Physiol Heart Circ Physiol 294:2497–2506
Treins C, Murdaca J, Van Obberghen E, Giorgetti-Peraldi S (2006) AMPK activation inhibits the expression of HIF-1alpha induced by insulin and IGF-1. Biochem Biophys Res Commun 342:1197–1202
Chiang GG, Abraham RT (2007) Targeting the mTOR signaling network in cancer. Trends Mol Med 13:433–442
Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590
Miller RA, Birnbaum MJ (2010) An energetic tale of AMPK-independent effects of metformin. J Clin Invest 120:2267–2270
Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 120:2355–2369
Scotland S, Saland E, Skuli N, de Toni F, Boutzen H, Micklow E, Sénégas I, Peyraud R, Peyriga L, Théodoro F, Dumon E, Martineau Y, Danet-Desnoyers G, Bono F, Rocher C, Levade T, Manenti S, Junot C, Portais JC, Alet N, Récher C, Selak MA, Carroll M, Sarry JE (2013) Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. Leukemia 27:2129–2138
Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F (2011) Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res 71:4366–4372
Corominas-Faja B, Quirantes-Piné R, Oliveras-Ferraros C, Vazquez-Martin A, Cufí S, Martin-Castillo B, Micol V, Joven J, Segura-Carretero A, Menendez JA (2012) Metabolomic fingerprint reveals that metformin impairs onecarbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging (Albany NY) 4:480–498
Pacifico F, Leonardi A (2006) NF-kappaB in solid tumors. Biochem Pharmacol 72:1142–1152
Gerondakis S, Fulford TS, Messina NL, Grumont RJ (2014) NF-κB control of T cell development. Nat Immunol 15:15–25
Hattori Y, Suzuki K, Hattori S, Kasai K (2006) Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 47:1183–1188
Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, Schönbeck U, Libby P (2006) Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol 26:611–617
Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66:10269–10273
Carmignani M, Volpe AR, Aldea M, Soritau O, Irimie A, Florian IS, Tomuleasa C, Baritchii A, Petrushev B, Crisan G, Valle G (2014) Glioblastoma stem cells: a new target for metformin and arsenic trioxide. J Biol Regul Homeost Agents 28:1–15
Queiroz EA, Puukila S, Eichler R, Sampaio SC, Forsyth HL, Lees SJ, Barbosa AM, Dekker RF, Fortes ZB, Khaper N (2014) Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PLoS One 9:e98207
Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67:6745–6752
Erices R, Bravo ML, Gonzalez P, Oliva B, Racordon D, Garrido M, Ibañez C, Kato S, Brañes J, Pizarro J, Barriga MI, Barra A, Bravo E, Alonso C, Bustamente E, Cuello MA, Owen GI (2013) Metformin, at concentrations corresponding to the treatment of diabetes, potentiates the cytotoxic effects of carboplatin in cultures of ovarian cancer cells. Reprod Sci 20:1433–1446
Wang LW, Li ZS, Zou DW, Jin ZD, Gao J, Xu GM (2008) Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol 14:7192–7198
Ashinuma H, Takiguchi Y, Kitazono S, Kitazono-Saitoh M, Kitamura A, Chiba T, Tada Y, Kurosu K, Sakaida E, Sekine I, Tanabe N, Iwama A, Yokosuka O, Tatsumi K (2012) Antiproliferative action of metformin in human lung cancer cell lines. Oncol Rep 28:8–14
Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F (2008) The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27:3576–3586
Fujihara S, Kato K, Morishita A, Iwama H, Nishioka T, Chiyo T, Nishiyama N, Miyoshi H, Kobayashi M, Kobara H, Mori H, Okano K, Suzuki Y, Masaki T (2015) Antidiabetic drug metformin inhibits esophageal adenocarcinoma cell proliferation in vitro and in vivo. Int J Oncol 46:2172–2180
Bao B, Wang Z, Ali S, Ahmad A, Azmi AS, Sarkar SH, Banerjee S, Kong D, Li Y, Thakur S, Sarkar FH (2012) Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res (Phila) 5:355–364
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715
Moreno-Bueno G, Peinado H, Molina P, Olmeda D, Cubillo E, Santos V, Palacios J, Portillo F, Cano A (2009) The morphological and molecular features of the epithelial-to-mesenchymal transition. Nat Protoc 4:1591–1613
Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J (2008) Epithelialmesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68:989–997
Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Menendez JA (2010) Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 9:3807–3814
Wang Y, Yao B, Wang Y, Zhang M, Fu S, Gao H, Peng R, Zhang L, Tang J (2014) Increased FoxM1 expression is a target for metformin in the suppression of EMT in prostate cancer. Int J Mol Med 33:1514–1522
Cerezo M, Tichet M, Abbe P, Ohanna M, Lehraiki A, Rouaud F, Allegra M, Giacchero D, Bahadoran P, Bertolotto C, Tartare-Deckert S, Ballotti R, Rocchi S (2013) Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner. Mol Cancer Ther 12:1605–1615
Cifarelli V, Lashinger LM, Devlin KL, Dunlap SM, Huang J, Kaaks R, Pollak MN, Hursting SD (2015) Metformin and rapamycin reduce pancreatic cancer growth in obese prediabetic mice by distinct microRNA-regulated mechanisms. Diabetes 64:1632–1642
Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS (2011) Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab 96:808–816
Tan XL, Bhattacharyya KK, Dutta SK, Bamlet WR, Rabe KG, Wang E, Smyrk TC, Oberg AL, Petersen GM, Mukhopadhyay D (2015) Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling. Pancreas 44:636–647
Rotondi M, Coperchini F, Pignatti P, Magri F, Chiovato L (2015) Metformin reverts the secretion of CXCL8 induced by TNF-α in primary cultures of human thyroid cells: an additional indirect anti-tumor effect of the drug. J Clin Endocrinol Metab 100:E427–E432
Rotondi M, Coperchini F, Chiovato L (2013) CXCL8 in thyroid disease: from basic notions to potential applications in clinical practice. Cytokine Growth Factor Rev 24:539–546
Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR (2010) Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 33:1304–1308
Bosco JL, Antonsen S, Sørensen HT, Pedersen L, Lash TL (2011) Metformin and incident breast cancer among diabetic women: a population-based case–control study in Denmark. Cancer Epidemiol Biomark Prev 20:101–111
Lee JH, Kim TI, Jeon SM, Hong SP, Cheon JH, Kim WH (2012) The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer 131:752–759
Tan BX, Yao WX, Ge J, Peng XC, Du XB, Zhang R, Yao B, Xie K, Li LH, Dong H, Gao F, Zhao F, Hou JM, Su JM, Liu JY (2011) Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer 117:5103–5111
Baur DM, Klotsche J, Hamnvik OP, Sievers C, Pieper L, Wittchen HU, Stalla GK, Schmid RM, Kales SN, Mantzoros CS (2011) Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort. Metabolism 60:1363–1371
Monami M, Colombi C, Balzi D, Dicembrini I, Giannini S, Melani C, Vitale V, Romano D, Barchielli A, Marchionni N, Rotella CM, Mannucci E (2011) Metformin and cancer occurrence in insulintreated type 2 diabetic patients. Diabetes Care 34:129–131
Leone A, Di Gennaro E, Bruzzese F, Avallone A, Budillon A (2014) New perspective for an old antidiabetic drug: metformin as anticancer agent. Cancer Treat Res 159:355–376
Yin M, Zhou J, Gorak EJ, Quddus F (2013) Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist 18:1248–1255
Sehdev A, Shih YC, Vekhter B, Bissonnette MB, Olopade OI, Polite BN (2015) Metformin for primary colorectal cancer prevention in patients with diabetes: a case–control study in a US population. Cancer 121:1071–1078
Lee CK, Jung M, Jung I, Heo SJ, Jeong YH, An JY, Kim HI, Cheong JH, Hyung WJ, Noh SH, Kim HS, Rha SY, Chung HC (2015) Cumulative metformin use and its impact on survival in gastric cancer patients after gastrectomy. Ann Surg (epub ahead of print)
Klubo-Gwiezdzinska J, Costello J Jr, Patel A, Bauer A, Jensen K, Mete M, Burman KD, Wartofsky L, Vasko V (2013) Treatment with metformin is associated with higher remission rate in diabetic patients with thyroid cancer. J Clin Endocrinol Metab 98:3269–3279
Tseng CH (2014) Metformin reduces thyroid cancer risk in Taiwanese patients with type 2 diabetes. PLoS One 9:e109852
Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL, Rastogi P, Mayer IA, Hobday TJ, Lemieux J, Thompson AM, Pritchard KI, Whelan TJ, Mukherjee SD, Chalchal HI, Oja CD, Tonkin KS, Bernstein V, Chen BE, Stambolic V (2015) Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst 4:107(3)
Niraula S, Dowling RJ, Ennis M, Chang MC, Done SJ, Hood N, Escallon J, Leong WL, McCready DR, Reedijk M, Stambolic V, Goodwin PJ (2012) Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat 135:821–830
Dowling RJ, Niraula S, Chang MC, Done SJ, Ennis M, McCready DR, Leong WL, Escallon JM, Reedijk M, Goodwin PJ, Stambolic V (2015) Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res 3:17–32
Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, Bottiglieri L, Varricchio C, Guerrieri-Gonzaga A, Gentilini OD, Pagani G, Dell’Orto P, Lazzeroni M, Serrano D, Viale G, Bonanni B (2013) The effect of metformin on apoptosis in a breast cancer presurgical trial. Br J Cancer 109:2792–2797
DeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson HA, Cazzaniga M, Pruneri G, Serrano D, Schwab M, Hofmann U, Mora S, Aristarco V, Macis D, Bassi F, Luini A, Lazzeroni M, Bonanni B, Pollak MN (2014) Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res Treat 148:81–90
Oppong BA, Pharmer LA, Oskar S, Eaton A, Stempel M, Patil S, King TA (2014) The effect of metformin on breast cancer outcomes in patients with type 2 diabetes. Cancer Med 3:1025–1034
Ko EM, Stürmer T, Hong JL, Castillo WC, Bae-Jump V, Funk MJ (2015) Metformin and the risk of endometrial cancer: a population-based cohort study. Gynecol Oncol 136:341–347
Luo J, Beresford S, Chen C, Chlebowski R, Garcia L, Kuller L, Regier M, Wactawski-Wende J, Margolis KL (2014) Association between diabetes, diabetes treatment and risk of developing endometrial cancer. Br J Cancer 111:1432–1439
Sakoda LC, Ferrara A, Achacoso NS, Peng T, Ehrlich SF, Quesenberry CP Jr, Habel LA (2015) Metformin use and lung cancer risk in patients with diabetes. Cancer Prev Res (Phila) 8:174–179
Merrick GS, Bennett A, Couture T, Butler WM, Galbreath RW, Adamovich E (2015) Metformin does not predict for prostate cancer diagnosis, grade, or volume of disease after transperineal template-guided mapping biopsy. Am J Clin Oncol (epub ahead of print)
Soffer D, Shi J, Chung J, Schottinger JE, Wallner LP, Chlebowski RT, Lentz SE, Haque R (2015) Metformin and breast and gynecological cancer risk among women with diabetes. BMJ Open Diabetes Res Care 3:e000049
Suissa S, Azoulay L (2014) Metformin and cancer: mounting evidence against an association. Diabetes Care 37:1786–1788
Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E (2014) Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila) 7:867–885
Tsilidis KK, Capothanassi D, Allen NE, Rizos EC, Lopez DS, van Veldhoven K, Sacerdote C, Ashby D, Vineis P, Tzoulaki I, Ioannidis JP (2014) Metformin does not affect cancer risk: a cohort study in the U.K. Clinical practice research datalink analyzed like an intention-to-treat trial. Diabetes Care 37:2522–2532
Kowall B, Rathmann W, Kostev K (2015) Are sulfonylurea and insulin therapies associated with a larger risk of cancer than metformin therapy? A retrospective database analysis. Diabetes Care 38:59–65
Vissers PA, Cardwell CR, van de Poll-Franse LV, Young IS, Pouwer F, Murray LJ (2015) The association between glucose-lowering drug use and mortality among breast cancer patients with type 2 diabetes. Breast Cancer Res Treat 150:427–437
Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3:1451–1461
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
For this type of study formal consent is not required.
Rights and permissions
About this article
Cite this article
Coperchini, F., Leporati, P., Rotondi, M. et al. Expanding the therapeutic spectrum of metformin: from diabetes to cancer. J Endocrinol Invest 38, 1047–1055 (2015). https://doi.org/10.1007/s40618-015-0370-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40618-015-0370-z