Digestive Diseases and Sciences

, Volume 63, Issue 11, pp 2840–2852 | Cite as

Metformin as an Adjunctive Therapy for Pancreatic Cancer: A Review of the Literature on Its Potential Therapeutic Use

  • Philip J. BroadhurstEmail author
  • Andrew R. Hart


Pancreatic ductal adenocarcinoma has the worst prognosis of any cancer. New adjuvant chemotherapies are urgently required, which are well tolerated by patients with unresectable cancers. This paper reviews the existing proof of concept data, namely laboratory, pharmacoepidemiological, experimental medicine and clinical trial evidence for investigating metformin in patients with pancreatic ductal adenocarcinoma. Laboratory evidence shows metformin inhibits mitochondrial ATP synthesis which directly and indirectly inhibits carcinogenesis. Drug–drug interactions of metformin with proton pump inhibitors and histamine H2-receptor antagonists may be of clinical relevance and pertinent to future research of metformin in pancreatic ductal adenocarcinoma. To date, most cohort studies have demonstrated a positive association with metformin on survival in pancreatic ductal adenocarcinoma, although there are many methodological limitations with such study designs. From experimental medicine studies, there are sparse data in humans. The current trials of metformin have methodological limitations. Two small randomized controlled trials (RCTs) reported null findings, but there were potential inequalities in cancer staging between groups and poor compliance with the intervention. Proof of concept data, predominantly from laboratory work, supports assessing metformin as an adjunct for pancreatic ductal adenocarcinoma in RCTs. Ideally, more experimental medicine studies are needed for proof of concept. However, many feasibility criteria need to be answered before such trials can progress.


Pancreatic cancer Metformin Survival Proof of concept 



P J Broadhurst was provided funding by the Wolfson Foundation.

Compliance with ethical standards

Conflict of interest

No conflict of interests to declare.


  1. 1.
    International Agency for Research on Cancer. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. 2013. Accessed 08 Sept 2017.
  2. 2.
    Conroy T, Bachet JB, Ayav A, et al. Current standards and new innovative approaches for treatment of pancreatic cancer. Eur J Cancer. 2016;57:10–22.CrossRefGoogle Scholar
  3. 3.
    Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–1825.CrossRefGoogle Scholar
  4. 4.
    Kordes S, Pollak MN, Zwinderman AH, et al. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015;16:839–847.CrossRefGoogle Scholar
  5. 5.
    Singh S, Tang SJ, Sreenarasimhaiah J, Lara LF, Siddiqui A. The clinical utility and limitations of serum carbohydrate antigen (CA19-9) as a diagnostic tool for pancreatic cancer and cholangiocarcinoma. Dig Dis Sci. 2011;56:2491–2496. CrossRefGoogle Scholar
  6. 6.
    Tempero MA, Uchida E, Takasaki H, Burnett DA, Steplewski Z, Pour PM. Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res. 1987;47:5501–5503.PubMedGoogle Scholar
  7. 7.
    Reni M, Dugnani E, Cereda S, et al. (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase II trial. Clin Cancer Res. 2016;22:1076–1085.CrossRefGoogle Scholar
  8. 8.
    Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60:1566–1576.CrossRefGoogle Scholar
  9. 9.
    WHO. Model list of essential medicines, 19th list, 2017. Accessed 26 Feb 2018.
  10. 10.
    Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–579.CrossRefGoogle Scholar
  11. 11.
    Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol. 2005;70:1851–1860.CrossRefGoogle Scholar
  12. 12.
    Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos Biol Fate Chem. 2007;35:1956–1962.CrossRefGoogle Scholar
  13. 13.
    Nies AT, Koepsell H, Damme K, Schwab M. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. In: Fromm MF, Kim RB, eds. Drug Transporters, City. Berlin: Springer; 2011:105–167.CrossRefGoogle Scholar
  14. 14.
    Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50:81–98.CrossRefGoogle Scholar
  15. 15.
    Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics. 2008;9:415–422.CrossRefGoogle Scholar
  16. 16.
    Kim A, Chung I, Yoon SH, et al. Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics. Drug Metab Dispos Biol Fate Chem. 2014;42:1174–1179.CrossRefGoogle Scholar
  17. 17.
    Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23:545–551.CrossRefGoogle Scholar
  18. 18.
    Turner RC. The U.K. prospective diabetes study: a review. Diabetes Care. 1998;21:C35–C38.CrossRefGoogle Scholar
  19. 19.
    Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–2443.CrossRefGoogle Scholar
  20. 20.
    Cook MN, Girman CJ, Stein PP, Alexander CM. Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with type 2 diabetes in UK primary care. Diabet Med J Br Diabet Assoc. 2007;24:350–358.CrossRefGoogle Scholar
  21. 21.
    Zhou K, Bellenguez C, Spencer CC, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011;43:117–120.CrossRefGoogle Scholar
  22. 22.
    Morris AD, Boyle DI, MacAlpine R, et al. The diabetes audit and research in Tayside Scotland (darts) study: electronic record linkage to create a diabetes register. BMJ. 1997;315:524–528.CrossRefGoogle Scholar
  23. 23.
    Tkac I. Replication of the association of gene variant near ATM and response to metformin. Pharmacogenomics. 2012;13:1331–1332.CrossRefGoogle Scholar
  24. 24.
    van Leeuwen N, Nijpels G, Becker ML, et al. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia. 2012;55:1971–1977.CrossRefGoogle Scholar
  25. 25.
    Yee SW, Chen L, Giacomini KM. The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet. 2012;44:359–360.CrossRefGoogle Scholar
  26. 26.
    Woods A, Leiper JM, Carling D. The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet. 2012;44:360–361.CrossRefGoogle Scholar
  27. 27.
    Zhou K, Bellenguez C, Spencer CCA, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011;43:117–120.CrossRefGoogle Scholar
  28. 28.
    Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab.. 1996;81:4059–4067.PubMedGoogle Scholar
  29. 29.
    Hawley SA, Ross FA, Chevtzoff C, et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 2010;11:554–565.CrossRefGoogle Scholar
  30. 30.
    Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348:607–614.CrossRefGoogle Scholar
  31. 31.
    Hardie DG, Alessi DR. LKB1 and AMPK and the cancer-metabolism link—ten years after. BMC Biol. 2013;11:36.CrossRefGoogle Scholar
  32. 32.
    Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8:774–785.CrossRefGoogle Scholar
  33. 33.
    Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251–262.CrossRefGoogle Scholar
  34. 34.
    Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–590.CrossRefGoogle Scholar
  35. 35.
    Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–484.CrossRefGoogle Scholar
  36. 36.
    Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159–169.CrossRefGoogle Scholar
  37. 37.
    Goalstone ML, Leitner JW, Wall K, et al. Effect of insulin on farnesyltransferase: specificity of insulin action and potentiation of nuclear effects of insulin-like growth factor-1, epidermal growth factor, and platelet-derived growth factor. J Biol Chem. 1998;273:23892–23896.CrossRefGoogle Scholar
  38. 38.
    Wang L-W, Li Z-S, Zou D-W, Jin Z-D, Gao J, Xu G-M. Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol. 2008;14:7192–7198.CrossRefGoogle Scholar
  39. 39.
    Zhou G, Yu J, Wang A, et al. Metformin restrains pancreatic duodenal homeobox-1 (PDX-1) function by inhibiting ERK signaling in pancreatic ductal adenocarcinoma. Curr Mol Med. 2016;16:83–90.CrossRefGoogle Scholar
  40. 40.
    Shi Y, He Z, Jia Z, Xu C. Inhibitory effect of metformin combined with gemcitabine on pancreatic cancer cells in vitro and in vivo. Mol Med Rep. 2016;14:2921–2928.CrossRefGoogle Scholar
  41. 41.
    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265.CrossRefGoogle Scholar
  42. 42.
    Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle. 2007;6:2332–2338.CrossRefGoogle Scholar
  43. 43.
    Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69:7507.CrossRefGoogle Scholar
  44. 44.
    Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011;71:3196.CrossRefGoogle Scholar
  45. 45.
    Deng X-S, Wang S, Deng A, et al. Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle. 2012;11:367–376.CrossRefGoogle Scholar
  46. 46.
    Liu B, Fan Z, Edgerton SM, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle. 2009;8:2031–2040.CrossRefGoogle Scholar
  47. 47.
    Alimova IN, Liu B, Fan Z, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 2009;8:909–915.CrossRefGoogle Scholar
  48. 48.
    Zhuang Y, Miskimins K, Zhuang Y, Miskimins WK. 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. 2009;3:18.CrossRefGoogle Scholar
  49. 49.
    Sahra IB, Laurent K, Loubat A, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008;27:3576.CrossRefGoogle Scholar
  50. 50.
    Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation—implications for a novel treatment strategy. Gynecol Oncol. 2010;116:92–98.CrossRefGoogle Scholar
  51. 51.
    Isakovic A, Harhaji L, Stevanovic D, et al. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci CMLS. 2007;64:1290–1302.CrossRefGoogle Scholar
  52. 52.
    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.CrossRefGoogle Scholar
  53. 53.
    Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL. Control of p70 s6 kinase by kinase activity of FRAP in vivo. Nature. 1995;377:441–446.CrossRefGoogle Scholar
  54. 54.
    Anisimov VN, Berstein LM, Egormin PA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 2005;40:685–693.CrossRefGoogle Scholar
  55. 55.
    Huang X, Wullschleger S, Shpiro N, et al. Important role of the LKB1–AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008;412:211–221.CrossRefGoogle Scholar
  56. 56.
    Tomimoto A, Endo H, Sugiyama M, et al. Metformin suppresses intestinal polyp growth in ApcMin/+mice. Cancer Sci. 2008;99:2136–2141.CrossRefGoogle Scholar
  57. 57.
    Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res. 2010;3:1066–1076.CrossRefGoogle Scholar
  58. 58.
    Ish-Shalom D, Christoffersen CT, Vorwerk P, et al. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia. 1997;40:S25–S31.CrossRefGoogle Scholar
  59. 59.
    Cerullo M, Gani F, Chen SY, Canner J, Pawlik TM. Metformin use is associated with improved survival in patients undergoing resection for pancreatic cancer. J Gastrointest Surg. 2016;20:1572–1580.CrossRefGoogle Scholar
  60. 60.
    Chaiteerakij R, Petersen GM, Bamlet WR, et al. Metformin use and survival of patients with pancreatic cancer: a cautionary lesson. J Clin Oncol. 2016;34:1898–1904.CrossRefGoogle Scholar
  61. 61.
    Currie CJ, Poole CD, Jenkins-Jones S, Gale EAM, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35:299–304.CrossRefGoogle Scholar
  62. 62.
    Frouws MA, Mulder BGS, Bastiaannet E, et al. No association between metformin use and survival in patients with pancreatic cancer: an observational cohort study. Medicine. 2017;96:e6229.CrossRefGoogle Scholar
  63. 63.
    Sadeghi N, Abbruzzese JL, Yeung S-CJ, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res. 2012;15:2905–2912.CrossRefGoogle Scholar
  64. 64.
    Bodmer M, Becker C, Meier C, Jick SS, Meier C. Use of antidiabetic agents and the risk of pancreatic cancer: a case–control analysis. Am J Gastroenterol. 2012;107:620–626.CrossRefGoogle Scholar
  65. 65.
    Higurashi T, Hosono K, Takahashi H, et al. 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;17:475–483.CrossRefGoogle Scholar
  66. 66.
    Zhao Y, Gong C, Wang Z, et al. A randomized phase II study of aromatase inhibitors plus metformin in pre-treated postmenopausal patients with hormone receptor positive metastatic breast cancer. Oncotarget. 2017;8:84224–84236.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:5928.CrossRefGoogle Scholar
  68. 68.
    Kozak MM, Anderson EM, von Eyben R, et al. Statin and metformin use prolongs survival in patients with resectable pancreatic cancer. Pancreas. 2016;45:64–70.CrossRefGoogle Scholar
  69. 69.
    Lee SH, Yoon SH, Lee HS, et al. Can metformin change the prognosis of pancreatic cancer? Retrospective study for pancreatic cancer patients with pre-existing diabetes mellitus type 2. Digest Liver Dis. 2016;48:435–440.CrossRefGoogle Scholar
  70. 70.
    Choi Y, Kim T-Y, Oh D-Y, et al. The impact of diabetes mellitus and metformin treatment on survival of patients with advanced pancreatic cancer undergoing chemotherapy. Cancer Res Treat. 2015;48:171–179.CrossRefGoogle Scholar
  71. 71.
    Hwang A, Haynes K, Hwang W-T, Yang Y-X. Metformin and survival in pancreatic cancer: a retrospective cohort study. Pancreas. 2013;42:1054–1059.CrossRefGoogle Scholar
  72. 72.
    Jo A, Kim Y, Kang S, Kim M, Ko M. PCN57 - The effect of metformin use and mortality among those with pancreatic cancer and type 2 diabetes mellitus: findings from a nationwide population retrospective cohort study. Value Health. 2015;18:A439.CrossRefGoogle Scholar
  73. 73.
    Amin S, Mhango G, Lin J, et al. Metformin improves survival in patients with pancreatic ductal adenocarcinoma and pre-existing diabetes: a propensity score analysis. Am J Gastroenterol. 2016;111:1350–1357.CrossRefGoogle Scholar
  74. 74.
    Ambe CM, Mahipal A, Fulp J, Chen L, Malafa MP. Effect of metformin use on survival in resectable pancreatic cancer: a single-institution experience and review of the literature. PLOS ONE. 2016;11:e0151632.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Norwich Medical SchoolUniversity of East AngliaNorwichUK
  2. 2.Norfolk and Norwich University Hospital NHS TrustUniversity of East AngliaNorwichUK

Personalised recommendations