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Exp Clin Endocrinol Diabetes 2019; 127(07): 445-454
DOI: 10.1055/a-0621-8830
Review
© Georg Thieme Verlag KG Stuttgart · New York

Metformin and Colorectal Cancer – A Systematic Review.

Jarek Kobiela
1   Department of General, Endocrine, and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
,
Małgorzata Dobrzycka
1   Department of General, Endocrine, and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
,
Piotr Jędrusik
2   Department of Internal Medicine, Hypertension, and Angiology, Medical University of Warsaw, Warsaw, Poland
,
Paulina Kobiela
4   Department of Neonalology, Medical University of Gdańsk, Gdańsk, Poland
,
Piotr Spychalski
1   Department of General, Endocrine, and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
,
Zbigniew Śledziński
1   Department of General, Endocrine, and Transplant Surgery, Medical University of Gdańsk, Gdańsk, Poland
,
Tomasz Zdrojewski
3   Department of Arterial Hypertension and Diabetology, Medical University of Gdańsk, Gdańsk, Poland
› Author Affiliations
Further Information

Publication History

received 28 February 2018
revised  24 April 2018

accepted   25 April 2018

Publication Date:
28 June 2018 (online)

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Abstract

Objectives Colorectal cancer (CRC) is the second leading cause of cancer-related deaths. The development of preventive strategies in CRC has been the subject of much research. Multiple studies have shown an association between diabetes and CRC. In addition to its glucose-lowering properties, metformin might have an additional role in the prevention and treatment of CRC.

Our objective was to summarize findings on role of metformin in colorectal cancer.

Methods We conducted a systematic review of the PubMed and Cochrane databases from January 2005 to December 2017 in search for studies on the association between metformin and CRC.

Results Of the total of 189 studies identified by the search, we excluded 123 studies and reviewed the remaining 66 studies on cell lines, animals, patients with diabetes, and healthy subjects. In vitro and animal studies have shown a protective effect of metformin use on the incidence of CRC and amplification of the therapeutic effects of CRC chemotherapy. Studies on patients with type 2 diabetes treated with metformin analyzed data on total of 146 496 patients. The results of those studies on the role of metformin in CRC suggest risk reduction and potential applications within therapeutic regimens, although some of those are conflicting.

Conclusion Further studies are warranted to define the role of metformin in both prevention and treatment of CRC.

Key words

colorectal cancer - diabetes mellitus - metformin - cancer risk - cancer prevention
 

  • References

  • 1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA. Cancer J Clin 2015; 65: 5-29
    CrossrefPubMedGoogle Scholar
  • 2 Cooper K, Squires H, Carroll C. et al. Chemoprevention of colorectal cancer: Systematic review and economic evaluation. Health Technol Assess (Rockv) 2010; 14: 1-206
    PubMedGoogle Scholar
  • 3 La Vecchia C, Negri E, Franceschi S. et al. A case-control study of diabetes mellitus and cancer risk. Br J Cancer 1994; 70: 950-953
    CrossrefPubMedGoogle Scholar
  • 4 Adami H-O, McLaughlin J, Ekbom A. et al. Cancer risk in patients with diabetes mellitus. Cancer Causes Control 1991; 2: 307-314
    CrossrefPubMedGoogle Scholar
  • 5 Noto H, Tsujimoto T, Sasazuki T. et al. Significantly increased risk of cancer in patients with diabetes mellitus: A systematic review and meta-analysis. Endocr Pract 2011; 17: 616-628
    CrossrefPubMedGoogle Scholar
  • 6 Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: A meta-analysis. Int J Cancer 2007; 121: 856-862
    CrossrefPubMedGoogle Scholar
  • 7 Huxley R, Ansary-Moghaddam A, Berrington de González A. et al Type-II diabetes and pancreatic cancer: A meta-analysis of 36 studies. Br J Cancer 2005; 92: 2076-2083
    CrossrefPubMedGoogle Scholar
  • 8 Ge Z, Ben Q, Qian J. et al. Diabetes mellitus and risk of gastric cancer: A systematic review and meta-analysis of observational studies. Eur J Gastroenterol Hepatol 2011; 23: 1127-1135
    CrossrefPubMedGoogle Scholar
  • 9 Müller AD, Sonnenberg A. Prevention of colorectal cancer by flexible endoscopy and polypectomy. A case-control study of 32,702 veterans. Ann Intern Med 1995; 123: 904-910
    PubMedGoogle Scholar
  • 10 Sehdev A, O’Neil BH. The Role of Aspirin, Vitamin D, Exercise, Diet, Statins, and Metformin in the Prevention and Treatment of Colorectal Cancer. Curr Treat Options Oncol 2015; 16: 43
    CrossrefPubMedGoogle Scholar
  • 11 Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: An update. Ann Intern Med 2002; 137: 25-33
    PubMedGoogle Scholar
  • 12 Collier CA, Bruce CR, Smith AC. et al. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol Endocrinol Metab 2006; 291: E182-E189
    CrossrefPubMedGoogle Scholar
  • 13 Madiraju AK, Erion DM, Rahimi Y. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510: 542-546
    CrossrefPubMedGoogle Scholar
  • 14 Viollet B, Guigas B, Sanz Garcia N. et al. Cellular and molecular mechanisms of metformin: An overview. Clin Sci (Lond) 2012; 122: 253-270
    CrossrefPubMedGoogle Scholar
  • 15 Cho S-Y, Lee H-J, Lee H-J. et al. Activation of AMP-Activated Protein Kinase α and Extracelluar Signal-Regulated Kinase Mediates CB-PIC-Induced Apoptosis in Hypoxic SW620 Colorectal Cancer Cells. Evid Based Complement. Alternat Med 2013; 2013: 974313
    PubMedGoogle Scholar
  • 16 Mogavero A, Maiorana MV, Zanutto S. et al. Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci Rep 2017; 7: 15992
    CrossrefPubMedGoogle Scholar
  • 17 Lan B, Zhang J, Zhang P. et al. Metformin suppresses CRC growth by inducing apoptosis via ADORA1. Front Biosci Landmark Ed 2017; 22: 248-257
    CrossrefPubMedGoogle Scholar
  • 18 Zhang Y, Guan M, Zheng Z. et al. Effects of Metformin on CD133+ Colorectal Cancer Cells in Diabetic Patients. Liu C, editor. PLoS One 2013; 8: e81264
    CrossrefPubMedGoogle Scholar
  • 19 Kim S-H, Kim S-C, Ku J-L. Metformin increases chemo-sensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells. Oncotarget 2017; 8: 56546-56557
    CrossrefPubMedGoogle Scholar
  • 20 Nangia-Makker P, Yu Y, Vasudevan A. et al. Metformin: A potential therapeutic agent for recurrent colon cancer. Anant S, editor. PLoS One 2014; 9: e84369
    CrossrefPubMedGoogle Scholar
  • 21 Mohamed Suhaimi N-A, Phyo WM, Yap HY. et al. Metformin Inhibits Cellular Proliferation and Bioenergetics in Colorectal Cancer Patient-Derived Xenografts. Mol Cancer Ther 2017; 16: 2035-2044
    CrossrefPubMedGoogle Scholar
  • 22 Lee J, Park D, Lee Y. Metformin Synergistically Potentiates the Antitumor Effects of Imatinib in Colorectal Cancer Cells. Dev Reprod 2017; 21: 139-150
    CrossrefPubMedGoogle Scholar
  • 23 Jeong YK, Kim M-S, Lee JY. et al. Metformin Radiosensitizes p53-Deficient Colorectal Cancer Cells through Induction of G2/M Arrest and Inhibition of DNA Repair Proteins. Borgmann K, editor. PLoS One 2015; 10: e0143596
    CrossrefPubMedGoogle Scholar
  • 24 Hackett ES, Twedt DC, Gustafson DL. Milk thistle and its derivative compounds: A review of opportunities for treatment of liver disease. J Vet Intern Med 2013; 27: 10-16
    CrossrefPubMedGoogle Scholar
  • 25 Tsai C-C, Chuang T-W, Chen L-J. et al. Increase in apoptosis by combination of metformin with silibinin in human colorectal cancer cells. World J Gastroenterol 2015; 21: 4169-4177
    CrossrefPubMedGoogle Scholar
  • 26 Feng Y-H, Wu C-L, Shiau A-L. et al. MicroRNA-21-mediated regulation of Sprouty2 protein expression enhances the cytotoxic effect of 5-fluorouracil and metformin in colon cancer cells. Int J Mol Med 2012; 29: 920-926
    PubMedGoogle Scholar
  • 27 Potack J, Itzkowitz SH. Colorectal cancer in inflammatory bowel disease. Gut Liver 2008; 2: 61-73
    CrossrefPubMedGoogle Scholar
  • 28 Koh S-J, Kim JM, Kim I-K. et al. Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer. J Gastroenterol Hepatol 2014; 29: 502-510
    CrossrefPubMedGoogle Scholar
  • 29 Saber MM, Galal MA, Ain-Shoka AA. et al Combination of metformin and 5-aminosalicylic acid cooperates to decrease proliferation and induce apoptosis in colorectal cancer cell lines. BMC Cancer 2016; 16: 126
    CrossrefPubMedGoogle Scholar
  • 30 Montales MTE, Simmen RCM, Ferreira ES. et al. Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells. Genes Nutr 2015; 10: 49
    CrossrefPubMedGoogle Scholar
  • 31 Berstein LM, Iyevleva AG, Vasilyev D. et al. Genetic polymorphisms potentially associated with response to metformin in postmenopausal diabetics suffering and not suffering with cancer. Cell Cycle 2013; 12: 3681-3688
    CrossrefPubMedGoogle Scholar
  • 32 Sui X, Xu Y, Yang J. et al. Use of Metformin Alone Is Not Associated with Survival Outcomes of Colorectal Cancer Cell but AMPK Activator AICAR Sensitizes Anticancer Effect of 5-Fluorouracil through AMPK Activation. Vavvas D, editor. PLoS One 2014; 9: e97781
    CrossrefPubMedGoogle Scholar
  • 33 Tomimoto A, Endo H, Sugiyama M. et al. Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci. 2008; 99: 2136-2141
    CrossrefPubMedGoogle Scholar
  • 34 Hosono K, Endo H, Takahashi H. et al. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog 2010; 49: 662-671
    CrossrefPubMedGoogle Scholar
  • 35 Bordini HP, Kremer JL, Fagundes TR. et al. Protective effect of metformin in an aberrant crypt foci model induced by 1,2-dimethylhydrazine: Modulation of oxidative stress and inflammatory process. Mol. Carcinog 2017; 56: 913-922
    CrossrefPubMedGoogle Scholar
  • 36 Bekusova VV, Patsanovskii VM, Nozdrachev AD. et al. Metformin inhibits development of colon malignant tumors induced by 1,2-dimethylhydrazine in rats. Dokl Biol Sci 2016; 468: 97-100
    CrossrefPubMedGoogle Scholar
  • 37 Jia Y, Ma Z, Liu X. et al. Metformin prevents DMH-induced colorectal cancer in diabetic rats by reversing the warburg effect. Cancer Med 2015; 4: 1730-1741
    CrossrefPubMedGoogle Scholar
  • 38 McDonnell SL, Baggerly C, French CB. et al. Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. Slominski AT, editor. PLoS One 2016; 11: e0152441
    CrossrefPubMedGoogle Scholar
  • 39 Li W, Wang Q-L, Liu X. et al. Combined use of vitamin D3 and metformin exhibits synergistic chemopreventive effects on colorectal neoplasia in rats and mice. Cancer Prev Res (Phila) 2015; 8: 139-148
    CrossrefPubMedGoogle Scholar
  • 40 Abu el Maaty MA, Strassburger W, Qaiser T. et al. Differences in p53 status significantly influence the cellular response and cell survival to 1,25-dihydroxyvitamin D3-metformin cotreatment in colorectal cancer cells. Mol Carcinog 2017; 56: 2486-2498
    CrossrefPubMedGoogle Scholar
  • 41 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27-31
    CrossrefPubMedGoogle Scholar
  • 42 Zaafar DK, Zaitone SA, Moustafa YM. Role of Metformin in Suppressing 1,2-Dimethylhydrazine-Induced Colon Cancer in Diabetic and Non-Diabetic Mice: Effect on Tumor Angiogenesis and Cell Proliferation. Aldabe R, editor. PLoS One 2014; 9: e100562
    CrossrefPubMedGoogle Scholar
  • 43 Hanyuda A, Ogino S, Qian ZR. et al. Body mass index and risk of colorectal cancer according to tumor lymphocytic infiltrate. Int J Cancer 2016; 139: 854-868
    CrossrefPubMedGoogle Scholar
  • 44 Lee SE, Jo HB, Kwack WG. et al. Characteristics of and risk factors for colorectal neoplasms in young adults in a screening population. World J Gastroenterol 2016; 22: 2981-2992
    CrossrefPubMedGoogle Scholar
  • 45 Algire C, Amrein L, Zakikhani M. et al. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr. Relat. Cancer 2010; 17: 351-360
    CrossrefPubMedGoogle Scholar
  • 46 Mashhedi H, Blouin M-J, Zakikhani M. et al. Metformin abolishes increased tumor (18)F-2-fluoro-2-deoxy-D-glucose uptake associated with a high energy diet. Cell Cycle 2011; 10: 2770-2778
    CrossrefPubMedGoogle Scholar
  • 47 Tseng C-H. Diabetes, metformin use, and colon cancer: A population-based cohort study in Taiwan. Eur J Endocrinol 2012; 167: 409-416
    CrossrefPubMedGoogle Scholar
  • 48 Sinagra E, Guarnotta V, Raimondo D. et al. Colorectal cancer in patients with type 2 diabetes mellitus: A single-center experience. J Biol Regul Homeost Agents 31: 1101-1107
    PubMedGoogle Scholar
  • 49 Lin C-M, Huang H-L, Chu F-Y. et al. Association between Gastroenterological Malignancy and Diabetes Mellitus and Anti-Diabetic Therapy: A Nationwide, Population-Based Cohort Study. Akiba S, editor. PLoS One 2015; 10: e0125421
    CrossrefPubMedGoogle Scholar
  • 50 Lee M-S, Hsu C-C, Wahlqvist ML. et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 2011; 11: 20
    CrossrefPubMedGoogle Scholar
  • 51 Currie CJ, Poole CD, Gale EAM. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52: 1766-1777
    CrossrefPubMedGoogle Scholar
  • 52 Smiechowski B, Azoulay L, Yin H. et al. The Use of Metformin and Colorectal Cancer Incidence in Patients with Type II Diabetes Mellitus. Cancer Epidemiol Biomarkers Prev 2013; 22: 1877-1883
    CrossrefPubMedGoogle Scholar
  • 53 Tsilidis KK, Capothanassi D, Allen NE. et al. 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 2014; 37: 2522-2532
    CrossrefPubMedGoogle Scholar
  • 54 Sehdev A, Shih Y-CT, Vekhter B. et al. Metformin for primary colorectal cancer prevention in patients with diabetes: a case-control study in a US population. Cancer 2015; 121: 1071-1078
    CrossrefPubMedGoogle Scholar
  • 55 Cardel M, Jensen SM, Pottegård A. et al. Long-term use of metformin and colorectal cancer risk in type II diabetics: A population-based case-control study. Cancer Med 2014; 3: 1458-1466
    CrossrefPubMedGoogle Scholar
  • 56 Bodmer M, Becker C, Meier C. et al. Use of Metformin Is Not Associated with a Decreased Risk of Colorectal Cancer: A Case-Control Analysis. Cancer Epidemiol Biomarkers Prev 2012; 21: 280-286
    CrossrefPubMedGoogle Scholar
  • 57 Suh S, Kang M, Kim MY. et al. Korean type 2 diabetes patients have multiple adenomatous polyps compared to non-diabetic controls. J Korean Med Sci 2011; 26: 1196-1200
    CrossrefPubMedGoogle Scholar
  • 58 Kanadiya MK, Gohel TD, Sanaka MR. et al. Relationship between type-2 diabetes and use of metformin with risk of colorectal adenoma in an American population receiving colonoscopy. J Diabetes Complications 2013; 27: 463-466
    CrossrefPubMedGoogle Scholar
  • 59 Cho YH, Ko BM, Kim SH. et al. Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 diabetes mellitus? Intest. Res 2014; 12: 139-145
    PubMedGoogle Scholar
  • 60 Kim YH, Noh R, Cho SY. et al. Inhibitory effect of metformin therapy on the incidence of colorectal advanced adenomas in patients with diabetes. Intest. Res 2015; 13: 145-152
    CrossrefPubMedGoogle Scholar
  • 61 Marks AR, Pietrofesa RA, Jensen CD. et al. Metformin use and risk of colorectal adenoma after polypectomy in patients with type 2 diabetes mellitus. Cancer Epidemiol Biomarkers Prev 2015; 24: 1692-1698
    CrossrefPubMedGoogle Scholar
  • 62 Han MS, Lee HJ, Park SJ. et al. The effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma. Int J Colorectal Dis 2017; 32: 1223-1226
    CrossrefPubMedGoogle Scholar
  • 63 Ioannou GN, Boyko EJ. Metformin and Colorectal Cancer Risk in Diabetic Patients. Diabetes Care 2011; 34: 2336-2337
    CrossrefPubMedGoogle Scholar
  • 64 Garrett CR, Hassabo HM, Bhadkamkar NA. et al. Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. Br J Cancer 2012; 106: 1374-1378
    CrossrefPubMedGoogle Scholar
  • 65 Lee JH, Kim Il T, Jeon SM. et al. The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus. Int J Cancer 2012; 131: 752-759
    CrossrefPubMedGoogle Scholar
  • 66 Ramjeesingh R, Orr C, Bricks CS. et al. A retrospective study on the role of diabetes and metformin in colorectal cancer disease survival. Curr Oncol 2016; 23: e116-e122
    CrossrefPubMedGoogle Scholar
  • 67 Zanders MMJ, van Herk-Sukel MPP, Vissers PAJ. et al. Are metformin, statin and aspirin use still associated with overall mortality among colorectal cancer patients with diabetes if adjusted for one another? Br. J. Cancer 2015; 113: 403-410
    CrossrefPubMedGoogle Scholar
  • 68 Zhu RC, Rattanakorn K, Pham S. et al. Survival benefits in colorectal adenocarcinoma with the use of metformin among a black diabetic inner city population. Color cancer 2017; 6: 33-41
    PubMedGoogle Scholar
  • 69 Henderson D, Frieson D, Zuber J. et al. Metformin Has Positive Therapeutic Effects in Colon Cancer and Lung Cancer. Am J Med Sci 2017; 354: 246-251
    CrossrefPubMedGoogle Scholar
  • 70 Fransgaard T, Thygesen LC, Gögenur I. Metformin Increases Overall Survival in Patients with Diabetes Undergoing Surgery for Colorectal Cancer. Ann Surg Oncol 2016; 23: 1569-1575
    CrossrefPubMedGoogle Scholar
  • 71 Ki Y-J, Kim HJ, Kim M-S. et al. Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study. Cancer Res Treat 2017; 49: 29-36
    CrossrefPubMedGoogle Scholar
  • 72 Mc Menamin ÚC, Murray LJ, Hughes CM. et al. Metformin use and survival after colorectal cancer: A population-based cohort study. Int J Cancer 2016; 138: 369-379
    CrossrefPubMedGoogle Scholar
  • 73 Cossor FI, Adams-Campbell LL, Chlebowski RT. et al. Diabetes, metformin use, and colorectal cancer survival in postmenopausal women. Cancer Epidemiol 2013; 37: 742-749
    CrossrefPubMedGoogle Scholar
  • 74 Park JW, Lee JH, Park YH. et al. Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients. World J Gastroenterol 2017; 23: 5196-5205
    CrossrefPubMedGoogle Scholar
  • 75 Miranda VC, Braghiroli MI, Faria LD. et al. Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients with Refractory Metastatic Colorectal Cancer. Clin. Colorectal Cancer 2016; 15: 321-328.e1
    CrossrefPubMedGoogle Scholar
  • 76 Wang Y, Wu Z, Hu L. Epithelial-Mesenchymal Transition Phenotype, Metformin, and Survival for Colorectal Cancer Patients with Diabetes Mellitus II. Gastroenterol Res Pract 2017; 2017: 2520581
    PubMedGoogle Scholar
  • 77 Singh PP, Shi Q, Foster NR. et al. Relationship Between Metformin Use and Recurrence and Survival in Patients with Resected Stage III Colon Cancer Receiving Adjuvant Chemotherapy: Results From North Central Cancer Treatment Group N0147 (Alliance). Oncologist 2016; 21: 1509-1521
    CrossrefPubMedGoogle Scholar
  • 78 van de Poll-Franse LV, Haak HR, Coebergh JWW. et al. Disease-specific mortality among stage I-III colorectal cancer patients with diabetes: a large population-based analysis. Diabetologia 2012; 55: 2163-2172
    CrossrefPubMedGoogle Scholar
  • 79 Skinner HD, Crane CH, Garrett CR. et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med 2013; 2: 99-107
    CrossrefPubMedGoogle Scholar
  • 80 Spillane S, Bennett K, Sharp L. et al. A cohort study of metformin exposure and survival in patients with stage I-III colorectal cancer. Cancer Epidemiol Biomarkers Prev 2013; 22: 1364-1373
    CrossrefPubMedGoogle Scholar
  • 81 Spillane S, Bennett K, Sharp L. et al. Metformin exposure and disseminated disease in patients with colorectal cancer. Cancer Epidemiol 2014; 38: 79-84
    CrossrefPubMedGoogle Scholar
  • 82 Oh BY, Park YA, Huh JW. et al. Metformin enhances the response to radiotherapy in diabetic patients with rectal cancer. J Cancer Res Clin Oncol 2016; 142: 1377-1385
    CrossrefPubMedGoogle Scholar
  • 83 Bae S, Wong H-L, Tie J. et al. Impact of Diabetes Status and Medication on Presentation, Treatment, and Outcome of Stage II Colon Cancer Patients. J Cancer Epidemiol 2015; 2015: 189132
    PubMedGoogle Scholar
  • 84 Hosono K, Endo H, Takahashi H. et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila) 2010; 3: 1077-1083
    CrossrefPubMedGoogle Scholar
  • 85 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
    CrossrefPubMedGoogle Scholar
  • 86 Evans JMM, Donnelly LA, Emslie-Smith AM. et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330: 1304-1305
    CrossrefPubMedGoogle Scholar
  • 87 DeCensi A, Puntoni M, Goodwin P. et al. Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis. Cancer Prev Res 2010; 3: 1451-1461
    CrossrefPubMedGoogle Scholar
  • 88 Zhang Z-J, Zheng Z-J, Kan H. et al. Reduced Risk of Colorectal Cancer With Metformin Therapy in Patients with Type 2 Diabetes: A meta-analysis. Diabetes Care 2011; 34: 2323-2328
    CrossrefPubMedGoogle Scholar
  • 89 Noto H, Goto A, Tsujimoto T. et al. Cancer Risk in Diabetic Patients Treated with Metformin: A Systematic Review and Meta-analysis. Biondi-Zoccai G, editor. PLoS One 2012; 7: e33411
    CrossrefPubMedGoogle Scholar
  • 90 Suissa S, Azoulay L. Metformin and the Risk of Cancer: Time-related biases in observational studies. Diabetes Care 2012; 35: 2665-2673
    CrossrefPubMedGoogle Scholar
  • 91 Suissa S, Azoulay L. Metformin and cancer: mounting evidence against an association. Diabetes Care 2014; 37: 1786-1788
    CrossrefPubMedGoogle Scholar
  • 92 Mamtani R, Pfanzelter N, Haynes K. et al. Incidence of Bladder Cancer in Patients with Type 2 Diabetes Treated With Metformin or Sulfonylureas. Diabetes Care 2014; 37: 1910-1917
    CrossrefPubMedGoogle Scholar
  • 93 Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: A meta-analysis. J Natl Cancer Inst 2005; 97: 1679-1687
    CrossrefPubMedGoogle Scholar
  • 94 Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med 2014; 2: 57
    PubMedGoogle Scholar
  • 95 Azoulay L, Dell’Aniello S, Gagnon B. et al. Metformin and the Incidence of Prostate Cancer in Patients with Type 2 Diabetes. Cancer Epidemiol Biomarkers Prev 2011; 20: 337-344
    CrossrefPubMedGoogle Scholar
  • 96 Smiechowski BB, Azoulay L, Yin H. et al. The Use of Metformin and the Incidence of Lung Cancer in Patients with Type 2 Diabetes. Diabetes Care 2013; 36: 124-129
    CrossrefPubMedGoogle Scholar
  • 97 Soranna D, Scotti L, Zambon A. et al. Cancer Risk Associated with Use of Metformin and Sulfonylurea in Type 2 Diabetes: A Meta-Analysis. Oncologist 2012; 17: 813-822
    CrossrefPubMedGoogle Scholar
  • 98 Coyle C, Cafferty FH, Vale C. et al. Metformin as an adjuvant treatment for cancer: A systematic review and meta-analysis. Ann Oncol 2016; 27: 2184-2195 A
    CrossrefPubMedGoogle Scholar