Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression

Abstract

Purpose

Metformin may have a role in reducing the incidence of colorectal cancer (CRC) and improving survival outcome. This meta-analysis explored the effect of metformin use on colorectal adenoma and cancer incidence, and colorectal oncological outcomes.

Methods

A database search was conducted on Medline, Embase and CNKI for studies comparing metformin vs. non-metformin users, metformin users vs. non-diabetics and metformin users vs. diabetics with diet-only treatment. Meta-analysis was done with DerSimonian and Laird with risk ratios (RR), and hazard ratios (HR) for survival outcomes.

Results

We included 58 studies and summarized incidences of colorectal adenoma and cancer, as well as cancer survival outcomes. Metformin users had a significant lower incidence of colorectal adenoma (RR 0.77, CI 0.67–0.88, p < 0.001), advanced adenoma (0.61, CI 0.42–0.88, p = 0.008) and CRC (RR 0.76, CI 0.69–0.84, p < 0.001) respectively compared with non-metformin users. Overall survival (HR 0.6, CI 0.53–0.67, p < 0.001) and CRC-specific survival (HR 0.66, CI 0.59–0.74, p < 0.001) were higher among metformin users compared with non-metformin users. Further analysis on overall survival of metastatic CRC patients revealed significantly higher survival rates in metformin users (HR 0.77, CI 0.68–0.87, p < 0.001).

Conclusion

This meta-analysis showed that metformin use significantly reduces colorectal adenoma and cancer incidence and improves colorectal cancer outcomes.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data availability

All data available upon request.

References

  1. 1.

    Ira S, Ockene NHM (1997) Cigarette smoking, cardiovascular disease, and stroke. Circulation

  2. 2.

    Collins KK (2014) The diabetes-cancer link. Diabetes Spectrum 27:276–280

    Article  Google Scholar 

  3. 3.

    Araghi M, Soerjomataram I, Jenkins M, Brierley J, Morris E, Arnold M (2018) Global trends in colorectal cancer mortality: projections to the year 2035. International Journal of Cancer

  4. 4.

    Guraya SY (2015) Association of type 2 diabetes mellitus and the risk of colorectal cancer: a meta-analysis and systematic review. World J Gastroenterol 21:6026–6031

    CAS  Article  Google Scholar 

  5. 5.

    Susanna C, Larsson, N.O, Alicja Wolk (2005). Diabetes mellitus and risk of colorectal cancer: a meta-analysis. Journal of the National Cancer Institute

  6. 6.

    Zanders MMJ, Vissers PAJ, Haak HR, van de Poll-Franse LV (2014) Colorectal cancer, diabetes and survival: epidemiological insights. Diabetes Metab 40:120–127

    CAS  Article  Google Scholar 

  7. 7.

    Association, A.D. (2019) Standards of medical care in diabetes—2019 abridged for primary care providers. Clinical Diabetes

  8. 8.

    Evans JM-DL, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305

    Article  Google Scholar 

  9. 9.

    Landman GW, Kleefstra N, van Hateren KJ et al (2010) Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 33:322–326

    CAS  Article  Google Scholar 

  10. 10.

    Min Li, X.L., Huijie Zhang, Yan Lu (2018) : Molecular Mechanisms of metformin for diabetes and cancer treatment. Frontiers in Endocrinology

  11. 11.

    Kowall B, Stang A, Rathmann W, Kostev K (2015) No reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK. Pharmacoepidemiology and drug safety 24(8):865–874. https://doi.org/10.1002/pds.3823

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Du L, Wang M, Kang Y, Li B, Guo M, Cheng Z, Bi C (2017) Prognostic role of metformin intake in diabetic patients with colorectal cancer: an updated qualitative evidence of cohort studies. Oncotarget 8(16):26448–26459. https://doi.org/10.18632/oncotarget.14688

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Yoon Suk Jung CHP, Eun CS, Park DI, Han DS (2016) Metformin use and the risk of colorectal adenoma: a systematic review and meta-analysis. Journal of Gastroenterology and Hepatology 32(2017):957–965

    Google Scholar 

  14. 14.

    Feifei Liu LY, Wang Z, Lu Y, Chu Y, Li X, Liu Y, Rui D, Nie S, Xiang H (2017) Metformin therapy and risk of colorectal adenomas and colorectal cancer in type 2 diabetes mellitus patients: a systematic review and meta-analysis. Oncotarget 8(9):16017–16026

    Article  Google Scholar 

  15. 15.

    Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8(1):16. https://doi.org/10.1186/1745-6215-8-16

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17(24):2815–2834. https://doi.org/10.1002/(sici)1097-0258(19981230)17:24<2815::aid-sim110>3.0.co;2-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    NCSS: Survival Parameter Conversion Tool. In

  18. 18.

    Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14(1):135

    Article  Google Scholar 

  19. 19.

    Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median, range, and the size of a sample. BMC Medical Research Methodology 5(1):13

    Article  Google Scholar 

  20. 20.

    Harbord RM, Higgins J (2008) Meta-Regression in Stata. The Stata Journal 8(4):493–519

    Article  Google Scholar 

  21. 21.

    Knapp G, Hartung J (2003) Improved tests for a random effects meta-regression with a single covariate. Stat Med 22(17):2693–2710

    Article  Google Scholar 

  22. 22.

    Egger M, S G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629

    CAS  Article  Google Scholar 

  23. 23.

    Wells G, S.B., O’Connell D, et al. : The Newcastle–Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analysis. (2000)

  24. 24.

    Stephen H. Halpern, M.J.D.: Jadad scale for reporting randomized controlled trials. Evidence-based Obstetric Anesthesia (2005)

  25. 25.

    Eddi R, Karki A, Shah A, Debari VA, Depasquale JR (2012) Association of type 2 diabetes and colon adenomas. Journal of Gastrointestinal Cancer 43(1):87–92. https://doi.org/10.1007/s12029-011-9316-7

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Marks, A.R., Pietrofesa, R.A., Jensen, C.D., Zebrowski, A., Corley, D.A., Doubeni, C.A.: Metformin use and risk of colorectal adenoma after polypectomy in patients with type 2 diabetes mellitus. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 24(11), 1692–1698 (2015). doi:https://doi.org/10.1158/1055-9965.EPI-15-0559

  27. 27.

    Jain D, Chhoda A, Uribe J (2016) Effect of insulin and metformin combination treatment on colon adenoma and advanced adenoma among DM II. Journal of gastrointestinal cancer 47(4):404–408

    CAS  Article  Google Scholar 

  28. 28.

    Murff HJ, Roumie CL, Greevy RA, Hackstadt AJ, McGowan LEDA, Hung AM, Grijalva CG, Griffin MR (2018) Metformin use and incidence cancer risk: evidence for a selective protective effect against liver cancer. Cancer Causes Control 29(9):823–832. https://doi.org/10.1007/s10552-018-1058-4

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    P. D. Home, S.E.K., N. P. Jones, D. Noronha, H. Beck-Nielsen, G. Viberti: Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia (2009)

  30. 30.

    Bradley, M.C., Ferrara, A., Achacoso, N., Ehrlich, S.F., Quesenberry, C.P., Jr., Habel, L.A.: A cohort study of metformin and colorectal cancer risk among patients with diabetes mellitus. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 27(5), 525–530 (2018). doi:https://doi.org/10.1158/1055-9965.EPI-17-0424

  31. 31.

    Yaseyyedi A, Liu L, Bustamante R, Earles A, Gutkind JS, Gawron AJ, Kaltenbach TR, Martinez ME, Gupta S (2018) Metformin is associated with reduced risk for colorectal cancer among diabetics. Gastroenterology 154(6):S-335. https://doi.org/10.1016/S0016-5085(18)31456-2

    Article  Google Scholar 

  32. 32.

    Demb J, Yaseyyedi A, Liu L, Bustamante R, Earles A, Ghosh P, Gutkind JS, Gawron AJ, Kaltenbach TR, Martinez ME, Gupta S et al (2019) Clinical and translational gastroenterology 10(11):e00092. https://doi.org/10.14309/ctg.0000000000000092

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Saeed A, Nouraie M, Shahnazi A, Lee EL, Shokrani B, Nunlee-bland G, Mustafa YM, Laiyemo AO, Brim H, Geramfard S, Ashktorab H (2015) Metformin, insulin therapy and risk of colorectal neoplasia among African American with type 2 diabetes mellitus. Gastroenterology 148(4):S591–S591

    Article  Google Scholar 

  34. 34.

    Sehdev A, Shih YCT, 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(7):1071–1078. https://doi.org/10.1002/cncr.29165

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Garrett CR, Hassabo HM, Bhadkamkar NA, Wen S, Baladandayuthapani V, Kee BK, Eng C, Hassan MM (2012) Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer. British journal of cancer 106(8):1374–1378. https://doi.org/10.1038/bjc.2012.71

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Zhu RC, Rattanakorn K, Pham S, Mallam D, McIntyre T, Salifu MO, Youssef I, McFarlane SI, Vignesh S (2017) Survival benefits in colorectal adenocarcinoma with the use of metformin among a black diabetic inner city population. Colorectal Cancer 6(1):33–41. https://doi.org/10.2217/crc-2017-0001

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Henderson D, Frieson D, Zuber J, Solomon SS Metformin has positive therapeutic effects in colon cancer and lung cancer. The American journal of the medical sciences 354, 2017(3):246–251. https://doi.org/10.1016/j.amjms.2017.05.006

  38. 38.

    Paulus, J.K., Williams, C.D., Cossor, F.I., Kelley, M.J., Martell, R.E.: Metformin, diabetes, and survival among U.S. veterans with colorectal cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 25(10), 1418–1425 (2016)

  39. 39.

    Cossor FI, Adams-Campbell LL, Chlebowski RT, Gunter MJ, Johnson K, Martell RE, McTiernan A, Simon MS, Rohan T, Wallace RB, Paulus JK (2013) Diabetes, metformin use, and colorectal cancer survival in postmenopausal women. Cancer epidemiology 37(5):742–749. https://doi.org/10.1016/j.canep.2013.04.015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Skinner HD, Crane CH, Garrett CR, Eng C, Chang GJ, Skibber JM, Rodriguez-Bigas MA, Kelly P, Sandulache VC, Delclos ME, Krishnan S, Das P (2013) Metformin use and improved response to therapy in rectal cancer. Cancer medicine 2(1):99–107. https://doi.org/10.1002/cam4.54

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Han MS, Lee HJ, Park SJ, Hong SP, Cheon JH, Kim WH, Kim TI (2017) The effect of metformin on the recurrence of colorectal adenoma in diabetic patients with previous colorectal adenoma. International journal of colorectal disease 32(8):1223–1226. https://doi.org/10.1007/s00384-017-2782-z

    Article  PubMed  Google Scholar 

  42. 42.

    Lee, J.H., Jeon, S.M., Hong, S.P., Cheon, J.H., Kim, T.I., Kim, W.H.: Metformin use is associated with a decreased incidence of colorectal adenomas in diabetic patients with previous colorectal cancer. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 44(12), 1042–1047 (2012). doi:https://doi.org/10.1016/j.dld.2012.06.007

  43. 43.

    Ko BM, Cho YH, Han JP, Hong SJ, Jeon SR, Kim JO, Lee MS (2014) Does metformin affect the incidence of colonic polyps and adenomas in patients with type 2 DM? Gastrointest Endosc 79(5):AB455. https://doi.org/10.1016/j.gie.2014.02.943

    Article  Google Scholar 

  44. 44.

    Yo Han Kim, R.N., Sun Young Cho, Seong Jun Park, Soung Min Jeon, Hyun Deok Shin, Suk Bae Kim, Jeong Eun Shin: Inhibitory effect of metformin therapy on the incidence of colorectal advanced adenomas in patients with diabetes. Intestinal Research (2015)

  45. 45.

    Shin, C.M., Kim, N., Han, K., Kim, B., Jung, J.H., Oh, T.J., Lee, D.H.: Anti-diabetic medications and the risk for colorectal cancer: a population-based nested case-control study. Cancer Epidemiology 64 (2020). doi:https://doi.org/10.1016/j.canep.2019.101658

  46. 46.

    Kim HJ, Lee S, Chun KH, Jeon JY, Han SJ, Kim DJ, Kim YS, Woo JT, Nam MS, Baik SH, Ahn KJ, Lee KW (2018) Metformin reduces the risk of cancer in patients with type 2 diabetes. Medicine (United States) 97(8). https://doi.org/10.1097/MD.0000000000010036

  47. 47.

    Choi YJ, Kim DJ, Shin S (2019) Incident cancer risk in dipeptidyl peptidase-4 inhibitor-treated patients with type 2 diabetes mellitus. Cancer Manag Res 11:7427–7438. https://doi.org/10.2147/CMAR.S215107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    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. International journal of cancer 131(3):752–759. https://doi.org/10.1002/ijc.26421

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Ki Y-J, Kim HJ, Kim M-S, Park CM, Ko MJ, Seo YS, Moon SM, Choi JA (2017) Association between metformin use and survival in nonmetastatic rectal cancer treated with a curative resection: a nationwide population study. Cancer research and treatment : official journal of Korean Cancer Association 49(1):29–36. https://doi.org/10.4143/crt.2016.128

    CAS  Article  Google Scholar 

  50. 50.

    Park JW, Lee JH, Park YH, Park SJ, Cheon JH, Kim WH, Kim TI (2017) Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients. World journal of gastroenterology (23, 28):5196–5205. https://doi.org/10.3748/wjg.v23.i28.5196

  51. 51.

    Park C, Choi J, Kim H, Ko M, Kim Y, Kang S, Jo A (2016) Oncologic outcomes of metformin in patients with non-metastatic colon cancer and type 2 diabetes in South Korea using nationwide database. Value Health 19(3):A142

    Article  Google Scholar 

  52. 52.

    Tseng C-H (2012) Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan. European journal of endocrinology 167(3):409–416. https://doi.org/10.1530/EJE-12-0369

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Chen YC, Kok VC, Chien CH, Horng JT, Tsai JJP (2015) Cancer risk in patients aged 30 years and above with type 2 diabetes receiving antidiabetic monotherapy: a cohort study using metformin as the comparator. Ther Clin Risk Manag 11:1315–1323. https://doi.org/10.2147/TCRM.S91513

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Chang YT, Tsai HL, Kung YT, Yeh YS, Huang CW, Ma CJ, Chiu HC, Wang JY (2018) Dose-dependent relationship between metformin and colorectal cancer occurrence among patients with type 2 diabetes—a nationwide cohort study. Transl Oncol 11(2):535–541. https://doi.org/10.1016/j.tranon.2018.02.012

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Tseng CH (2017) Metformin is associated with a lower risk of colorectal cancer in Taiwanese patients with type 2 diabetes: a retrospective cohort analysis. Diabetes & metabolism 43(5):438–445. https://doi.org/10.1016/j.diabet.2017.03.004

    CAS  Article  Google Scholar 

  56. 56.

    Ming-Chia Hsieh T-CL, Cheng S-M, Tu S-T, Yen M-H, Tseng C-H (2012) The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese. Exp Diabetes Res 2012:1–6. https://doi.org/10.1155/2012/413782

    CAS  Article  Google Scholar 

  57. 57.

    Cardel M, Jensen SM, Pottegård A, Jørgensen TL, Hallas J (2014) Long-term use of metformin and colorectal cancer risk in type II diabetics: a population-based case-control study. Cancer Medicine 3(5):1458–1466. https://doi.org/10.1002/cam4.306

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Fransgaard T, Thygesen LC, Gögenur I (2018) Association between metformin use after surgery for colorectal cancer and oncological outcomes: a nationwide register-based study. Int J Cancer 143(1):63–72. https://doi.org/10.1002/ijc.31305

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Fransgaard T, Thygesen LC, Gögenur I (2016) Metformin increases overall survival in patients with diabetes undergoing surgery for colorectal cancer. Ann Surg Oncol 23(5):1569–1575. https://doi.org/10.1245/s10434-015-5028-8

    Article  PubMed  Google Scholar 

  60. 60.

    De Jong RG, Burden AM, De Kort S, Van Herk-Sukel MP, Vissers PA, Janssen PK, Haak HR, Masclee AA, De Vries F, Janssen-Heijnen ML (2017) No decreased risk of gastrointestinal cancers in users of metformin in the Netherlands: a time-varying analysis of metformin exposure. Cancer Prevention Research 10(5):290–297. https://doi.org/10.1158/1940-6207.CAPR-16-0277

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Ruiter R, Visser LE, Van Herk-Sukel MPP, Coebergh JWW, Haak HR, Geelhoed-Duijvestijn PH, Straus SMJM, Herings RMC, Stricker BHC (2012) Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study. Diabetes Care 35(1):119–124. https://doi.org/10.2337/dc11-0857

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Michael Bodmer, C.B., Christian Meier, Susan S. Jick, Christoph R. Meier. Use of metformin is not associated with a decreased risk of colorectal cancer: a case-control analysis. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 21(2), 280–286 (2012). doi:https://doi.org/10.1158/1055-9965.EPI-11-0992-T

  63. 63.

    Smiechowski, B., Azoulay, L., Yin, H., Pollak, M.N., Suissa, S.: The use of metformin and colorectal cancer incidence in patients with type II diabetes mellitus. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 22(10), 1877–1883 (2013). doi:https://doi.org/10.1158/1055-9965.EPI-13-0196

  64. 64.

    Mc Menamin ÚC, Murray LJ, Hughes CM, Cardwell CR (2016) Metformin use and survival after colorectal cancer: a population-based cohort study. International Journal of Cancer 138(2):369–379. https://doi.org/10.1002/ijc.29720

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Libby G, D L, Donnan PT, Alessi DR, Morris AD, JMM E (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625

    CAS  Article  Google Scholar 

  66. 66.

    Tsilidis KK, Capothanassi D, Allen NE, Rizos EC, Lopez DS, Van Veldhoven K, Sacerdote C, Ashby D, Vineis P, Tzoulaki I, Ioannidis JPA (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(9):2522–2532. https://doi.org/10.2337/dc14-0584

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Dulskas, A., Patasius, A., Linkeviciute-Ulinskiene, D., Zabuliene, L., Urbonas, V., Smailyte, G.: Metformin increases cancer specific survival in colorectal cancer patients—national cohort study. Cancer Epidemiology 62 (2019). doi:https://doi.org/10.1016/j.canep.2019.101587

  68. 68.

    Powell, M.K., Cempirkova, D., Dundr, P., Grimmichova, T., Trebicky, F., R, E.B., Gregorova, J., Litschmannova, M., Janurova, K., Pesta, M., Heneberg, P.: Metformin treatment for diabetes mellitus correlates with progression and survival in colorectal carcinoma. Translational Oncology 13(2), 383–392 (2020). doi:https://doi.org/10.1016/j.tranon.2019.10.011

  69. 69.

    Spillane, S., Bennett, K., Sharp, L., Barron, T.I.: A cohort study of metformin exposure and survival in patients with stage I-III colorectal cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 22(8), 1364–1373 (2013). doi:https://doi.org/10.1158/1055-9965.EPI-13-0347

  70. 70.

    Rosato V, Tavani A, Gracia-Lavedan E, Guinó E, Castaño-Vinyals G, Villanueva CM, Kogevinas M, Polesel J, Serraino D, Pisa FE, Barbone F, Moreno V, La Vecchia C, Bosetti C (2016) Type 2 diabetes, antidiabetic medications, and colorectal cancer risk: two case-control studies from Italy and Spain. Frontiers in Oncology 6(OCT). https://doi.org/10.3389/fonc.2016.00210

  71. 71.

    Vicentini M, Ballotari P, Giorgi Rossi P, Venturelli F, Sacchettini C, Greci M, Mangone L, Pezzarossi A, Manicardi V (2018) Effect of different glucose-lowering therapies on cancer incidence in type 2 diabetes: an observational population-based study. Diabetes Res Clin Pract 143:398–408. https://doi.org/10.1016/j.diabres.2018.04.036

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Vernieri C, Galli F, Ferrari L, Marchetti P, Lonardi S, Maiello E, Iaffaioli RV, Zampino MG, Zaniboni A, De Placido S, Banzi M, Damiani A, Ferrari D, Rosati G, Labianca RF, Bidoli P, Frassineti GL, Nicolini M, Pavesi L, Tronconi MC, Buonadonna A, Ferrario S, Re GL, Adamo V, Tamburini E, Clerico M, Giordani P, Leonardi F, Barni S, Ciarlo A, Cavanna L, Gori S, Cinieri S, Faedi M, Aglietta M, Antista M, Dotti KF, Galli F, Di Bartolomeo M (2019) Impact of metformin use and diabetic status during adjuvant fluoropyrimidine-oxaliplatin chemotherapy on the outcome of patients with resected colon cancer: a TOSCA study subanalysis. Oncologist 24(3):385–393. https://doi.org/10.1634/theoncologist.2018-0442

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    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 (2016) 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. The Lancet Oncology (17, 4):475–483. https://doi.org/10.1016/S1470-2045(15)00565-3

  74. 74.

    Lee GE, Aung T, Lim KH, Tan WS, Tai WMD, Suhaimi NAB, Tan MH, Tan IB (2012) Examining the effects of metformin on survival outcome in stage II/III colorectal cancer patients with diabetes mellitus. Journal of Clinical Oncology 30(15)

  75. 75.

    Omari AA, Abdelkhaleq H, Al-Hussaini M, Turfa R, Awad N, Hassan MM, Alfaqih MA, Garrett CR (2018, 2018) Validation of the survival benefits of metformin in Middle Eastern patients with type II diabetes mellitus and colorectal cancer. Journal of Global Oncology (4). https://doi.org/10.1200/JGO.18.00018

  76. 76.

    Mafiana RN, Al-Kindi MS, Mafiana N, Al Lawati AS, Al Moundhri M (2019) Impact of metabolic syndrome diagnosis and its treatment on survival of colorectal cancer patients. Journal of Cancer Epidemiology 2019:1–9. https://doi.org/10.1155/2019/6527457

    CAS  Article  Google Scholar 

  77. 77.

    He WZ, Xia LP (2015) Impact of metformin on survival in patients with type II diabetes and metastatic colorectal cancer. Journal of Clinical Oncology 33(15)

  78. 78.

    Gao X, Zhang L, Yang Z (2019) Effect of metformin on prognosis of type 2 diabetic patients with colon cancer. Journal of Practical Oncology 34(2):118–121. https://doi.org/10.13267/j.cnki.syzlzz.2019.02.004

    Article  Google Scholar 

  79. 79.

    Ramjeesingh R, Orr C, Bricks CS, Hopman WM, Hammad N (2016) A retrospective study on the role of diabetes and metformin in colorectal cancer disease survival. Curr Oncol 23(2):e116–e122. https://doi.org/10.3747/co.23.2809

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Bae S, Wong HL, Tie J, Desai J, Field K, Kosmider S, Fourlanos S, Jones I, Skinner I, Gibbs P (2015) Impact of diabetes status and medication on presentation, treatment, and outcome of stage II colon cancer patients. Journal of Cancer Epidemiology 2015:1–8. https://doi.org/10.1155/2015/189132

    CAS  Article  Google Scholar 

  81. 81.

    Singh PP, Shi Q, Foster NR, Grothey A, Nair SG, Chan E, Shields AF, Goldberg RM, Gill S, Kahlenberg MS, Sinicrope FA, Sargent DJ, Alberts SR (2016) 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 21(12):1509–1521

    CAS  Article  Google Scholar 

  82. 82.

    Muhamad Noor Alfarizal Kamarudin, M. M. R. S., Jin-Rong Zhou and Ishwar Parhar: Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects. Journal of Experimental and Clinical Cancer Research (2019)

  83. 83.

    Pouya Saraei IA, Kakar MA, Moradi-Kor N (2019) The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer Manag Res

  84. 84.

    Pranay Ramteke, A.D., Varsha Shepal and Manoj Kumar Bhat: Hyperglycemia associated metabolic and molecular alterations in cancer risk, progression, treatment, and mortality. Cancers (2019)

  85. 85.

    FUMING ZI, H Z, LI YI, HE JINGSONG, SHI QINGZHI, CAI ZHEN (2018) Metformin and cancer: an existing drug for cancer prevention and therapy (review). Oncol Lett

  86. 86.

    GuillaumeVial D, Guigas B (2019) Role of mitochondria in the mechanism(s) of action of metformin. Front Endocrinol

  87. 87.

    V. C. Miranda, M. I. B., L. D. Faria et al: Phase 2 trial of metformin combined with 5-fluorouracil in patients with refractory metastatic colorectal cancer. Clinical Colorectal Cancer (2016)

  88. 88.

    M. Yang, P. L, and P. Huang: Cancer stem cells, metabolism, and therapeutic significance. Tumor Biology (2016)

  89. 89.

    Ghodratollah Soltani, A.P., Maryam Yassi, Abdorasool Hayatbakhsh, Matin Kerachian, Mohammad Amin Kerachian: Obesity, diabetes and the risk of colorectal adenoma and cancer. BMC Endocrine Disorders (2019)

  90. 90.

    Feifei Yu YG, Wang H, Feng J, Jin Z, Chen Q, Liu Y, He J (2016) Type 2 diabetes mellitus and risk of colorectal adenoma: a meta-analysis of observational studies. BMC Cancer

  91. 91.

    Ying Gao, H.K., Barry Graubard, Michael Pollak, Michael Martin, Yuzhen Tao, Robert E. Schoen, Timothy Church, Richard B. Hayes, Mark H. Greene, and Sonja I. Berndt: Serum IGF1, IGF2, and IGFBP3 and risk of advanced colorectal adenoma. Int J Cancer (2012)

  92. 92.

    X. Garcia-Albeniz, A.T.C.: Aspirin for the prevention of colorectal cancer. Best Pract Res Clin Gastroenterol. 2011 (2011)

  93. 93.

    S. GOYA WANNAMETHEE, A. G. S, IVAN, J. PERRY: S. GOYA WANNAMETHEE, A. GERALD SHAPER, IVAN J. PERRY. Smoking as a modifiable risk factor for type 2 diabetes in middle-aged men. Diabetes care (2001)

  94. 94.

    Emily Banks, G.J., Rosemary J. Korda, Bill Stavreski, Kay Soga, Sam Egger, Cathy Day, Naomi E. Clarke, Sarah Lewington and Alan D. Lopez: Tobacco smoking and risk of 36 cardiovascular disease subtypes: fatal and non-fatal outcomes in a large prospective Australian study. BMC Medicine (2019)

  95. 95.

    Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E, Uchiyama T, Suzuki K, Iida H, Sakamoto Y, Yoneda K, Koide T, Tokoro C, Abe Y, Inamori M, Nakagama H, Nakajima A (2010) Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer prevention research (Philadelphia, Pa.) 3(9):1077–1083. https://doi.org/10.1158/1940-6207.CAPR-10-0186

    CAS  Article  Google Scholar 

  96. 96.

    Kevin Van der Jeught, H.-C.X., Yu-Jing Li, Xiong-Bin Lu, and Guang Ji: Drug resistance and new therapies in colorectal cancer. World journal of gastroenterology (2018)

  97. 97.

    Higurashi T, N. A.: Metformin and colorectal cancer. Cancer Endocrinology (2018)

  98. 98.

    Shin Jun Lee, J.H.K., Seun Ja Park, So Young Ock, Su Kyoung Kwon, Young Sik Choi, Bu KyungKim: Optimal glycemic target level for colon cancer patients with diabetes. Diabetes research and clinical practice (2016)

  99. 99.

    Chiara De Divitiis, G.N., Massimo Montano, Rossella Fisichella, Rosario Vincenzo Iaffaioli, and Massimiliano Berretta: Prognostic and predictive response factors in colorectal cancer patients: Between hope and reality. World journal of gastroenterology (2014)

  100. 100.

    Sleeboom JA, Hossein, Nair, Poornima, Sahlgren, Cecilia, Toonder, Jaap (2018) Metastasis in context: modeling the tumor microenvironment with cancer-on-a-chip approaches. Dis Model Mech 11:dmm033100

    Article  Google Scholar 

  101. 101.

    Yaodu Wang ZW, Hu L (2017) Epithelial-mesenchymal transition phenotype, metformin, and survival for colorectal cancer patients with diabetes mellitus II. Gastroenterol Res Pract

  102. 102.

    Lugli IZAA (2010) Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget. Oncotarget

  103. 103.

    Gulhati P, B KA, Liu J et al (2011) mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Research

  104. 104.

    Kang S, Kim BR, Kang M-H, Kim D-Y, Lee D-H, Oh SC, Min BW, Um JW (2018) Anti-metastatic effect of metformin via repression of interleukin 6-induced epithelial-mesenchymal transition in human colon cancer cells. PloS one 13(10):e0205449. https://doi.org/10.1371/journal.pone.0205449

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Zhang C, Wang Y (2019) Metformin attenuates cells stemness and epithelial-mesenchymal transition in colorectal cancer cells by inhibiting the Wnt3a/beta-catenin pathway. Molecular medicine reports 19(2):1203–1209. https://doi.org/10.3892/mmr.2018.9765

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Casanovas IZ-GAO (2018) Unraveling the Role of Angiogenesis in Cancer Ecosystems. frontiers in Oncology

  107. 107.

    Bowker SL, M S, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258

    Article  Google Scholar 

  108. 108.

    Azoulay SSAL (2012) Metformin and the risk of cancer. Diabetes Care

Download references

Code availability

Not applicable.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Chin Meng Khoo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 802 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ng, C.W., Jiang, A.A., Toh, E.M.S. et al. Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression. Int J Colorectal Dis 35, 1501–1512 (2020). https://doi.org/10.1007/s00384-020-03676-x

Download citation

Keywords

  • Adenoma
  • Malignant
  • Incidence
  • Survival outcomes
  • Type 2 diabetes mellitus