Lee et al. BMC Cancer 2011, 11:20 http://www.biomedcentral.com/1471-2407/11/20 Conclusions Low dose metformin is protective against total cancer and several cancers, including CRC in women, HCC in men and pancreatic for treated DM patients. This is evi- dent in a population with an increasing prevalence of DM and at increasing risk of cancer profiles characteris- tic of economic development. Cancer prevention may be enhanced by avoiding DM or by its control with metfor- min. Since metformin would seem to act through cellu- lar energy regulation, diet and exercise operate to reduce cancer risk in a similar way, although gender dif- ferences indicate that ancillary mechanisms and preven- tive and management approaches may be possible. Acknowledgements This study was sponsored by the National Health Research Institutes. We thank their data management staff for coordinating the scrambling protocol between the Bureau of NHI and the investigators. Author details 1School of Public Health, National Defense Medical Center, Taipei, ROC. 2Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan, ROC. Authors’ contributions MSL, CCH, MLW and YHC participated in developing the conceptual framework, in analysis, and interpretation, drafting, and approval of the final version of the report. HNT and YCH performed data analysis and approved the final version of the report. Competing interests The authors declare that they have no competing interests. Received: 2 March 2010 Accepted: 18 January 2011 Published: 18 January 2011 References 1. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ: Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004, 159(12):1160-1167. 2. Levine W, Dyer AR, Shekelle RB, Schoenberger JA, Stamler J: Post-load plasma glucose and cancer mortality in middle-aged men and women. 12-year follow-up findings of the Chicago Heart Association Detection Project in Industry. Am J Epidemiol 1990, 131(2):254-262. 3. Saydah SH, Loria CM, Eberhardt MS, Brancati FL: Abnormal glucose tolerance and the risk of cancer death in the United States. Am J Epidemiol 2003, 157(12):1092-1100. 4. Weiderpass E, Gridley G, Nyren O, Ekbom A, Persson I, Adami HO: Diabetes mellitus and risk of large bowel cancer. J Natl Cancer Inst 1997, 89(9):660-661. 5. Will JC, Galuska DA, Vinicor F, Calle EE: Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol 1998, 147(9):816-825. 6. Everhart J, Wright D: Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA 1995, 273(20):1605-1609. 7. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL: Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009, 137(2):482-488. 8. Yang YX: Do diabetes drugs modify the risk of pancreatic cancer? Gastroenterology 2009, 137(2):412-415. 9. Yang YX, Hennessy S, Lewis JD: Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004, 127(4):1044-1050. 10. Chong CR, Chabner BA: Mysterious metformin. Oncologist 2009, 14(12):1178-1181. Page 9 of 10 11. Duncan BB, Schmidt MI: Metformin, cancer, alphabet soup, and the role of epidemiology in etiologic research. Diabetes Care 2009, 32(9):1748-1750. 12. Jiralerspong S, Giordano SH, Meric-Bernstam F, Barnett CM, Kau S, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM: The effects of metformin on pathologic complete response (pCR) rates in diabetic breast cancer (BC) patients receiving neoadjuvant systemic therapy (NST). American Society of Clinical Oncology 2008, 26:508. 13. Oliveria SA, Koro CE, Yood MU, Sowell M: Cancer incidence among patients treated with antidiabetic pharmacotherapy. Cancer incidence among patients treated with antidiabetic pharmacotherapy 2008, 2(1):47-57. 14. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B: Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009, 32(1):193-203. 15. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ 2005, 330(7503):1304-1305. 16. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM: New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009, 32(9):1620-1625. 17. Bowker SL, Majumdar SR, Veugelers P, Johnson JA: Increased cancer- related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006, 29(2):254-258. 18. Currie CJ, Poole CD, Gale EA: The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009, 52(9):1766-1777. 19. Donadon V, Balbi M, Ghersetti M, Grazioli S, Perciaccante A, Della Valentina G, Gardenal R, Dal Mas M, Casarin P, Zanette G, et al: Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol 2009, 15(20):2506-2511. 20. Park S, Bae J, Nam BH, Yoo KY: Aetiology of cancer in Asia. Asian Pac J Cancer Prev 2008, 9(3):371-380. 21. World Cancer Research Fund/American Institute for Cancer Research: Policy and Action for Cancer Prevention. Food, Nutrition, and Physical Activity: a Global Perspective. Washington DC: AICR; 2009. 22. World Cancer Research Fund/American Institute for Cancer Research: Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington DC: AICR; 2007. 23. Ten Leading Cancer Ranked by Incidence and Mortality Rate in Taiwan. 2006 [http://tcr.cph.ntu.edu.tw/uploadimages/Leading_10.pdf]. 24. National Health Insurance Research Database (NHIRD). [http://w3.nhri.org. tw/nhird/date_01.html]. 25. Suissa S: Immortal Time Bias in Pharmacoepidemiology. Am J Epidemio 2008, 167:492-499. 26. Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987, 40:373-383. 27. Chen CJ, You SL, Lin LH, Hsu WL, Yang YW: Cancer epidemiology and control in Taiwan: a brief review. Jpn J Clin Oncol 2002, 32(Suppl):S66-81. 28. Chitturi S, Farrell GC, Hashimoto E, Saibara T, Lau GK, Sollano JD: Non- alcoholic fatty liver disease in the Asia-Pacific region: definitions and overview of proposed guidelines. J Gastroenterol Hepatol 2007, 22(6):778-787. 29. Black SA: Diabetes, diversity, and disparity: what do we do with the evidence? Am J Public Health 2002, 92(4):543-548. 30. DeFronzo RA, Tripathy D: Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 2009, 32(Suppl 2):S157-163. 31. Gabal LL, Goodman-Gruen D, Barrett-Connor E: The effect of postmenopausal estrogen therapy on the risk of non-insulin-dependent diabetes mellitus. Am J Public Health 1997, 87(3):443-445. 32. Guercio G, Di Palma MI, Pepe C, Saraco NI, Prieto M, Saure C, Mazza C, Rivarola MA, Belgorosky A: Metformin, Estrogen Replacement Therapy and Gonadotropin Inhibition Fail to Improve Insulin Sensitivity in a Girl with Aromatase Deficiency. Horm Res 2009, 72(6):370-376. 33. Kannel WB, Wilson PW: Risk factors that attenuate the female coronary disease advantage. Arch Intern Med 1995, 155(1):57-61. 34. de Kok IM, Wong CS, Chia KS, Sim X, Tan CS, Kiemeney LA, Verkooijen HM: Gender differences in the trend of colorectal cancer incidence in Singapore, 1968-2002. Int J Colorectal Dis 2008, 23(5):461-467.