Lee et al. BMC Cancer 2011, 11:20 http://www.biomedcentral.com/1471-2407/11/20 R E S E A R C H A R T I C L E Open Access 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 Meei-Shyuan Lee1*†, Chih-Cheng Hsu2†, Mark L Wahlqvist1,2†, Hsin-Ni Tsai2, Yu-Hung Chang2, Yi-Chen Huang2 Abstract Background: Metformin protection against cancer risk in Orientals is uncertain. We examined the possible metformin effect on total, esophageal, gastric, colorectal (CRC), hepatocellular (HCC) and pancreatic cancers in a Taiwanese cohort. Methods: A representative sample of 800,000 was drawn from the Taiwanese National Health Insurance data of 2000. A cohort of 480,984 participants 20 years or older, diabetes-cancer-free on 1st January 2000 was formed and categorized as four groups by DM and metformin usage status. Eligible incident cancer events had to occur one year after the index date until the end of 2007. The Cox proportional-hazards model evaluated relative risk of cancer for treated DM patients with or without metformin. The covariates included age, gender, other oral anti- hyperglycemic medication, Charlson comorbidity index (CCI) score and metformin exposure dosage and duration. Results: With diabetes but no anti-hyperglycemic medication, cancer incidence density increased at least 2-fold for total, CRC and HCC. On metformin, total, CRC and HCC incidences decreased to near non-diabetic levels but to varying degrees depending on gender and cancer type (CRC in women, liver in men). Adjustment for other oral anti-hyperglycemic agents usage and CCI made the benefit of metformin more evident [hazard ratios (95% confidence intervals): total 0.12 (0.08-0.19), CRC 0.36 (0.13-0.98), liver 0.06 (0.02-0.16), pancreas 0.15 (0.03-0.79)]. There was a significant gender interaction with metformin in CRC which favored women. Metformin dosage for a significant decrease in cancer incidence was ≤500 mg/day. Conclusions: Metformin can reduce the incidences of several gastroenterological cancers in treated diabetes. Background Diabetes (DM) is a significant risk factor for total cancer incidence and mortality [1-3] and for some site-specific cancers, notably breast and colorectal (CRC) [4,5], and probably endometrial, prostate, and pancreas [6-8]. These cancers have possible underlying mechanisms to do with energy throughput and balance, hyperinsulinemia or insulin resistance, or other hormone sensitivity [9]. * Correspondence: mmsl@ndmctsgh.edu.tw † Contributed equally 1School of Public Health, National Defense Medical Center, Taipei, ROC Full list of author information is available at the end of the article Such findings may be relevant even before DM is clinically manifest or biochemical criteria are met, which is to say with pre-DM or the metabolic syndrome. Diabetes treatment might affect cancer incidence and mortality [8-13]. Since the 1960s, metformin (one of the biguanides) has become the first line anti-hyperglycemic agent in type 2 diabetes (T2DM) treatment worldwide [14]. It has been shown to be potentially cancer protec- tive in a pilot study on incidence in Scotland [15], in a later cohort study [16] and, indirectly, in an administrative population-based study on mortality in Saskatchewan, Canada [17]. © 2011 Lee et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.