Dose-Dependent Relationship Between Metformin and Colorectal Cancer Occurrence Among Patients with Type 2 Diabetes—A Nationwide Cohort Study123

BACKGROUND Increasing bodies of evidence suggest that metformin may be beneficial in the primary prevention of colorectal cancer (CRC), and a dose-response relationship has been reported. However, long-term epidemiological observations between the treatment period, cumulative dose, and intensity of metformin and CRC are rarely reported. The aim of this study was to identify the association between the effect of metformin and CRC development in a nationwide cohort study. METHODS This nationwide population-based study examined a cohort of 1,000,000 patients randomly sampled from individuals enrolled in the Taiwan National Health Insurance system. Patients with newly diagnosed type 2 diabetes mellitus (DM) between 1997 and 2007 were enrolled. A statistical variables, including the demographic data, treatment period, cumulative dose, and intensity of metformin use, was compared between patients developing CRC and those without CRC. RESULTS This study included 47,597 patients. The mean follow-time was 7.17 ± 3.21 years. After adjustment, metformin use was an independent protective factor against CRC development (P < .001). Although the protective ability of metformin against CRC development was reduced during long-term therapy, the risk of CRC decreased progressively with a higher cumulative dose or higher intensity of metformin use (both P < .001). CONCLUSION This study revealed that metformin use significantly reduced the risk of CRC in a dose-dependent manner in patients with type 2 DM in the Taiwanese population. However, a gradual decline in medication adherence may reduce the protective ability of metformin against CRC development during long-term therapy.