Suppressive effects of metformin on colorectal adenoma incidence and malignant progression

Abstract Background The linear progression from normal colonic epithelium to adenoma initiation, carcinoma transformation and metastasis is considered the classical model of colorectal cancer (CRC) development. Although metformin has been extensively reported to be negatively related to cancer incidence, the effect of metformin on CRC development remains unclear. We aimed to evaluate the role of metformin in the entire CRC linear progression. Methods Systematic searches and data extraction were performed in the PubMed, Embase, and Cochrane Library databases on Jan 31, 2019. The combined relative ratios (RRs) of colorectal tumor incidence and the hazard ratios (HRs) of overall survival (OS) and cancer-specific survival (CSS) were evaluated by a random-effects model. Then, the effects of metformin were further assessed through stratified analyses by population, medication duration and dosage, dose-response analysis and comparison with other antidiabetic agents. Results A total of 50 studies consisting of 238,540 cases of diabetes mellitus (DM) were included in this study. Metformin use was negatively associated with the incidence of colorectal adenoma (RR: 0.75, 95% CI: 0.65-0.86) and CRC (RR: 0.73, 95% CI: 0.58-0.90). Moreover, CRC patients benefited from metformin in terms of both OS (HR: 0.73, 95% Cl: 0.63-0.84) and CSS (HR: 0.60, 95% Cl: 0.50-0.73). Stratified analyses suggested that a long duration of high-dose metformin (RR: 0.52, 95% Cl: 0.36-0.83) was more effective than a short duration in Asian populations against colorectal adenoma (RR: 0.66, 95% Cl: 056-0.70) and CRC (RR: 0.45, 95% Cl: 0.29-0.70). Interestingly, metformin use decreased CRC risk in a dose-dependent manner (RR: 0.91, 95% CI: 0.87-0.95). In addition, the benefit of metformin on CRC was more significant than that of other antidiabetic agents, including insulin. Conclusions The use of metformin is associated with a lower incidence of adenoma and CRC and a better prognosis, especially in Asian populations.