The Potential Effect of Metformin on Cancer: An Umbrella Review

Background: Metformin has been reported to possess anti-cancer properties in addition to glucose-lowering activity and numerous systematic reviews and meta-analyses have studied the association between metformin use and cancer incidence or survival outcomes. We performed an umbrella review to assess the robustness of these associations to facilitate proper interpretation of these results to inform clinical and policy decisions. Methods: We searched PubMed and Embase systematic reviews and meta-analyses investigating the effect of metformin use on cancer incidence or survival outcomes published from inception to September 2, 2018. We estimated the summary effect size, the 95% CI, and the 95% prediction interval, heterogeneity, evidence of small-study effects, and evidence of excess significance bias. Results: We included 21 systematic reviews and meta-analyses covering 11 major anatomical sites and 33 associations. There was strong evidence for the association between metformin use and decreased pancreatic cancer incidence. The association between metformin use and improved colorectal cancer overall survival (OS) was supported by highly suggestive evidence. Seven associations (all cancer incidence, all cancer OS, breast cancer OS, colorectal cancer incidence, liver cancer incidence, lung cancer OS, and pancreatic cancer OS) presented only suggestive evidence. The remaining 24 associations were supported by weak or not-suggestive evidence. Conclusions: Associations between metformin use and pancreatic cancer incidence or colorectal cancer OS are supported by strong or highly suggestive evidence, respectively. However, these results should be interpreted with caution due to the poor methodological quality of the systematic reviews and meta-analyses.