Association of metformin with reduced mortality in patients with colorectal cancer: A systematic review and meta-analysis of observational studies.

Abstract

522 Background: Metformin inhibits mTOR and downstream pathways involved in cell proliferation and survival by inducing AMPK activation. Although its use has been associated with decreased risk of colorectal cancer (CRC), the effect of metformin on cancer related mortality is unclear. We performed a meta-analysis of published observational studies evaluating metformin use in patients with CRC and its association with overall and CRC-specific survival. Methods: Through a systematic search of PubMed and conference presentations (cut-off: August 2013), we identified 8 observational studies (18,537 total patients with CRC; 6242 CRC patients with DM) reporting the association between metformin use and survival after diagnosis of CRC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated using the random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, metformin use was associated with a 34% reduction in mortality in CRC patients as compared to non-use (adjusted HR, 0.66; 95% CI, 0.54-0.81), albeit with high heterogeneity (I2=66.9%). After exclusion of one study, which contributed to considerable heterogeneity, a 28% reduction in mortality was considered a more conservative, consistent effect estimate (adjusted HR, 0.72; 95% CI, 0.64-0.81), with minimal heterogeneity (I2=16.2%). On restricting analysis only to patients with DM, use of metformin (vs non-use) was associated with decreased all-cause mortality (6 studies; adjusted HR, 0.63; 95% CI, 0.49-0.81) and CRC-specific mortality (3 studies; adjusted HR, 0.66; 95% CI, 0.50-0.87). Conclusions: Based on meta-analysis of observational studies, the use of metformin in diabetic patients with CRC appears to be associated with reduced all-cause mortality and CRC-specific mortality. Further prospective investigation of metformin’s effect on outcome in CRC patients is warranted.