Abstract
Several observational studies have shown that metformin can modify the risk and survival of colorectal cancer (CRC) in patients with diabetes mellitus, although the magnitude of this relationship has not been determined. We conducted an updated systematic review and meta-analysis to analyze the association between metformin and CRC mortality and searched relevant databases up to July 2016. The primary outcome was overall survival (OS). Secondary outcomes were cancer-specific survival (CS) and disease-free survival (DFS). Summary hazard ratios (HRs) were calculated using a random-effects model. Seventeen studies enrolling 269,417 participants were eligible for inclusion. Comparing with non-metformin users in diabetic CRC patients, the summary HRs for OS in metformin users were 0.69 (95% CI, 0.61-0.77). Subgroup analyses stratified by the study characteristics and sensitivity analysis by the trim-and-fill method (adjusted HR 0.77, 95% CI, 0.67-0.87) confirmed the robustness of the results. However, significant OS benefit was noted in patients with stage II and III disease. Five studies reported the CRC prognosis for CS and three for DFS; metformin intake was significantly associated with patient CS (HR 0.75, 95% CI, 0.59-0.94), but not DFS (HR 0.38, 95% CI, 0.13-1.17). Our findings suggest that metformin intake is associated with improved survival outcomes in terms of OS and CS in CRC patients with diabetes, particular for OS in stage II and stage III patients. Further studies should be conducted to determine CRC survival between metformin use and patient specific clinical and molecular profiles.
Highlights
As a commonly used oral anti-hyperglycaemic agent for type 2 diabetes mellitus (DM), metformin can improve insulin sensitivity by increasing peripheral glucose intake and utilization [1]
We did not explore the publication bias for cancer-specific survival (CS) or disease-free survival (DFS) due to the limited number of studies involved. This meta-analysis based on patient survival data from observational studies comparing metformin use and non-use in patients with colorectal cancer (CRC) revealed that metformin intake was associated with better outcomes in terms of overall survival (OS) and CS
The significant association between metformin intake and OS of patients was noted in most baseline subsets, further confirming the prognostic role of metformin in CRC
Summary
As a commonly used oral anti-hyperglycaemic agent for type 2 diabetes mellitus (DM), metformin can improve insulin sensitivity by increasing peripheral glucose intake and utilization [1]. Metformin intake has been reported to be associated with reduced risk of colorectal cancer (CRC) as well as improved survival in CRC patients [11,12,13,14,15,16,17,18], such as pathologic complete response in locally advanced rectal cancer treated www.impactjournals.com/oncotarget with chemoradiotherapy [19]. Several meta-analyses have examined the association between metformin and CRC survival [20, 21]. These systematic reviwews are quite preliminary with limited number of studies included and low statistical power to draw a definite conclusion.
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