Retrospective Cohort Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2017; 23(28): 5196-5205
Published online Jul 28, 2017. doi: 10.3748/wjg.v23.i28.5196
Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients
Jung Won Park, Jin Ha Lee, Ye Hyun Park, Soo Jung Park, Jae Hee Cheon, Won Ho Kim, Tae Il Kim
Jung Won Park, Jin Ha Lee, Ye Hyun Park, Soo Jung Park, Jae Hee Cheon, Won Ho Kim, Tae Il Kim, Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, South Korea
Tae Il Kim, Cancer Prevention Center, Yonsei University College of Medicine, Seoul 03722, South Korea
Author contributions: Park JW and Kim TI designed the study; Park JW, Lee JH and Park SJ performed the research; Park JW, Park YH, Park SJ, Cheon JH, Kim WH and Kim TI analyzed the data; and Kim TI revised the manuscript for important intellectual content.
Supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, No. 2013R1A1A2010733; and National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea, No. 1631020.
Institutional review board statement: This study was approved by the Institutional Review Board of Severance Hospital, Yonsei University, Seoul, South Korea.
Informed consent statement: All involved persons (subjects or legally authorized representative) gave their informed consent (written or verbal) prior to study inclusion.
Conflict-of-interest statement: All authors declare no conflict of interest.
Data sharing statement: The original anonymous dataset is available on request from the corresponding author at taeilkim@yuhs.ac.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Tae Il Kim, MD, PhD, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea. taeilkim@yuhs.ac
Telephone: +82-2-22281965 Fax: +82-2-3936884
Received: April 12, 2017
Peer-review started: April 20, 2017
First decision: May 12, 2017
Revised: May 16, 2017
Accepted: July 4, 2017
Article in press: July 4, 2017
Published online: July 28, 2017
Processing time: 110 Days and 22.1 Hours
Abstract
AIM

To assess factors associated with the higher effect of metformin on mortality in diabetic colorectal cancer (CRC) patients, since the factors related to the effectiveness of metformin have not been identified yet.

METHODS

Between January 2000 and December 2010, 413 patients diagnosed with both stage 3/4 CRC and diabetes mellitus were identified. Patients’ demographics and clinical characteristics were analyzed. The effect of metformin on CRC-specific mortality and the interactions between metformin and each adjusted factor were evaluated.

RESULTS

Total follow-up duration was median 50 mo (range: 1-218 mo). There were 85 deaths (45.9%) and 72 CRC-specific deaths (38.9%) among 185 patients who used metformin, compared to 130 total deaths (57.0%) and 107 CRC-specific deaths (46.9%) among 228 patients who did not use metformin. In multivariate analysis, survival benefit associated with metformin administration was identified (HR = 0.985, 95%CI: 0.974-0.997, P = 0.012). Interaction test between metformin and sex after adjustment for relevant factors revealed that female CRC patients taking metformin exhibited a significantly lower CRC-specific mortality rate than male CRC patients taking metformin (HR = 0.369, 95%CI: 0.155-0.881, P = 0.025). Furthermore, subgroup analysis revealed significant differences in CRC-specific mortality between the metformin and non-metformin groups in female patients (HR = 0.501, 95%CI: 0.286-0.879, P = 0.013) but not male patients (HR = 0.848, 95%CI: 0.594-1.211, P = 0.365). There were no significant interactions between metformin and other adjusted factors on CRC-specific mortality.

CONCLUSION

We showed a strong sex-dependent difference in the effect of metformin on CRC-specific mortality in advanced stage CRC patients with diabetes.

Keywords: Colorectal cancer; Metformin; Survival; Sex

Core tip: Evidence from previous studies has identified the anti-tumor effect of metformin; however, the factors related to effectiveness of metformin in diabetic colorectal cancer (CRC) patients have not been identified yet. Identifying subgroup patients who benefit from metformin treatment is important for future clinical application of metformin, and a strong sex-dependent difference of metformin effect in advanced CRC patients has been identified in this present study.