Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients

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.