The impact of metformin on survival in diabetes patients with operable colorectal cancer: A nationwide retrospective cohort study

Abstract

Objective To investigate the impact of metformin on survival of diabetic patients following surgery for colorectal cancer (CRC). Methods This was a retrospective cohort study. From Taiwan’s population-based National Health Insurance Research Database (NHIRD) we identified 12,512 patients with CRC and type II diabetes who underwent curative surgery between 2000 and 2012. Of these, 6222 patients were included in a matched cohort. Using Cox regression models with time-dependent covariates we examined the impact of metformin on survival. Results Average duration of follow-up was 49 and 54 months for metformin users and non-users, respectively. Cox proportional hazard model showed that metformin was associated with 5-year overall survival benefit (Hazard ratio, 0.23 [95% CI, 0.20–0.26]) and inverse association with risk of liver metastasis (Hazard ratio, 0.79 [95% CI, 0.68–0.93]). Conclusions Metformin was associated with a survival benefit in diabetic patients with CRC following surgery, and an inverse association with risk of liver metastases suggesting a potential anti-tumorigenic effect.

Metabolic Alteration Bridging the Prediabetic State and Colorectal Cancer

“…Metformin-derived antineoplastic effects are also mediated by suppression of tumor growth factor (TGF)-β/Inhibin Subunit βA (INHBA) signaling with downregulated cyclin D1 expression and cell cycle inhibition [177], along with urea cycle suppression and reduced putrescine levels [178]. A retrospective study in CRC diabetic patients reported a metformin-mediated survival benefit and reduced risk of liver metastasis after surgery [179]. Metformin induced caspase 3-independent apoptotic death in HCT116 and SW620 CRC cells [180] and disrupted the immunosuppressive effect of the tumor microenvironment [181].…”

“…Glucose homeostasis enhancement [152,153,155] Inhibition of prediabetes to DM progression [152,153] Increase in GLUT4 expression levels [157] Promotion of GLUT4 membrane translocation [157] Reduction in systemic inflammation and oxidative stress and miR-195 and miR-27 [158] SIRT6 upregulation [159] SGLT2 downregulation [159] Leptin/adiponectin ratio reduction [159] Overall and disease-free CRC survival increase Reduced liver metastasis [174,175,179] Inhibition of mTOR and PI3K/Akt signaling [176,183] AMPK activation [97,176,183] TGF-β/INHBA signaling suppression [177] CyclinD downregulation [177] Urea cycle suppression [178] Reduced putrescin levels [178] Caspase 3-mediated apoptosis [180] Disruption of tumor-mediated immunosuppression [181][182][183] Chemosensitivity increase [97,184]…”