Metformin and Biliary Tract Cancer in Patients With Type 2 Diabetes

Abstract

Aim: This retrospective cohort study evaluated whether metformin use in patients with type 2 diabetes mellitus might reduce the risk of biliary tract cancer (BTC); and explored whether metformin use might affect the overall survival in patients who developed BTC. Methods: New-onset type 2 diabetes patients aged 25-75 years during 1999-2005 were enrolled from the Taiwan's National Health Insurance and followed up until December 31, 2011. A total of 287,995 ever users and 16,229 never users were identified (unmatched original cohort) and a 1:1 matched pairs of 16,229 ever users and 16,229 never users based on propensity score (PS) were created (matched cohort). Hazard ratios were estimated by three Cox regression models: 1) adjusted for PS; 2) incorporated with the inverse probability of treatment weighting using PS; and 3) all covariates treated as independent variables. Overall survival was compared between ever users and never users of metformin who developed BTC. Results: In the unmatched cohort, 73 never users and 523 ever users developed BTC, with respective incidence of 100.36 and 38.06 per 100,000 person-years. An overall risk reduction was observed in metformin users in all three regression models with respective hazard ratio (95% confidence interval) of 0.442 (0.344-0.568), 0.377 (0.295-0.481), and 0.477 (0.370-0.615). The tertile analyses showed a dose-response pattern with a neutral effect in the first tertile when metformin use was <2 years and a significant risk reduction in the second and third tertiles. Findings in the matched cohort were consistent with those observed in the unmatched cohort. The overall survival did not differ significantly between ever and never users of metformin among patients who developed BTC. Conclusions: Metformin significantly reduces the overall risk of BTC by 50%-60%. A dose-response effect is observed and users of approximately 2 years show significantly reduced risk. However, metformin does not affect the overall survival in patients with BTC.

Metabolic reprogramming in cholangiocarcinoma

“…68 Furthermore, a retrospective study by Tseng et al, demonstrated that metformin significantly decreases the risk of biliary tract cancer by 50%-60%, although it does not affect OS in these patients. 69 Accordingly, Yang et al reported that metformin does not improve survival in patients with CCA and diabetes. 70 Thus, in light of this still controversial evidence, inhibition of OXPHOS in cancer cells as an approach to counteract CCA progression deserves further investigation.…”

Impact of metformin on the incidence of human cholangiocarcinoma in diabetic patients: a systematic review and meta-analysis

“…The aim was clear in all the studies analyzed. As the four selected studies were retrospective (one case–control study [32], one cohort study [31], and two population-based data studies [33,34]), any of the studies were judged to apply the most appropriate recruitment strategy to explore the aim. The study design and the qualitative methodology were judged appropriate in all but one paper [33], in which considerable biases could be held-up by the creation of a simulated control population and by the discrepancy between the groups as regards potential risk factors for CCA other than diabetes and metformin intake.…”

“…Regarding the anatomical location of CCA, one study [31] considered both intrahepatic and extrahepatic forms, whereas another study investigated GBC carcinoma, intrahepatic and extrahepatic CCA [34], another [32] considered only the intrahepatic type, whereas for the fourth study [33], no information was provided regarding the anatomical classification. However, we considered for the analysis only intrahepatic CCA and possibly perihilar CCA, excluding distal CCA, GBC, and AVCs.…”

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus

“…Second, our previous observational studies conducted in patients with type 2 diabetes mellitus in Taiwan by using the nationwide NHI database suggest that metformin use is associated with a lower risk of various types of cancer, including lung cancer [24], colorectal cancer [25,27], breast cancer [37], thyroid cancer [38], bladder cancer [39], prostate cancer [40], endometrial cancer [41], ovarian cancer [42], cervical cancer [43], kidney cancer [44], oral cancer [45], gastric cancer [46], esophageal cancer [47], nasopharyngeal cancer [48], skin cancer [49], pancreatic cancer [50], hepatocellular cancer [51], biliary tract cancer [52], non-Hodgkin's lymphoma [53], and bone cancer [54]. These findings suggest that the anti-cancer effects of metformin may involve some common pathophysiological pathways in cancer development, probably targeting many of the hallmarks of cancer [55].…”