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Abrahami et al(1) concludes that the use of dipeptidyl peptidase-4 (DPP-4) inhibitors might be associated with increased risk of cholangiocarcinoma (CCA) and suggests that this is biologically plausible due to the proliferative and anti-apoptotic effects of incretin based drugs on cholangiocytes. However, proliferation or immortalization does not automatically lead to cancers, and there is no evidence that DPP-4 inhibitors are carcinogenic. The duration of exposure (around 2 years) is also short; in a recent epidemic from Japan involving workers exposed to chemicals in printing works, duration of exposure ranged from 7 – 17 years(2).
Incidence of CCA has been increasing in developed countries. An earlier report using 32P postlabelling studies demonstrated DNA-adducts (a biomarker of genotoxin exposure) in samples of CCA from UK(3) but the origin of these environmental genotoxins were never studied. It is possible that DPP-4 inhibitors are acting as promoters (rather than initiators) in a background of cholangiocytes already genetically damaged by an environmental carcinogen. The increasing use of DPP-4 inhibitors warrants urgent investigation into identifying the possible mutagen(s) before we are faced with an epidemic. Abrahmi’s study is a wake-up call and should be taken with the seriousness it deserves.
1. Abrahami D, Douros A, Yin H, et al. Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study. BMJ. 2018 Dec 5;363: k4880. doi: 10.1136/bmj.k4880.
2. Kumagai S, Kurumatani N, Arimoto A, Ichihara G. Cholangiocarcinoma among offset colour proof‐printing workers exposed to 1,2‐dichloropropane and/or dichloromethane. Occup Environ Med. 2013;70:508–10.
3. Khan SA, Carmichael PL, Taylor-Robinson SD, Habib N, Thomas HC. DNA adducts, detected by 32P postlabelling, in human cholangiocarcinoma. Gut. 2003;52:586-91.
No competing interests
08 December 2018
Senior Consultant Oncology
National Oncology Center, The Royal Hospital, Oman
Senior Consultant Oncology, National Oncology Center, The Royal Hospital, Muscat, Sultanate of Oman