Intended for healthcare professionals

CCBYNC Open access

Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study

BMJ 2018; 363 doi: (Published 05 December 2018) Cite this as: BMJ 2018;363:k4880

Linked editorial

Incretins and cancer of the bile duct in type 2 diabetes

  1. Devin Abrahami, doctoral student12,
  2. Antonios Douros, postdoctoral fellow123,
  3. Hui Yin, statistician1,
  4. Oriana HY Yu, assistant professor and endocrinologist14,
  5. Jean-Luc Faillie, assistant professor of pharmacology5,
  6. François Montastruc, postdoctoral fellow16,
  7. Robert W Platt, professor of biostatistics12,
  8. Nathaniel Bouganim, assistant professor and oncologist78,
  9. Laurent Azoulay, associate professor of epidemiology and oncology128
  1. 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Sainte-Catherine Road, H425.1, Montreal, QC, H3T 1E2, Canada
  2. 2Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada
  3. 3Institute of Clinical Pharmacology and Toxicology, Charité University Medicine Berlin, Berlin, Germany
  4. 4Division of Endocrinology, Jewish General Hospital, Montreal, QC, Canada
  5. 5Department of Medical Pharmacology and Toxicology, CHU Montpellier; Laboratory of Biostatistics, Epidemiology and Public Health, University of Montpellier, Montpellier, France
  6. 6Department of Medical and Clinical Pharmacology, Centre of PharmacoVigilance and Pharmacoepidemiology, INSERM UMR 1027, CIC 1426, Toulouse University Hospital, Faculty of Medicine, University of Toulouse, France
  7. 7Department of Oncology, McGill University Health Centre, Montreal, QC, Canada
  8. 8Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada
  1. Correspondence to: L Azoulay laurent.azoulay{at} (or @laurentazoulay0 on Twitter)
  • Accepted 25 October 2018


Objective To determine whether use of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.

Design Population based cohort study.

Setting General practices contributing data to the UK Clinical Practice Research Datalink.

Participants 154 162 adults newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2017, followed until 31 March 2018.

Main outcome measures Use of DPP-4 inhibitors and GLP-1 receptor agonists was modelled as a time varying variable and compared with use of other second or third line antidiabetic drugs. All exposures were lagged by one year to account for cancer latency and to minimise reverse causality. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of incident cholangiocarcinoma associated with use of DPP-4 inhibitors and GLP-1 receptor agonists, separately. A post hoc pharmacovigilance analysis was conducted using the World Health Organization’s global individual case safety report database, VigiBase, to estimate reporting odds ratios of cholangiocarcinoma.

Results During 614 274 person years of follow-up, 105 incident cholangiocarcinoma events occurred (rate 17.1 per 100 000 person years). Use of DPP-4 inhibitors was associated with a 77% increased hazard of cholangiocarcinoma (hazard ratio 1.77, 95% confidence interval 1.04 to 3.01). Use of GLP-1 receptor agonists was associated with an increased hazard with a wide confidence interval (hazard ratio 1.97, 0.83 to 4.66). In the pharmacovigilance analysis, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased reporting odds ratios for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones (1.63, 1.00 to 2.66, 4.73, 2.95 to 7.58, respectively).

Conclusion Compared with use of other second or third line antidiabetic drugs, use of DPP-4 inhibitors, and possibly GLP-1 receptor agonists, might be associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.


  • Contributors: All authors conceived and designed the study. LA acquired the data. DA, AD, HY, and LA did the statistical analyses. All authors analysed and interpreted the data. DA wrote the manuscript, and all authors critically revised the manuscript. LA supervised the study and is the guarantor. All authors approved the final version of the manuscript and agree to be accountable for the accuracy of the work. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This study was funded by a foundation scheme grant from the Canadian Institutes of Health Research (FDN-333744). The sponsor had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: this study was funded by the Canadian Institutes of Health Research. RWP received consulting fees for work unrelated to this project from Amgen, Eli Lilly, Merck, and Pfizer. All other authors have no conflicts to disclose, and have no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The study protocol was approved by the independent scientific advisory committee of the Clinical Practice Research Datalink (protocol No 17_271RMn2A) and by the research ethics board of Jewish General Hospital, Montreal, Quebec, Canada.

  • Data sharing: No additional data available.

  • Transparency: The guarantor (LA) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This is an Open Access article 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:

View Full Text