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BMJ. 2018 Dec 5;363:k4880. doi: 10.1136/bmj.k4880.

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

Author information

1
Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Sainte-Catherine Road, H425.1, Montreal, QC, H3T 1E2, Canada.
2
Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada.
3
Institute of Clinical Pharmacology and Toxicology, Charité University Medicine Berlin, Berlin, Germany.
4
Division of Endocrinology, Jewish General Hospital, Montreal, QC, Canada.
5
Department of Medical Pharmacology and Toxicology, CHU Montpellier; Laboratory of Biostatistics, Epidemiology and Public Health, University of Montpellier, Montpellier, France.
6
Department 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
Department of Oncology, McGill University Health Centre, Montreal, QC, Canada.
8
Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
9
Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Cote Sainte-Catherine Road, H425.1, Montreal, QC, H3T 1E2, Canada laurent.azoulay@mcgill.ca.

Abstract

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.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf 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.

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