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

Devin Abrahami (1, 2) , Antonios Douros (2, 1, 3) , Hui Yin (1) , Oriana Hy Yu (1, 4) , Jean-Luc Faillie (5, 6) , François Montastruc (7, 1, 8) , Robert W Platt (1, 2) , Nathaniel Bouganim (9) , Laurent Azoulay (1, 2)

1 CCECS - Centre for Clinical Epidemiology and Community Studies [Montreal, Canada]
2 Department of Epidemiology, Biostatistics and Occupational Health [Montréal]
3 Institute of Clinical Pharmacology and Toxicology [Berlin, Germany]
4 Division of Endocrinology [Montreal, QC, Canada]
5 Département de Pharmacologie Médicale et de Toxicologie [CHRU Montpellier]
6 AIDMP - Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415
7 LEASP - Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps
8 CIC 1426 - Centre d'Investigation Clinique 1426
9 Department of Oncology [Montréal]

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.

Domaines: Pharmacologie; Endocrinologie et métabolisme; Cancer; Santé publique et épidémiologie

Devin Abrahami, Antonios Douros, Hui Yin, Oriana Hy Yu, Jean-Luc Faillie, et al.. Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study. BMJ, 2018, 363, pp.k4880. ⟨10.1136/bmj.k4880⟩. ⟨hal-02309224⟩