title: Association of Bile Duct and Gallbladder Diseases With the Use of Incretin-Based Drugs in Patients With Type 2 Diabetes Mellitus.
abstract: OBJECTIVE
  The use of dipeptidyl-peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues-a group of drugs used in the management of type 2 diabetes mellitus-may be associated with an increased risk of bile duct and gallbladder disease. To date, no observational study has assessed this possible association.
  
  
  OBJECTIVE
  To determine whether the use of DPP-4 inhibitors and GLP-1 analogues is associated with an increased risk of incident bile duct and gallbladder disease in patients with type 2 diabetes.
  
  
  METHODS
  A population-based cohort study linked the United Kingdom Clinical Practice Research Datalink with the Hospital Episodes Statistics database, yielding a cohort of 71 369 patients, 18 years or older, initiating an antidiabetic drug (including oral and injectable agents) between January 1, 2007, and March 31, 2014.
  
  
  METHODS
  Current use of DPP-4 inhibitors and GLP-1 analogues (alone or in combination therapy) compared with current use of at least 2 oral antidiabetic drugs.
  
  
  METHODS
  Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of incident bile duct or gallbladder events (cholelithiasis, cholecystitis, cholangitis) causing hospitalization, comparing current use of DPP-4 inhibitors and GLP-1 analogues with current use of at least 2 oral antidiabetic drugs.
  
  
  RESULTS
  During 227 994 person-years of follow-up, 853 of the 71 369 patients were hospitalized for bile duct and gallbladder disease (incidence rate per 1000 person-years, 3.7; 95% CI, 3.5-4.0). Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (3.6 vs 3.3 per 1000 person-years; adjusted HR, 0.99; 95% CI, 0.75-1.32). In contrast, the use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease compared with current use of at least 2 oral antidiabetic drugs (6.1 vs 3.3 per 1000 person-years; adjusted HR, 1.79; 95% CI, 1.21-2.67). In a secondary analysis, GLP-1 analogues were also associated with an increased risk of cholecystectomy (adjusted HR, 2.08; 95% CI, 1.08-4.02).
  
  
  CONCLUSIONS
  The use of GLP-1 analogues was associated with an increased risk of bile duct and gallbladder disease. Physicians should be aware of this potential adverse event when prescribing these drugs.
authors.affiliation: Laboratory of Biostatistics, Epidemiology, and Public Health (Equipe d'Acceuil 2415), Faculty of Medicine, University of Montpellier, Montpellier, France2Department of Medical Pharmacology and Toxicology, Montpellier University Hospital, Montpellier, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Faillie
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada4Division of Endocrinology, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Oriana H
authors.initials: OH
authors.lastname: Yu
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Medical Pharmacology and Toxicology, Montpellier University Hospital, Montpellier, France5Institut National de la Santé et de la Récherche Médicale (INSERM), Unité 1058, Faculty of Medicine, University Montpellier 1, Montpellier, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Hillaire-Buys
authors.affiliation: Division of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Barkun
authors.affiliation: Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada7Department of Oncology, McGill University, Montreal, Quebec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Azoulay
mesh_terms: D000328:Adult; D001649:Bile Duct Diseases / Q000139:chemically induced* / Q000453:epidemiology; D002763:Cholecystectomy / Q000706:statistics & numerical data; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects*; D005260:Female; D005705:Gallbladder Diseases / Q000139:chemically induced* / Q000453:epidemiology; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D015994:Incidence; D008297:Male; D016016:Proportional Hazards Models; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D052216:Glucagon-Like Peptide 1