The incretin-based drugs, which include dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogues are a relatively new class of drugs used to treat type 2 diabetes. These drugs have become increasingly popular since being introduced in the United Kingdom in 2007. These drugs effectively lower blood sugar without the side effects of other antidiabetic drugs. However, there is evidence that these drugs may be associated with cholangiocarcinoma (bile duct cancer), a rare but deadly cancer. To date, no observational study has been conducted to assess whether the use of the incretin-based drugs is associated with cholangiocarcinoma. Thus, using the Clinical Practice Research Datalink, we will investigate this possible link within a large group of patients with type 2 diabetes. This study will provide important information regarding the safety of the incretin-based drugs.
The incretin-based drugs are typically used as second-to-third line treatments in the management of type 2 diabetes. While they effectively lower blood glucose via the incretin system, there is some evidence that targeting this system may produce unintended effects. Indeed, the incretin-based drugs may be involved in the development of cholangiocarcinoma, through a mechanism potentially mediated by the expression of GLP-1 receptors on cholangiocytes. Patients with intrahepatic cholangiocarcinoma have increased expression of cholangiocytes in tumour tissues, and activation of the GLP-1 receptor via GLP-1 analogues has been shown to proliferate cholangiocytes in vitro and in vivo. To address this, we will assemble a cohort of approximately 190,000 patients newly-treated with antidiabetic drugs between 2007 and 2016, with follow-up until 2017. Use of the incretin-based drugs will be modelled as a time-varying variable, allowing a 1-year lag period for latency. Time-dependent Cox proportional hazards models will be used to estimate hazard ratios with 95% confidence intervals of cholangiocarcinoma associated with use of DPP-4 inhibitors or GLP-1 analogues, compared with use of 2 or more different antidiabetic drug classes. Secondary analyses will assess whether risk varies by duration of use, time since initiation or by type of cholangiocarcinoma (intrahepatic, extrahepatic or unspecified).
Cholangiocarcinoma.
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Corresponding Applicant - McGill University
Antonios Douros - Collaborator - McGill University
Devin Abrahami - Collaborator - McGill University
Hui Yin - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Jean-Luc Faillie - Collaborator - Montpellier University Hospital
Nathaniel Bouganim - Collaborator - McGill University
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Robert Platt - Collaborator - McGill University
HES Admitted Patient Care