Type 2 diabetes is a disease where the body cannot properly regulate blood sugar levels. People with diabetes are at higher risk for many diseases, including gallbladder inflammation and gallstones. Incretin-based drugs, which include dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs), are a type of medication used to treat type 2 diabetes. GLP-1 RAs have been shown to increase the risk of gallbladder diseases, but the effect of DPP-4 inhibitors on gallbladder diseases remains unclear. Few studies have been conducted on this association. To address this question, we will use the Clinical Practice Research Datalink to conduct a large cohort study to determine whether the use of DPP-4 inhibitors or GLP-1 RAs is associated with an increased risk of gallbladder diseases. The findings of this study could have important implications for prescribing practices for patients with type 2 diabetes.
Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are second- to third-line treatments for type 2 diabetes that both exert their effects through GLP-1 signalling. GLP-1 RAs have been shown to increase the risk of gallbladder and bile duct diseases; however, it is unclear if DPP-4 inhibitors increase the risk of this outcome as well. A recently published meta-analysis of randomized controlled trials reported an increased risk of a composite of gallbladder or biliary diseases and of cholecystitis associated with use of DPP-4 inhibitors; however, this meta-analysis did not account for time-to-event data and used non-adjudicated data extracted from adverse event reporting. To our knowledge, only one observational study has evaluated the association between DPP-4 inhibitors and gallbladder and bile duct diseases and did not find an association.
Our study will explore the relationship between the use of DPP-4 inhibitors and GLP-1 RAs and gallbladder and bile duct diseases. We will assemble a cohort of patients aged 18 and older who were newly prescribed DPP-4 inhibitors, GLP-1 RAs, or sodium-glucose cotransporter-2 (SGLT-2) inhibitors between January 2013 and March 2021. We will use Cox proportional hazards models with propensity score fine stratification weighting to estimate hazard ratios and 95% confidence intervals of gallbladder and bile duct disease incidence separately comparing DPP-4 inhibitor users and GLP-1 RA users to SGLT-2 inhibitor users. Gallbladder and bile duct disease will be identified using data from the CPRD and Hospital Episode Statistics, and mortality will be identified using data from the Office for National Statistics. We will conduct analyses to assess whether there is a duration-response or a dose-response relationship and whether the relationship varies by drug, age, sex, and body mass index. The findings of this study could have relevant implications for prescribing practices for patients with type 2 diabetes.
The study outcome will be the first occurrence of an incident gallbladder or bile duct disease during the follow-up period, which will be defined by ICD-10 codes.
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Corresponding Applicant - McGill University
Hui Yin - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Samantha Shapiro - Collaborator - McGill University
HES Admitted Patient Care;ONS Death Registration Data