Dipeptidyl Peptidase-4 Inhibitors and the Risk of Biliary Tract Diseases Among Patients With Type 2 Diabetes

Background: A recent meta-analysis of randomized controlled trials reported an increased risk of gallbladder and bile duct diseases associated with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, a commonly prescribed class of antihyperglycemic drugs. However, there is limited real-world evidence of this possible association.

Objectives: To determine whether the use of DPP-4 inhibitors is associated with an increased risk of gallbladder and bile duct diseases when compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors among patients with type 2 diabetes.

Methods: Using data from the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episodes Statistics and Office for National Statistics databases, we assembled a cohort of patients with type 2 diabetes who were newly prescribed DPP-4 inhibitors or SGLT-2 inhibitors between 1 January 2013 and 31 December 2020, with follow-up until 29 March 2021. Propensity score fine stratification weighting was used to balance the exposure groups on over 40 potential confounders, which included age, sex, smoking, body mass index, proxies for diabetes severity, common comorbidities, other medication use, and markers of health-seeking behaviour. Patients were followed using an on-treatment exposure definition. We fit weighted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident biliary tract disease, comparing the use of DPP-4 inhibitors with SGLT-2 inhibitors. In secondary analyses, we assessed the presence of a duration-response relation according to the following categories: <6 months, 6–12 months, and >12 months use.

Results: The cohort included 147,934 new users of DPP-4 inhibitors and 52,922 new users of SGLT-2 inhibitors. After a median follow-up of 0.74 years, the use of DPP-4 inhibitors was associated with an increased risk of biliary tract diseases compared with the use of SGLT-2 inhibitors (4.3 vs. 3.0 events per 1,000 person-years, respectively; HR 1.46, 95% CI 1.17–1.83). The association was highest in the first 6 months of use (HR 1.92, 95% CI 1.31–2.82) and decreased with subsequent durations of use (6¬-12 months, HR 1.18, 95% CI 0.68–2.06; >12 months, HR 1.26, 95% CI 0.87–1.81).

Conclusions: In this large, population-based study from the United Kingdom, the use of DPP-4 inhibitors was associated with an increased risk of gallbladder and bile duct disease, particularly in the first six months of use.