(A-010) Risk of Acute Pancreatitis Associated with the Use of Dipeptidyl Peptidase-4 Inhibitors: Application of the Trend-in-Trend Design

Background: There are conflicting findings regarding the risk of acute pancreatitis associated with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors between observational studies and randomized controlled trials, primarily due to the influence of confounding factors (e.g., HbA1c, obesity, beta-cell function status).

Objectives: To evaluate the risk of acute pancreatitis associated with use of DPP-4 inhibitor using trend-in-trend design.

Methods: We conduct the current study using data derived from the National Health Insurance Database, which covered more than 2.3 million Taiwanese patients. We applied trend-in-trend design to evaluate the risk of acute pancreatitis associated with the use of DPP-4 inhibitor. The trend‐in‐trend is a hybrid epidemiologic‐ecologic research design that examining trends in the frequency of the outcome of interest as a function of trends in exposure. The trend-in-trend method has been proposed to mitigate the impact of unmeasured confounders by estimating causal effects using population-level aggregate data. We enrolled patients with any diagnosis of type 2 diabetes mellitus (T2DM) between 2013 to 2021. Patients aged less than 20 years old and with prior diagnosis of T2DM between 2011 and 2012. The index date was defined as either the date of the first DPP-4 inhibitor prescription or a randomly selected date following the diagnosis of incident T2DM for patients without exposure to DPP-4 inhibitors. The risk of acute pancreatitis was analyzed using logistic regression, stratified by cumulative exposure probability and 90-day time intervals.

Results: We identified 2,101,584 T2DM patients with 543,715 patients ever exposed to DPP-4 inhibitor during the study period. The overall prevalence of DPP-4 inhibitor use increased from 0.51% to 14.44%, while the prevalence of acute pancreatitis rose slightly from 0.17% to 0.30% between 2013 and 2021. In the trend-in-trend analysis, the logistic regression model indicated a 1.6-fold increase in the risk of acute pancreatitis, with 95% confidence intervals (CI) ranging from 0.56 to 2.23. However, when we conducted a subgroup analysis by restricting the cohort to patients aged more than 65 years old, the use of DPP-4 inhibitor showed lower risk of acute pancreatitis (Odds ratio: 0.60; 95% CI 0.34-1.66). The result was consistent with previous meta-analyses based on randomized controlled trials.

Conclusions: Our findings suggested that the use of DPP-4 inhibitor was not associated with increase risk of acute pancreatitis.