Nationwide Trends in Pancreatitis and Pancreatic Cancer Risk Among Patients With Newly Diagnosed Type 2 Diabetes Receiving Dipeptidyl Peptidase 4 Inhibitors

Abstract

OBJECTIVE Dipeptidyl peptidase 4 inhibitors (DPP-4i) are useful incretin-based antidiabetes drugs. However, there is a concern that DPP-4i may adversely impact the exocrine pancreas, owing to their pleiotropic effects. In this study, we investigated whether DPP-4i are associated with pancreatitis and pancreatic cancer using a nationwide population-based cohort study. RESEARCH DESIGN AND METHODS We included patients newly diagnosed with type 2 diabetes who were treated with antidiabetes drugs (n = 33,208) from 2007 to 2013. The data were obtained from the Korean National Health Insurance Service–Health Screening Cohort database (n = 514,866). Risk was estimated using a Cox proportional hazards model with time-dependent covariates. A 6-month lag time was used to account for a possible latency time. The risk across various time segments since the first prescription of DPP-4i was also analyzed. RESULTS Out of 33,208 subjects, 10,218 were new users of DPP-4i and 22,990 were new users of other antidiabetes drugs. DPP-4i significantly increased the risks of pancreatitis (adjusted hazard ratio [aHR] 1.24, 95% CI 1.01–1.52; P = 0.037) and pancreatic cancer (aHR 1.81, 95% CI 1.16–2.82; P = 0.009) with a 6-month drug use lag period. The risk of pancreatitis and pancreatic cancer was generally consistent in the first 12 months and 1 year after the initial prescription without showing an increasing trend according to exposure duration. CONCLUSIONS DPP-4i use is associated with increased risks of pancreatitis and pancreatic cancer in patients with newly diagnosed type 2 diabetes. However, the absence of increasing trend according to exposure duration suggests the chances of reverse causality, and long-term pancreatic safety of DPP-4i has to be further investigated.

Metformin and Gastrointestinal Cancer Development in Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea

“…Thus, it was impossible to consider the magnitude of DM control because we did not have available data on hemoglobin A1c levels. Second, the claims do not contain important GI cancer-related information, such as family medical history, obesity, drinking, and smoking ( 27 – 30 ), which may have introduced some bias into our findings. Third, this study had a relatively short follow-up duration because it takes an average of 10–20 years for normal colonic crypts to develop into overt adenocarcinoma ( 31 ).…”

“…The complexity of this association may explain the varying findings on the association between metformin use and pancreatic cancer. Furthermore, Lee et al ( 27 ) reported that dipeptidyl peptidase-4 inhibitors increased the risk of pancreatic cancer among patients with newly diagnosed type 2 diabetes. However, there was no increasing trend according to duration of exposure.…”

Potential linkage between dipeptidyl peptidase‐4 inhibitor use and the risk of pancreatitis/pancreatic cancer

“…According to a study by Lee et al. , the treatment duration with DPP‐4 inhibitors did not appear to influence the risk profiles for pancreatitis and pancreatic cancer associated with DPP‐4 inhibitor use, although the follow‐up period of the study was limited. Because a trend toward an increase of the risk with the exposure duration was absent, there is a chance of reverse causality having influenced the results of that study.…”

“…Lee et al . from the Yonsei University College of Medicine in Korea also investigated the associations between DPP‐4 inhibitor use and the risk of pancreatitis and pancreatic cancer, using the Korean National Health Insurance Service‐Health Screening Cohort database.…”

CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology

“…More recently, Lee et al also reported that DPP-4 inhibitor users have a 50% increased risk of pancreatic cancer incidence (aHR 1.50, 95%CI: 1.02–2.20) among newly diagnosed T2DM patients. It is likely that such a risk was increased during the early exposure period of DPP-4 inhibitor prescription [ 116 ]. Sitagliptin also increased the risk of thyroid cancer only in the first year of its use [ 105 ].…”