Risk of Pancreatic Adenocarcinoma in Patients on Oral Hypoglycemic Agents for Type 2 Diabetes Mellitus

Introduction: Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the United States (US). Seminal studies have linked diabetes mellitus (DM) with PDAC, but studies are lacking on the role of oral hypoglycemic agents (OHAs) in the risk of PDAC. We sought to investigate the effect of antidiabetic medications on the risk of developing PDAC. Methods: We performed a retrospective cohort study using administrative claims data from TriNetX, a multi-institutional database of over 79 million patients across 49 healthcare organizations. Patients ≥18 years old with a diagnosis of type 2 DM (T2DM) determined by the ICD-10 codes and a hemoglobin A1c ≥ 6.5 2006-2022 were included in the analysis cohort. Patients with a history of pancreas surgery and/or PDAC before a diagnosis of T2DM and neuroendocrine tumors were excluded from the study. OHAs were divided into DPP-4 inhibitors, SGLT-2 inhibitors, thiazolidinediones (TZDs), GLP-1 agonists, and metformin. We assessed PDAC risk in patients on different OHAs compared to metformin and insulin therapy after 1:1 propensity score matching (PSM) for age, gender, race, tobacco, alcohol, chronic pancreatitis, exocrine pancreatic insufficiency, BMI, and family history of GI or pancreatic malignancy. The risk was expressed as adjusted odds ratios (aOR) with 95% confidence intervals. Results: In the analysis, 5 medication classes were studied: Metformin (N=267,252), DPP-4 inhibitors (N=37,482), Thiazolidinediones (N=18,460), GLP-1 receptor agonists (N=11,497), and SGLT-2 inhibitors (N=5,625). PDAC incidence was highest in patients on TZDs (0.27%), followed by DPP-4 inhibitors (0.25%), SGLT-2 inhibitors (0.17%), and GLP-1 receptor agonists (0.13%). After PSM, DPP-4 inhibitors (aOR 0.62, 95% CI 0.48-0.81) and GLP-1 receptor agonists (aOR 0.41, 95% CI 0.22-0.75) were associated with a decreased risk of PDAC compared to insulin therapy. No significant difference in PDAC risk was observed between Metformin and DPP-4 inhibitors (aOR 1.1, 95% CI 0.82-1.48), GLP-1 receptor agonists (aOR 0.78, 95% CI 0.40-1.55), SGLT-2 inhibitors (aOR 1, 95% CI 0.41-2.41), and TZDs (aOR 1.25, 95% CI 0.82-1.91) (Table 1). Conclusion: Among all antidiabetic medications studied, TZDs had the highest incidence of PDAC while GLP-1 receptors had the least incidence. More research is needed to ascertain the impact of OHA on PDAC risk particularly in patients at highest risk. Table 1. - Comparing the Risk of Pancreatic Adenocarcinoma in Patients on Oral Hypoglycemic Agents to Metformin and Insulin After Propensity Score Matching Risk of PDAC N % aOR 95% CI P-value DPP4 95 0.25 1.1 0.82-1.48 0.5 Metformin 86 0.23 GLP-1 15 0.13 0.78 0.40-1.55 0.49 Metformin 19 0.16 SGLT-2 10 0.17 1 0.41-2.41 0.99 Metformin 10 0.17 Thiazolidinediones 49 0.27 1.25 0.82-1.91 0.28 Metformin 39 0.22 DPP4 95 0.25 0.62 0.48-0.81 0.0004 Insulin 150 0.40 GLP-1 15 0.13 0.41 0.22-0.75 0.003 Insulin 36 0.31 SGLT-2 10 0.17 0.55 0.25-1.19 0.12 Insulin 18 0.32 Thiazolidinediones 49 0.27 0.87 0.59-1.27 0.47 Insulin 56 0.31