Comparative Risk of Adverse Pancreatic Events With GLP-1 Receptor Agonists, SGLT2 Inhibitors, DPP4 Inhibitors, and Sulfonylureas Among Adults With Type 2 Diabetes at Moderate Cardiovascular Disease Risk.
Publication Title
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
Document Type
Article
Publication Date
9-11-2025
Keywords
DPP-4 inhibitor; GLP-1 receptor agonist; causal inference; incretin; target trial; type 2 diabetes.; washington; spokane; pmrc
Abstract
OBJECTIVE: Evidence on acute pancreatitis and pancreatic cancer with glucagon-like peptide-1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy is mixed, and no studies examined this risk directly across all commonly used classes of type 2 diabetes medications, particularly sodium-glucose cotransporter 2 inhibitors (SGLT2is) and sulfonylureas.
METHODS: De-identified claims data from OptumLabs Data Warehouse and fee-for-service Medicare were used to emulate a target trial examining the risks of incident acute pancreatitis and pancreatic cancer among adults with type 2 diabetes and moderate cardiovascular risk. Propensity scores (estimated using the SuperLearner ensemble method) and inverse probability of treatment weighting emulated random treatment assignment to GLP-1RA, DPP-4i, SGLT2i, or sulfonylurea.
RESULTS: The weighted study cohort included 388 262 patients starting GLP-1RA (N = 44 084), DPP-4i (N = 82 079), SGLT2i (N = 56 463), or a sulfonylurea (N = 205 636). SGLT2i was associated with a lower risk of acute pancreatitis compared with DPP-4i (hazard ratio [HR], 0.82; 95% CI, 0.68-0.98). Conversely, sulfonylurea was associated with a higher risk compared with GLP-1RA (HR, 1.28; 95% CI, 1.03-1.56) and SGLT2i (HR, 1.32; 95% CI, 1.12-1.57). There was no difference in acute pancreatitis risk between GLP-1RA and DPP-4i or GLP-1RA and SGLT2i. The risk of pancreatic cancer was lower with GLP-1RA compared with DPP-4i (HR, 0.56; 95% CI, 0.40-0.77). In contrast, risk was higher with SGLT2i and sulfonylurea compared with GLP-1RA (HR, 1.67; 95% CI, 1.12-2.49 and HR, 1.60; 95% CI, 1.17-2.19, respectively).
CONCLUSION: GLP-1RA and DPP-4i therapy was not associated with increased risk of adverse pancreatic events. The lower risk of acute pancreatitis with SGLT2i therapy warrants further exploration.
Area of Special Interest
Cardiovascular (Heart)
Area of Special Interest
Kidney & Diabetes
Specialty/Research Institute
Cardiology
Specialty/Research Institute
Endocrinology
Specialty/Research Institute
Nephrology
DOI
10.1016/j.eprac.2025.09.004
