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

Sep 13, 2025Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists

Risk of Pancreatic Problems with Different Diabetes Medicines in Adults with Type 2 Diabetes and Moderate Heart Disease Risk

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Abstract

The weighted study cohort included 388,262 patients starting various diabetes medications.

SGLT2 inhibitors (SGLT2i) may lower the risk of acute pancreatitis compared to dipeptidyl peptidase-4 inhibitors (DPP-4i).
Sulfonylureas are associated with a higher risk of acute pancreatitis compared to GLP-1 receptor agonists (GLP-1RA) and SGLT2i.
No significant difference in acute pancreatitis risk was observed between GLP-1RA and DPP-4i or GLP-1RA and SGLT2i.
GLP-1RA therapy is linked to a lower risk of pancreatic cancer compared to DPP-4i.
In contrast, SGLT2i and sulfonylureas are associated with a higher risk of pancreatic cancer compared to GLP-1RA.

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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.

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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

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