Incretin-Based Drugs Not Tied to Increased Risk of Acute Pancreatitis Among Diabetics: Study
USA: Researchers have found in a new study that among patients with type 2 diabetes, incretin-based medications (GLP-1 receptor agonists and DPP-4 inhibitors) were not linked to an increased risk of acute pancreatitis when compared with SGLT2 inhibitors. However, their use was associated with a small but notable increase in the risk of biliary disease.
People with type 2 diabetes are already known to have a higher baseline risk of acute pancreatitis and biliary complications, making medication safety in this population an ongoing clinical concern. Incretin-based therapies, widely prescribed for glycaemic control and cardiometabolic benefits, have previously been scrutinised for potential pancreatic and biliary adverse effects, with inconsistent findings across earlier studies.
To clarify these associations, researchers led by Yichen E. Fang from the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School conducted a large real-world analysis using U.S. claims data.
The study, published in Diabetes Care, evaluated adult patients with type 2 diabetes who initiated treatment with GLP-1 receptor agonists, DPP-4 inhibitors, or SGLT2 inhibitors between 2014 and 2021. Using Medicare Fee-for-Service data alongside two large commercial insurance databases, the investigators assembled three pairwise comparison cohorts, each including more than 1.2 million patients. Individuals with a prior history of acute pancreatitis, biliary disease, pancreatic or biliary cancer, or bariatric surgery were excluded to reduce confounding.
To ensure balanced comparisons, the researchers applied propensity score–based fine stratification weighting using 92 clinical and demographic variables. The primary outcomes were hospitalisation for acute pancreatitis or for biliary events, assessed through diagnostic coding and follow-up data.
The analysis revealed the following findings:
- Initiation of GLP-1 receptor agonists was associated with a risk of acute pancreatitis similar to that observed with SGLT2 inhibitors.
- Use of DPP-4 inhibitors also showed a comparable risk of acute pancreatitis when compared with SGLT2 inhibitors.
- Hazard ratios for acute pancreatitis were close to one, indicating no meaningful increase in pancreatitis risk with incretin-based therapies.
- Direct comparison between GLP-1 receptor agonists and DPP-4 inhibitors showed no significant difference in the risk of acute pancreatitis.
- A modestly higher risk of biliary disease was observed among patients initiating incretin-based medications compared with those starting SGLT2 inhibitors.
- Both GLP-1 receptor agonists and DPP-4 inhibitors were associated with increased hazard ratios for biliary events relative to SGLT2 inhibitors.
- The absolute increase in biliary risk was small, amounting to fewer than one additional biliary event per 1,000 person-years.
- No significant difference in biliary disease risk was found between GLP-1 receptor agonists and DPP-4 inhibitors.
The authors noted that these findings align with earlier signals linking incretin therapies to gallbladder-related events, possibly mediated by effects on gallbladder motility or weight loss. They emphasised that while the absolute risk is low, clinicians should consider biliary risk factors when prescribing these agents.
"Overall, the study provides reassurance regarding pancreatitis risk while underscoring the importance of individualized benefit–risk assessment, particularly for patients with type 2 diabetes who may already be at risk for biliary disease," the authors concluded.
Reference:
Yichen E. Fang, Julie M. Paik, Janinne Ortega-Montiel, Helen Tesfaye, Deborah J. Wexler, Elisabetta Patorno; Risk of Acute Pancreatitis and Biliary Events After Initiation of Incretin-Based Medications in Patients With Type 2 Diabetes. Diabetes Care 20 November 2025; 48 (12): 2127–2137. https://doi.org/10.2337/dc25-1840
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