How does Ozempic (semaglutide) cause pancreatitis?

From the Guidelines

Ozempic (semaglutide) can potentially cause pancreatitis through several mechanisms, including direct stimulation of pancreatic acinar cells, gallbladder dysfunction, and ductal hypertension, as noted in the most recent study 1. The medication works by mimicking GLP-1 (glucagon-like peptide-1), which stimulates insulin secretion and slows gastric emptying. This action increases pancreatic enzyme production and may lead to pancreatic inflammation in susceptible individuals. Key points to consider:

• Ozempic can cause direct stimulation of pancreatic acinar cells, leading to excessive enzyme production that can trigger autodigestion of pancreatic tissue.
• It may cause gallbladder dysfunction and gallstone formation, which are known risk factors for pancreatitis.
• The medication can also cause ductal hypertension by increasing pancreatic secretions while potentially causing sphincter of Oddi dysfunction, creating a backup of digestive enzymes within the pancreas.
• Patients with a history of pancreatitis, gallbladder disease, or excessive alcohol consumption are at higher risk, as indicated in the study 1.
• Warning signs include severe abdominal pain radiating to the back, nausea, vomiting, and elevated pancreatic enzymes.
• If these symptoms occur, patients should immediately discontinue Ozempic and seek medical attention, as recommended in the guidelines 2. The American Gastroenterological Association suggests using semaglutide 2.4 mg with lifestyle modifications for the long-term treatment of obesity, but also notes the potential increased risk of pancreatitis and gallbladder disease, as seen in the study 2. Overall, while the exact mechanisms of Ozempic-induced pancreatitis are complex and multifactorial, the most recent evidence suggests that it is a rare but potential side effect of the medication, and patients should be closely monitored for warning signs, as recommended in the study 1.

From the FDA Drug Label

5. 2 Pancreatitis

In glycemic control trials, acute pancreatitis was confirmed by adjudication in 7 OZEMPIC-treated patients (0.3 cases per 100 patient years) versus 3 in comparator-treated patients (0. 2 cases per 100 patient years). One case of chronic pancreatitis was confirmed in an OZEMPIC-treated patient. After initiation of OZEMPIC, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting) If pancreatitis is suspected, OZEMPIC should be discontinued and appropriate management initiated; if confirmed, OZEMPIC should not be restarted.

The exact mechanism of how Ozempic (semaglutide) causes pancreatitis is not directly stated in the drug label. However, it is noted that acute pancreatitis was confirmed in some OZEMPIC-treated patients, indicating a potential association between the use of Ozempic and the development of pancreatitis.

• Key points:
  • Ozempic may be associated with an increased risk of pancreatitis.
  • Patients should be monitored for signs and symptoms of pancreatitis after initiation of Ozempic.
  • If pancreatitis is suspected or confirmed, Ozempic should be discontinued and appropriate management initiated. 3

From the Research

Mechanism of Ozempic (Semaglutide) Induced Pancreatitis

• The exact mechanism of semaglutide-induced pancreatitis is not fully understood, but several studies suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may increase the risk of pancreatitis 4, 5, 6.
• A study published in 2024 reported a case of semaglutide-induced acute pancreatitis leading to death after four years of use, with a dose increase occurring four weeks prior to admission 4.
• Another study published in 2023 presented a case of acute pancreatitis in a patient taking semaglutide, highlighting the potential link between GLP-1RA use and pancreatitis 5.
• A retrospective case-control study published in 2025 found that the risk of developing pancreatitis increases with the administered dose of GLP-1 agonist, suggesting a dose-dependent relationship 6.

Risk Factors and Associations

• The studies suggest that patients with a high cumulative dose of GLP-1 agonist are associated with a higher risk of developing drug-induced pancreatitis 6.
• A study published in 2012 reviewed the evidence surrounding a potential association between liraglutide (another GLP-1RA) and pancreatitis, and found that pancreatitis is a potential complication with liraglutide therapy, particularly in patients at risk of pancreatitis (e.g., alcohol abuse, history of pancreatitis, cholelithiasis) 7.
• The absence of typical risk factors in some cases suggests a potential link between long-term use and dose changes of GLP-1RAs and severe pancreatitis 4.

Clinical Implications

• Clinicians should be aware of the potential risk of acute pancreatitis associated with GLP-1RA use, particularly with high cumulative doses or dose increases 4, 5, 6.
• Patients taking semaglutide or other GLP-1RAs should be monitored for signs and symptoms of pancreatitis, and the medication should be used cautiously in patients at risk of pancreatitis 7.