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Mechanisms Underlying Gut Hormone Secretion Using the Isolated Perfused Rat Small Intestine
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The pancreatic signal of GLP-1 receptor agonists: A biliary phenomenon rather than direct toxicity

Andro Koren1, Luciana Koren1

  • 1School of Medicine, University of Zagreb, Zagreb, Croatia.

British Journal of Clinical Pharmacology
|March 5, 2026
PubMed

Insights

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show no independent link to acute pancreatitis. A temporary risk increase in early treatment is likely due to weight loss and gallbladder issues, not direct GLP-1 RA toxicity.

Area of Science:

  • Endocrinology
  • Gastroenterology
  • Pharmacology

Background:

  • Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are key treatments for type 2 diabetes mellitus (T2DM) and obesity.
  • Initial concerns about GLP-1 RA pancreatic toxicity have been largely alleviated by recent human studies.
  • Cardioprotective benefits of GLP-1 RAs are well-established.

Purpose of the Study:

  • To re-evaluate the association between GLP-1 RA use and acute pancreatitis (AP).
  • To investigate the mechanism behind the observed transient increase in AP risk during early GLP-1 RA therapy.
  • To inform clinical practice regarding the safe use of GLP-1 RAs.

Main Methods:

  • Meta-analyses of randomized controlled trials (RCTs) were conducted to assess the independent risk of AP with GLP-1 RA use.
  • Real-world data analysis was performed to examine the temporal risk of AP during the initial months of GLP-1 RA treatment.
  • A mechanistic hypothesis involving biliary pathways and cholecystokinin (CCK) inhibition was proposed.

Main Results:

  • Meta-analyses of RCTs found no statistically significant independent association between GLP-1 RAs and AP (MH-OR 1.24 [0.94, 1.64]; P=.13).
  • Real-world data revealed a transient increase in AP risk within the first six months of GLP-1 RA therapy (HR 1.340; P=.019).
  • The observed 'pancreatic signal' is hypothesized to be an indirect, biliary-mediated effect linked to rapid weight loss and drug-induced gallbladder dysmotility via CCK inhibition.

Conclusions:

  • Contemporary evidence suggests GLP-1 RAs do not independently cause acute pancreatitis.
  • The transient AP risk observed early in treatment is likely a secondary effect of rapid weight loss and gallbladder dysmotility.
  • Clinical management should focus on proactive biliary monitoring during the initial 24 weeks of GLP-1 RA therapy rather than restricting use.

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