What is the relationship between Glucagon-like peptide-1 (GLP-1) and pancreatitis?

From the Guidelines

GLP-1 receptor agonists should be used with caution in patients with a history of pancreatitis, as they may have a small but real association with acute pancreatitis, and alternative treatments should be considered to minimize the risk of morbidity and mortality. The association between GLP-1 receptor agonists and pancreatitis is supported by studies such as the one published in Anaesthesia in 2024 1, which notes that acute pancreatitis is a rare adverse effect linked to the use of exenatide. The American Association of Clinical Endocrinologists recommends using GLP-1 receptor agonists with caution in patients with a history of pancreatitis 1.

Some key points to consider when prescribing GLP-1 receptor agonists include:

• Patients with a history of pancreatitis should generally avoid these medications, including semaglutide, liraglutide, dulaglutide, and tirzepatide.
• If a patient on a GLP-1 RA develops severe abdominal pain, especially with radiation to the back, nausea, vomiting, or elevated pancreatic enzymes, the medication should be discontinued immediately and pancreatitis should be ruled out.
• The mechanism behind this association likely involves direct stimulation of pancreatic enzyme secretion and altered sphincter of Oddi function.
• The risk appears highest during the first months of therapy and in patients with gallstones, excessive alcohol use, hypertriglyceridemia, or prior pancreatic disease.
• While routine monitoring of pancreatic enzymes isn't recommended for asymptomatic patients, clinicians should maintain a low threshold for investigation when symptoms arise.

It's also important to note that the relationship between diabetes and pancreatitis is bidirectional, and people with diabetes are at an approximately twofold higher risk of developing acute pancreatitis, as reported in the 2024 standards of care in diabetes 1. However, the most recent and highest quality study on this topic is the 2024 narrative review of clinical pharmacology and implications for peri-operative practice published in Anaesthesia 1, which provides the most up-to-date guidance on the use of GLP-1 receptor agonists in patients with a history of pancreatitis.

From the FDA Drug Label

Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. (1) Has not been studied in patients with a history of pancreatitis. Consider another antidiabetic therapy (1,5.2)

GLP-1 and Pancreatitis: The FDA drug labels for exenatide (2) and semaglutide (3) do not provide direct evidence of a link between GLP-1 receptor agonists and pancreatitis. However, they do indicate that these medications have not been studied in patients with a history of pancreatitis, and recommend considering alternative antidiabetic therapies for such patients.

• Key points:
  • No direct study on GLP-1 and pancreatitis
  • Consider alternative therapies for patients with a history of pancreatitis

From the Research

GLP-1 and Pancreatitis Association

• The association between GLP-1 receptor agonists and the risk of pancreatitis has been studied in several research papers 4, 5, 6, 7, 8.
• A study published in the Journal of Clinical Medicine found that the use of GLP-1 receptor agonists did not increase the risk of pancreatitis in a comorbidity-free subgroup of patients with type 2 diabetes mellitus in the United States 4.
• Another study published in the Journal of Diabetes and Metabolic Disorders found that the risk of pancreatitis associated with GLP-1 agonists is dose-dependent, with higher cumulative doses associated with a higher risk of developing pancreatitis 5.

Risk of Pancreatitis with GLP-1 Receptor Agonists

• A systematic review and meta-analysis of randomized controlled trials found no evidence that treatment with GLP-1 receptor agonists increases the risk of acute pancreatitis in patients with type 2 diabetes 6.
• An updated meta-analysis of randomized controlled trials found that GLP-1 receptor agonists showed no association with pancreatitis and pancreatic cancer 7.
• A network meta-analysis found a neutral relationship between GLP-1 agonists and pancreatitis or pancreatic cancer compared with placebo 8.

Comparison of GLP-1 Agonists and Other Drugs

• A network meta-analysis compared the risk of pancreatitis associated with GLP-1 agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors in the treatment of type 2 diabetes mellitus, and found that both classes of drugs are safe with respect to the risk of pancreatitis and pancreatic cancer compared with placebo 8.
• The same study found that lixisenatide and saxagliptin may be the safest drugs compared with other drugs according to the ranking of probability 8.