It is theorized that patients who are taking a GLP-1 agonist are at a greater risk for pancreatitis due to the medication causing an increase in stimulation of GLP-1 receptors located in the pancreas. This could lead to an overgrowth or overactivation of pancreatic cells which could theoretically lead to inflammation and damage. Another theory involves GLP-1 agonists causing the digestive system to slow down resulting in the accumulation of enzymes in the pancreas. Theories are all well and good, but what data do we have on GLP-1 agonists and pancreatitis?
Evidence of Risk
GLP-1 agonists have become a popular choice for patients who are looking to lose weight and/or have type 2 diabetes. Although this drug class has thought to have a low-risk side effect profile, the risk of developing pancreatitis may be concerning to patients and healthcare professionals. This concern may have stemmed from a study that looked at post-marketing FDA adverse event reports from exenatide and sitagliptin usage from 2004-2009. It found that there was a greater than 6-fold increase in pancreatitis (odds ratio=10.68 in Exenatide patients). 2This study also found that patients on Exenatide were 2.9 times more likely to be diagnosed with pancreatic cancer. Although these numbers are reason to be concerned, data was pulled from AERS which has potential flaws due to incomplete information and reporting bias.
GLP-1 Agonists and Pancreatitis – Supporting Data
One meta-analysis study looking at over 14,000 participants involved in 80 trials found that there was no significant increase in the risk of pancreatitis associated with the use of GLP-1 agonist. These trials were compared against placebo along with other diabetic medications.4 In a second meta-analysis study from 2019, which collected data from large-scale cardiovascular outcome trials, found that of the 56,004 patients on a GLP-1 agonist with type 2 diabetes, 180 experienced acute pancreatitis, and 108 cases of pancreatic cancer were reported.1These numbers were not significantly different than patients in the placebo arm. Lastly, in the SURPASS-2 trial, of the 1878 patients either prescribed Tirzepatide or Semaglutide, 7 participants experienced pancreatitis.
In an American College of Gastroenterology Scientific meeting back in October 2022, healthcare professionals discussed results from their single-center study from an academic institution weight wellness program involving 2,245 participants (who were not diagnosed with type 2 diabetes) in which they gave more guidance on what puts people at higher risk for acute pancreatitis.6 These included things like tobacco use, advanced chronic kidney disease (stage III or greater), and type 2 diabetes. An interesting note about the study was that a higher BMI appeared to be protective against acute pancreatitis. There was no association between age, sex, and history of bariatric surgery in developing acute pancreatitis after GLP-1 usage. It was also brought up that known clinical risk factors for acute pancreatitis such as prior history, gallstone disease, and alcohol use were not associated with an increased risk of acute pancreatitis after starting a GLP-1 agonist in patients using it for weight loss.
Case reports of the safe use of GLP-1 agonists in patients with a pancreatitis history do exist. In one such case report, a 51-year-old male, with a past medical history of diabetes, hypertension, and dyslipidemia, reported to the emergency department for back/abdominal pain, nausea, and vomiting. Lab values showed triglycerides: 7,686 mg/dL, serum lipase: 7,901 U/L, and serum amylase: 39 U/L.5The patient denied any history of alcohol, and ultrasound ruled out gallstones. At his 2 month- follow up appointment, the patient expressed interest in discontinuing insulin therapy. The provider suggested Exenatide 2mg extended release weekly. The patient was informed about the risk of pancreatitis and the medication was started. The patient came back after 15 months of being on Exenatide and reported no symptoms associated with pancreatitis. Lab values from that visit showed amylase: 43U/L, lipase: 34U/L, and triglycerides: 102mg/dL. This report demonstrated that it is not a complete contraindication to administer GLP-1 agonists in a patient with a history of acute pancreatitis.
Although the link between GLP-1 agonists and pancreatitis remains a question for debate among medical professionals, the overall risk is low and the benefits of using the medication include but are not limited to reducing a1C and weight. The most recent evidence suggests that the risk is lower than previously thought and some studies have shown no significant differences between placebo and treatment groups. It is important that each person who starts on a GLP-1 agonist know the risks and benefits to help guide their decision on what’s best for them. Identifying potential alternative medications, assessment of pancreatitis risk factors, and careful monitoring, are all important tenets in addressing GLP-1 agonists and pancreatitis.
Looking for more on GLP-1 agonists? Check out this previous article on drug interactions.
Endocrine Medication Podcasts Including GLP-1 Agonists
This article was written by Cody Springer PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP
- Cao, Chuqing et al. “GLP-1 receptor agonists and pancreatic safety concerns in type 2 diabetic patients: data from cardiovascular outcome trials.” Endocrine vol. 68,3 (2020): 518-525. doi:10.1007/s12020-020-02223-6
- Elashoff, Michael et al. “Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.” Gastroenterology vol. 141,1 (2011): 150-6. doi:10.1053/j.gastro.2011.02.018
- Frías, Juan P et al. “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.” The New England journal of medicine vol. 385,6 (2021): 503-515. doi:10.1056/NEJMoa2107519
- Monami, Matteo et al. “Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials.” Diabetes research and clinical practice vol. 103,2 (2014): 269-75. doi:10.1016/j.diabres.2014.01.010
- Sean M. Brady 1, et al. “GLP-1 Agonist Use in a Patient with an Explainable Cause of Pancreatitis.” AACE Clinical Case Reports, Elsevier, 28 Dec. 2020, www.sciencedirect.com/science/article/pii/S2376060520302881#:~:text=GLP%2D1%20receptors%20are%20expressed,acute%20inflammation%2C%20potentially%20causing%20acute.
- Staff. “Factors That Increase Pancreatitis Risk with GLP-1 Initiation.” U.S. Pharmacist – The Leading Journal in Pharmacy, 2 Nov. 2022, www.uspharmacist.com/article/factors-that-increase-pancreatitis-risk-with-glp1-initiation