What is the frequency of pancreatitis with semaglutide or tirzepatide?

Comment by InpharmD Researcher

While there is no standardized risk value of pancreatitis associated with GLP-1 receptor agonists, as the risk would likely vary from patient to patient, pooled data consistently suggest the risk of pancreatitis is not significantly increased compared to placebo.

Background

A recently published 2025 meta-analysis included 11 trials involving 85,373 participants to evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs). The analysis found the risk of acute pancreatitis to not be significantly increased with the use of GLP-1RAs compared to placebo (hazard ratio [HR] 1.02; 95% confidence interval [CI] 0.78 to 1.33). Overall, there was no difference in the risk of serious adverse events, including acute pancreatitis and severe hypoglycemia, between GLP-1RAs and placebo (risk ratio [RR] 0.95; 95% CI 0.90 to 1.01). However, it should be noted that treatment discontinuation due to adverse events occurred more frequently with GLP-1RAs compared to placebo (RR 1.51; 95% CI 1.18 to 1.94). [1]

Another meta-analysis published in 2024 evaluated the safety and efficacy of GLP-1RAs on cardiovascular events in overweight or obese non-diabetic patients. A total of 10 randomized controlled trials, comprising 29,325 patients, were included for analysis (n= 16,900 GLP-1RAs; n= 12,425 placebo). Of note, no significant difference was found between the groups for the odds of acute pancreatitis occurring (odds ratio [OR] 0.87; 95% CI 0.52 to 1.48; p= 0.62). [2]

Based on data from 43 trials reporting use of any GLP-1RA (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) compared to placebo or any other non-GLP-1RA drug, a 2023 meta-analysis found no association between GLP-1RAs as a whole when evaluating incidence of pancreatitis (OR 1.24; 95% CI 0.94 to 1.64; p= 0.13) or pancreatic cancer (OR 1.28; 95% CI 0.87 to 1.89; p= 0.20) when compared to placebo or non-GLP-1RA drugs. The authors noted data regarding pancreatic cancer was limited, hindering the formation of a firm conclusion, but suggested no clear evidence of risk for pancreatitis. [3]

In a comprehensive 2025 study, researchers propensity score-matched patients to evaluate the association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the risk of pancreatitis in a comorbidity-free subgroup of type 2 diabetes mellitus (T2DM) patients in the United States. The study identified a total of 969,240 patients with T2DM, divided into two cohorts: one group receiving GLP-1 RAs (93,608 patients) and another group not receiving these medications (875,632 patients). Notably, tirzepatide was not included in this analysis. Results of this analysis revealed that the risk of pancreatitis was not statistically different between the cohorts at six months (0.1% for both groups, p = 0.04). Over a more extended follow-up at one, three, and five years, the risk remained comparable but demonstrated a trend toward a lower incidence in the GLP-1 RA group at each time point (one year: 0.1% vs. 0.2%, p = 0.02; three years: 0.2% vs. 0.3%, p = 0.001; five years: 0.3% vs. 0.4%, p <0.001). Notably, the lifetime risk of pancreatitis was significantly lower in the GLP-1 RA cohort (0.3% vs. 0.4%, p <0.001). The findings suggest that in this specific comorbidity-free U.S. population, GLP-1 RA usage is not associated with an increased risk of pancreatitis. In fact, it correlates with a reduced lifetime risk, offering reassurance regarding the cardiovascular and glycemic benefits of these medications without heightened concern for pancreatitis. [4]

References:

[1] Badve SV, Bilal A, Lee MMY, et al. Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2025;13(1):15-28. doi:10.1016/S2213-8587(24)00271-7
[2] Singh S, Garg A, Tantry US, Bliden K, Gurbel PA, Gulati M. Safety and efficacy of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese non-diabetic patients. Curr Probl Cardiol. 2024;49(3):102403. doi:10.1016/j.cpcardiol.2024.102403
[3] Dankner R, Murad H, Agay N, Olmer L, Freedman LS. Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes. JAMA Netw Open. 2024;7(1):e2350408. doi:10.1001/jamanetworkopen.2023.50408
[4] Ayoub M, Chela H, Amin N, et al. Pancreatitis Risk Associated with GLP-1 Receptor Agonists, Considered as a Single Class, in a Comorbidity-Free Subgroup of Type 2 Diabetes Patients in the United States: A Propensity Score-Matched Analysis. J Clin Med. 2025;14(3):944. Published 2025 Feb 1. doi:10.3390/jcm14030944
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the frequency of pancreatitis with semaglutide or tirzepatide?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Table 1 for your response.

 

Acute Pancreatitis Caused by Tirzepatide

Design

 Case report

Case presentation

A 59-year-old Caucasian male with a medical history of type 2 diabetes mellitus (T2DM), hyperlipidemia, and hypertension presented to the emergency department (ED) with severe epigastric pain. Initially, he experienced abdominal fullness, which he attributed to bloating or constipation. The symptoms progressed to include nausea and repeated non-bloody vomiting, eventually culminating in severe upper abdominal pain spanning from the epigastric to the periumbilical region. He denied prior incidences of pancreatitis or similar symptoms and reported no use of alcohol or illicit drugs. The patient had been on Ozempic (semaglutide) 1 mg weekly and had recently switched to Mounjaro (tirzepatide) 7.5 mg weekly, starting just before the onset of symptoms.

Upon arrival, he met the systemic inflammatory response syndrome (SIRS) criteria with leukocytosis and tachycardia. Laboratory evaluations showed a significantly elevated lipase level at 847, suggesting acute pancreatitis, while other parameters such as troponin, bilirubin, liver enzymes, and triglyceride levels were within normal limits. A CT scan revealed extensive and diffuse peripancreatic stranding with surrounding fluid, indicative of acute pancreatitis. An ultrasound ruled out gallstones.

The patient was diagnosed with acute pancreatitis, suspected to be induced by the GLP-1 receptor agonist tirzepatide. During hospitalization, he received supportive care for symptom management and gastroenterology consultation. Despite initial management, he developed persistent fevers and a repeat CT scan on the fifth day showed worsening pancreatitis with colonic involvement, ileus, and lung atelectasis accompanied by a pleural effusion. Empiric antibiotics were initiated, and with continued IV fluid support, his condition improved, ileus resolved, and he was able to resume oral intake. He was discharged with instructions to discontinue Mounjaro and scheduled for close follow-up with gastroenterology.

Study Author Conclusions

Serious adverse events related to Mounjaro (tirzepatide) include hypoglycemia, acute pancreatitis, cholelithiasis, and cholecystitis, while more common side effects are gastrointestinal, such as nausea and vomiting. These GI side effects are a major reason for non-compliance; however, they can potentially be mitigated with vitamin B12 and corrin ring-containing compounds. It was noted that the rates of acute pancreatitis, cholelithiasis, and cholecystitis are consistent across dosages, but nausea and vomiting are dose-dependent.

The occurrence of pancreatitis with tirzepatide is reportedly rare, which might lead to underreporting and lack of awareness among clinicians, though it is noted as a potential risk by pharmaceutical companies. Pancreatitis presents with symptoms like epigastric pain, nausea, fever, and may lead to severe outcomes like multi-organ failure. It is crucial to diagnose pancreatitis using criteria such as elevated serum lipase and confirm its cause to guide treatment, with alcohol and gallstones being common etiologies in the US.

Switching between GLP-1 agonists due to factors such as efficacy or cost should be approached with caution, starting at the lowest dose, especially if the change is prompted by GI symptoms. This transition strategy is important to minimize acute pancreatitis risk and manage side effects effectively.

 

References:

Mando N, Thomson E, Fowler M, Short L, Gillen N. Acute Pancreatitis Caused by Tirzepatide. Cureus. 2024;16(12):e76007. Published 2024 Dec 19. doi:10.7759/cureus.76007