Incidence of Pancreatitis in STEP and SURMOUNT Trials
The available evidence does not demonstrate an increased risk of pancreatitis with semaglutide in the STEP trials or tirzepatide in the SURMOUNT trials compared to placebo.
Evidence from STEP Trials (Semaglutide)
The STEP trials evaluated semaglutide 2.4mg weekly in patients with obesity. While specific pancreatitis incidence rates from STEP trials are not directly reported in the provided evidence, the broader semaglutide safety data is highly relevant:
An updated meta-analysis of 21 randomized controlled trials including 34,721 patients found that semaglutide therapy was not associated with an increased risk of acute pancreatitis compared to placebo (OR 0.7; 95% CI 0.5-1.2) 1
When stratified by dosing regimen, high subcutaneous doses of semaglutide (which would include the 2.4mg dose used in STEP trials) showed similar results (OR 0.70; 95% CI 0.50-1.20) 1
In glycemic control trials with lower doses of semaglutide, acute pancreatitis was confirmed in 7 semaglutide-treated patients (0.3 cases per 100 patient-years) versus 3 comparator-treated patients (0.2 cases per 100 patient-years) 2
The FDA label for semaglutide notes that in a 2-year cardiovascular outcomes trial, acute pancreatitis occurred in 8 semaglutide-treated patients (0.27 cases per 100 patient-years) and 10 placebo-treated patients (0.33 cases per 100 patient-years) 2
Evidence from SURMOUNT Trials (Tirzepatide)
The SURMOUNT-1 trial evaluated tirzepatide in obese adults without diabetes over 72 weeks, demonstrating dose-dependent weight loss up to 20.9% 3. However, specific pancreatitis incidence data from SURMOUNT trials is not provided in the available evidence.
The FDA and European Medicines Agency have not identified a causal link between GLP-1 receptor agonist drugs and pancreatitis or pancreatic cancer 3
Pancreatitis has been reported in clinical trials of tirzepatide, but causality has not been established 4
Clinical Context and Monitoring
Despite the lack of increased risk in controlled trials, clinicians should remain vigilant:
After initiation of semaglutide, patients should be observed 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 2
If pancreatitis is suspected, the medication should be discontinued and appropriate management initiated; if confirmed, it should not be restarted 2
The American Association of Clinical Endocrinologists recommends using GLP-1 receptor agonists with caution in patients with a history of pancreatitis 3
Post-marketing case reports have suggested possible associations between GLP-1 receptor agonists and acute pancreatitis, though the LEADER trial with liraglutide did not demonstrate any increase in pancreatitis risk 3