Authors: Isaac Sauvageau, Kerri Smith, Brittney Bright, Ryan Imel, Blake Sloan
Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a therapeutic class that mimics the naturally occurring incretin hormone GLP-1. Through this mechanism, they enhance glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and promote satiety. These effects make GLP-1 RAs effective agents for the management of type 2 diabetes mellitus (T2DM) and chronic weight management. They have also demonstrated cardiovascular and renal protective benefits, leading to increased use in patients with cardio-renal comorbidities. Despite their broad acceptance in clinical practice, early clinical trials and observational studies suggest a potential increase in the risk of pancreatitis (0.4% versus 0.03% in the general population). Multiple studies identify an increased risk of pancreatitis across the class, though results remain inconsistent, and the underlying mechanisms are not fully established.
Methods: This was a multi-center, matched case-control design that included adult patients with active GLP-1 RAs on their home medication lists from May 1, 2024 – October 1, 2025. The primary objective was to determine the incidence of pancreatitis in patients using GLP-1 RAs at North Carolina Baptist Hospital, Highpoint Medical Center, and Davie Medical Center. The secondary objective was to identify patient-specific factors associated with pancreatitis risk among GLP-1 RA users. Patients were excluded from the study if they initiated GLP-1 RA therapy within 30 days of data collection. The incidence of pancreatitis was calculated from the unadjusted population prior to case matching. Cases were defined as GLP-1 RA users admitted to the hospital with a primary diagnosis of pancreatitis. Controls consist of GLP-1 RA users without hospitalization for pancreatitis and were matched to cases in a 1:1 ratio by age category, sex, and residential zip code to minimize confounding variables.
Results: A total of 6,109 GLP-1 RA users were identified, of which 34 were admitted to the hospital with a primary problem of pancreatitis. This corelates with an 0.56% incidence of pancreatitis. After matching, 50 patients were included; 25 pancreatitis cases and 25 matched controls. The median age was 54 years, and 60% of the cohort was male. The median BMI was 35 kg/m2. The majority of patients were obese (82%) and had type 2 diabetes (78%). Semaglutide (56%) and tirzepatide (32%) were the most common GLP‑1 RAs used. Significant differences between cases and controls were observed for GLP‑1 RA agent distribution (p = 0.004), presence of chronic kidney disease (CKD) (36% vs. 8%; p = 0.017), cholelithiasis/cholecystitis (32% vs. 0%; p = 0.004), and serum creatinine levels (0.99 vs. 0.81 mg/dL; p = 0.038).
Univariable logistic regression indicated increased odds of pancreatitis associated with CKD (OR 6.47; 95% CI 1.43–46.3; p = 0.027) and higher serum creatinine (OR 5.32; 95% CI 1.32–42.7; p = 0.059). Tirzepatide use was associated with significantly lower odds of pancreatitis (OR 0.11; 95% CI 0.02–0.44; p = 0.003) compared with semaglutide. GLP‑1 RA dose category, HbA1c, triglycerides, alcohol use, smoking status, and baseline metabolic parameters were not significantly associated with pancreatitis. In multivariable regression adjusting for CKD and agent, CKD remained an independent predictor (OR 8.95; p = 0.028), while tirzepatide maintained a protective association (OR 0.10; p = 0.005).
Conclusions: The incidence of pancreatitis in GLP-1 RA users was 0.56%, which correlates with a higher risk of pancreatitis when compared to 0.03% in the general population. CKD and elevated serum creatinine were significantly associated with increased odds of pancreatitis in GLP-1 RA users, whereas tirzepatide was associated with reduced risk compared with semaglutide.
