This study investigates the impact of GLP-1 receptor agonists (GLP-1 RAs) on patients with intraductal papillary mucinous neoplasms (IPMNs), a type of pancreatic cystic neoplasm that can progress to malignancy. With the increasing use of GLP-1 RAs for managing diabetes and obesity, concerns about their potential to influence pancreatic conditions, like IPMNs, have emerged. Although GLP-1 RAs are generally safe, their effects on pre-existing pancreatic conditions remain unclear.

The study aims to evaluate whether GLP-1 RA use in IPMN patients is linked to changes in pancreatic cyst characteristics, the incidence of acute pancreatitis, variations in tumor markers, and the progression of IPMNs to high-grade dysplasia or malignancy. A retrospective analysis will be conducted using medical data from patients diagnosed with IPMNs and treated with GLP-1 RAs between 2010 and 2024 at three Swiss hospitals. Key outcomes will include radiological changes, the incidence of acute pancreatitis, and potential shifts in IPMN surveillance or need for surgical intervention

This is a retrospective, multicentric cohort study designed to investigate the impact of GLP-1 receptor agonists (GLP-1 RAs) on patients with intraductal papillary mucinous neoplasms (IPMNs), a subtype of pancreatic cystic neoplasms with variable but potentially significant malignant potential. IPMNs are increasingly diagnosed due to advancements in cross-sectional imaging techniques, and their management often includes long-term radiological and clinical surveillance.

Concurrently, the prescription of GLP-1 RAs for type 2 diabetes mellitus and obesity has grown substantially. While GLP-1 RAs have shown excellent efficacy in glycemic control and weight reduction, concerns persist regarding their potential effects on the exocrine pancreas, particularly in patients with preexisting pancreatic abnormalities. Preclinical data in rodent models have been inconsistent, showing both pro-inflammatory and anti-inflammatory effects on the pancreas. Moreover, changes in pancreatic ductal morphology, including ductal gland proliferation, have been reported in animal studies, but with limited translation to human models. Meta-analyses of human clinical trials have not established a conclusive association between GLP-1 RAs and acute pancreatitis or pancreatic cancer; however, these studies typically exclude patients with underlying pancreatic lesions, such as IPMNs.

To address this gap, this study aims to assess the real-world effects of GLP-1 RA therapy on patients diagnosed with IPMNs. The hypothesis driving this research is that GLP-1 RA use may influence IPMN characteristics or related outcomes, which could affect management decisions including surveillance intervals, imaging modality choice, and surgical indications.

Study Setting and Data Sources The study is being conducted across 3 major Swiss medical centers: Hôpital Fribourgeois (HFR), Hôpitaux Universitaires de Genève (HUG), and the Inselspital in Bern. Data will be extracted from electronic medical records and include radiological images, laboratory test results, medication history, and clinical notes. The retrospective inclusion period ranges from January 2010 to May 2025.

Study Population Eligible participants are adult patients (aged ≥18 years) with a radiological diagnosis of IPMN who have been treated with any GLP-1 RA (e.g., exenatide, liraglutide, dulaglutide, semaglutide) during the study period. IPMN diagnoses will be validated based on radiologic criteria, with reference to the Kyoto 2023 Consensus. Patients must have complete medical records including at least one cross-sectional imaging (MRI or CT), serum tumor markers (CA19-9, CEA), and documented use of a GLP-1 RA.

Data Collection and Variables Collected variables include demographic information (age, sex, BMI), medical history (including diabetes subtype and comorbidities), GLP-1 RA treatment details (agent, dose, duration), laboratory values (HbA1c, fasting glucose, insulin, C-peptide, CA19-9, CEA, lipase, amylase), imaging features (cyst morphology, mural nodules, duct dilation), and clinical outcomes (acute pancreatitis, histopathologic progression, surveillance or surgical changes).

Radiological Evaluation All imaging studies will be re-reviewed by two independent, senior radiologists at HFR. Radiologists will be blinded to GLP-1 RA exposure. MRI is preferred; CT scans will be evaluated when MRI is unavailable. Radiological criteria from the Kyoto 2023 Consensus will be used, including assessment of cyst size, mural nodules, main duct diameter, enhancement features, and glandular morphology.

Statistical Analysis Descriptive statistics will be used to summarize baseline characteristics. Chi-square or Fisher's exact tests will be used for categorical variables, and t-tests or Mann-Whitney U tests for continuous variables. Multivariable logistic regression will control for potential confounders. Significance will be set at p < 0.05. A formal power calculation is not possible due to the exploratory and rare nature of the cohort, but the estimated sample size is 10-15 patients.

Data Quality and Management Data will be coded and entered into a centralized, secure RedCap database. Only authorized users will access the data. All changes will be tracked with an audit trail. Data validation procedures will include logic checks, range checks, and cross-field consistency. Periodic internal monitoring will be conducted to ensure protocol adherence.

Ethical Considerations All participating centers have received approval from their respective ethics committees. Patients provided general consent for use of anonymized medical data in research. Data will be anonymized and securely stored in compliance with Swiss data protection laws.

Expected Impact This study addresses an important clinical question that has not yet been explored in the literature. Its findings will help inform clinicians on whether GLP-1 RAs are safe for use in patients with IPMNs, potentially affecting surveillance strategies and therapeutic decisions. Results are expected to guide future prospective studies and could influence clinical guidelines related to pancreatic cystic lesions in patients with metabolic disease.

Inclusion Criteria:

• > 18 years old
• Radiological diagnosis of IPMN
• Treated with GLP-1 RAs.
• Patients must have provided prior informed consent for the use of their coded clinical data in research.

Exclusion Criteria:

• radiological diagnosis of IPMN is unclear,
• no documented history of GLP-1 RAs use
• patients did not provide signed informed consent, or have documented refusal for research.

The study population consists of adult patients diagnosed with intraductal papillary mucinous neoplasms (IPMNs) who have been treated with GLP-1 receptor agonists (GLP-1 RAs) for diabetes or obesity management