Pancreatic Mucinous Cystic Neoplasms Following GLP-1 Receptor Agonists Use: A Report of Two Cases with Literature Review.

Introduction
Glucagon-like peptide-1 receptor agonists (GLP-1 RA) like samaglutide and Terzipatide, are widely utilized for the treatment of type 2 diabetes mellitus and obesity due to its proven efficacy in glucose regulation, weight loss, and cardiovascular protection [1, 2]. Despite a generally favorable safety profile, recent reports have drawn attention to potential pancreatic adverse effects, particularly in the form of cystic lesions [3–6].
While GLP-1 RAs have classically been associated with acute pancreatitis, emerging case reports and pharmacovigilance data indicate that structural pancreatic abnormalities may also develop independently of pancreatitis, including mucinous cystic lesions [7].
The underlying mechanism remains speculative but may include GLP-1–induced ductal hyperplasia, alterations in exocrine function, or secondary effects of rapid weight loss such as gallbladder dysfunction and biliary stasis [2, 3].
Given the rising use of GLP-1 RAs, including off-label use in non-diabetic populations for weight reduction, clinicians should be aware of its potential pancreatic effects. This case report describes two patients who developed large mucinous pancreatic cysts following GLP-1 RAs use and were managed surgically. The report adheres to the SCARE 2020 criteria [8].

Case Report

Case 1
A 28-year-old pre-diabetic, obese female (BMI 34.3) was started on metformin 750 mg daily along with tirzepatide injections for three months with the aim of reducing weight and blood sugar. Two weeks prior to presentation, she discontinued the injections due to worsening epigastric pain and recurrent vomiting. Her history was negative for previous abdominal pain, alcoholism, gallstones, pancreatitis, and her family history was negative for biliary disease. She did not have any previous investigations as she had never had any complaints. She was referred to the hepato-pancreatico-biliary team by the gastroenterology team after gastroscopy for gastritis and endoscopic ultrasound revealed a large pancreatic cyst.

Physical Examination
On presentation, the patient was conscious, alert, and oriented, and hemodynamically stable, with a temperature of 36.8 °C, heart rate of 78 bpm, blood pressure of 122/76 mmHg, respiratory rate of 16 breaths/min, and oxygen saturation of 98% on room air. Abdominal examination revealed mild epigastric tenderness without rebound or guarding. No palpable masses were noted, and the rest of the examination was unremarkable. Laboratory findings, including tumor markers, were normal.
CT abdomen with pancreatic protocol revealed a large distal pancreatic cystic lesion highly suspicious for a mucinous cystic neoplasm. MRCP confirmed a unilocular, well-defined cyst arising from the body and tail of the pancreas, abutting the left kidney and spleen, with no evident communication with the pancreatic duct (Fig. 1). The cyst measured 11 × 13.5 × 10.5 cm (AP × TR × CC). Endoscopic aspiration of the lesion yielded brownish fluid, which was sent for cytology and culture analysis; results returned negative for malignancy, with markedly elevated carcinoembryonic antigen (CEA) of 70,363 and an amylase level of 246 U/L. CT chest was unremarkable.

Treatment Course
After the multidisciplinary team (MDT) meeting, the consensus was to proceed with a distal pancreatectomy with splenectomy. During exploratory laparotomy, a large cystic lesion was visualized arising from the distal pancreas and adherent to the spleen and a segment of small bowel. A lateral-to-medial splenectomy was performed with the spleen kept attached to the cyst. A small bowel segment adherent to the specimen was included in the resection. A stapled distal pancreatectomy was performed, and the cystic lesion was completely resected (Fig. 2). The patient had an uneventful postoperative recovery and was discharged home on day 6 in good condition. Pathology confirmed a mucinous cystic neoplasm measuring 18 × 14 × 9 cm, with no evidence of malignancy. (Fig. 3). On follow-up visits, the patient was pain-free, completely healthy, and had a well-healed wound. Follow-up one year later showed no recurrence.

Case 2
A 45-year-old female with a history of secondary infertility was found to have elevated HbA1c during a fertility evaluation. She was started on semaglutide for three months. She presented to our Emergency Department with abdominal pain and recurrent vomiting. Her history was negative for alcoholism, gallstones, pancreatitis, and her family history was negative for biliary disease. Her previous OB/GYN abdominal ultrasound, done 2 weeks prior to starting semaglutide, was unremarkable. An abdominal ultrasound performed in the ER revealed a distal pancreatic cyst measuring 13 × 12 cm with turbid contents, and she was referred to our clinic.

Physical Examination
On presentation, the patient was conscious, alert, and oriented, and hemodynamically stable, with a temperature of 37.1 °C, heart rate of 82 bpm, blood pressure of 126/72 mmHg, respiratory rate of 17 breaths/min, and oxygen saturation of 97% on room air. Abdominal and systemic examinations were unremarkable. Laboratory findings, including tumor markers, were normal. Her abdominal CT demonstrated a large, thin-walled, low-density lesion replacing the distal pancreas, measuring 10 × 15 cm (Fig. 4). CT chest was unremarkable. Further evaluation with endoscopic ultrasound showed a 13 × 10 cm cyst in the tail of the pancreas. Aspiration was performed; cytology was negative for malignancy, and CEA was > 15,000.

Treatment Course
After discussing the treatment plan in the multidisciplinary team (MDT) meeting, surgery was decided. A laparoscopic approach was initiated, but due to dense adhesions to the posterior wall of the stomach and transverse colon, we proceeded with open adhesiolysis and en bloc resection of the cyst, spleen, involved gastric wall, and distal pancreas. Hemostasis was secured, and the abdominal cavity was closed (Fig. 5). The patient was transferred postoperatively to the ICU in stable condition. Her postoperative course was uneventful, and she was discharged home on day 5 in good condition. The pathology report confirmed a mucinous cystic neoplasm with low-grade dysplasia measuring 16 × 12 × 10 cm, with negative surgical margins. (Fig. 6). On follow-up visits, she was asymptomatic with a well-healed wound, and follow-up one year later showed no recurrence.

Clinical Discussion
We report two cases of pancreatic mucinous cystic neoplasms (MCNs) in female patients with no prior history of pancreatic disease or known risk factors, both of whom had recent exposure to GLP-1 RAs. While the association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and pancreatic cystic lesions remains under investigation, these cases contribute to the growing body of literature suggesting a potential link.
GLP-1 RAs, including semaglutide, have been previously associated with exocrine pancreatic effects, primarily acute pancreatitis. However, emerging pharmacovigilance data and radiological studies indicate that prolonged exposure may also correlate with structural changes such as cystic lesions and ductal proliferation, even in the absence of overt pancreatitis [4, 5]. Though infrequent, these findings raise clinically relevant concerns regarding the broader impact of GLP-1 RA therapy on pancreatic architecture.
The underlying pathophysiological mechanisms remain speculative. Preclinical studies have demonstrated that extended GLP-1 RA exposure can lead to ductal hyperplasia, increased pancreatic mass, and tissue remodeling [7–10]. Such changes may facilitate cyst formation or promote the progression of subclinical lesions. Moreover, semaglutide-induced weight reduction may influence biliary and pancreatic dynamics, potentially contributing indirectly to cyst development [1–3, 6, 7]. Murtajiz M. Raza et al. reported a case of a patient with a preexisting pancreatic pseudocyst found on CT scan in whom the use of GLP-1 RAs was a trigger for exacerbation, with all other possible causes excluded, emphasizing previously published data on the effects of GLP-1 RAs on pancreatic tissue [11].
On the other hand, some recent articles have suggested contradictory findings. A 2024 study published in JAMA Network Open examined over 543,000 adults with type 2 diabetes to assess the link between GLP-1 receptor agonists (GLP-1 RA) and pancreatic cancer. Over an average follow-up of 7 years, the study found no significant increase in risk. The adjusted hazard ratio (HR) for pancreatic cancer comparing GLP-1 RA to basal insulin was 0.50 (95% CI, 0.15–1.71), indicating no elevated risk during the observed period [12]. Another retrospective study by Mark Ayoub and colleagues comparing patients with type 2 diabetes mellitus treated with GLP-1 receptor agonists versus those not treated suggested that GLP-1 RAs may have a pancreatic protective effect. After 7 years of therapy, the cancer risk was lower in the GLP-1 RA group (0.14%) compared to the non–GLP-1 RA group (0.2%) (p < 0.0001). The risk ratio for developing pancreatic cancer in the GLP-1 RA group was 0.69 with a 95% confidence interval of 0.639–0.752. Consequently, patients who received GLP-1 RA had a calculated pancreatic cancer risk reduction of 31% [13].
In our cases, both patients presented with sizable mucinous cystic lesions confirmed by cytology and histopathology, with markedly elevated carcinoembryonic antigen (CEA) levels and no evidence of malignancy. Although one might debate the existence of a cyst prior to initiation of GLP-1 RA, we hypothesized that if a cyst of this size had been present, it would likely have been symptomatic. The temporal association between GLP-1 RA administration and lesion development, coupled with the absence of other known risk factors, suggests a possible drug-related etiology warranting further investigation.
Although reports of mucinous pancreatic cysts in the context of GLP-1 RA use remain limited, these findings emphasize the importance of clinical vigilance. Given the widespread use of GLP-1 RAs for both diabetic and non-diabetic indications, clinicians should maintain a high index of suspicion for pancreatic abnormalities in patients developing new gastrointestinal symptoms while on therapy. Consideration of baseline and interval imaging may be appropriate in symptomatic individuals or those with risk factors.
Limitations of this study include the lack of previous pancreatic CT imaging in both patients to exclude preexisting small or asymptomatic cysts.
While our findings do not establish causation, they highlight the need for further observational studies, post-marketing surveillance, and mechanistic research to clarify the relationship between GLP-1 RAs and pancreatic mucinous cystic neoplasms, in addition to their effect on preexisting cysts.

Conclusion
These two cases of pancreatic mucinous cystic neoplasms in previously healthy female patients following GLP-1 RA use raise important clinical considerations regarding the potential exocrine pancreatic effects of GLP-1 receptor agonists. Although a causal relationship cannot be confirmed, the temporal association, elevated tumor markers, absence of other risk factors, and supportive literature highlight the need for further investigation. With the expanding use of GLP-1 RAs in both diabetic and non-diabetic populations, clinicians should remain vigilant for pancreatic structural abnormalities and maintain a high index of suspicion in patients developing new gastrointestinal symptoms while on therapy. Large-scale observational studies and mechanistic research are warranted to better understand this emerging safety signal.