DOI: https://doi.org/https://doi.org/10.57187/s.4850
Despite numerous studies exploring the relationship between GLP-1 receptor agonists and pancreatic complications, a definitive correlation remains unclear [1–3]. As the indications for GLP-1 receptor agonist therapy expand to include obesity patients, their use in patients with intraductal papillary mucinous neoplasms – one of the most common cystic pancreatic neoplasms – is increasing. This article reviews existing literature on the association between GLP-1 receptor agonists, pancreatitis and pancreatic cancer, with a focus on implications for intraductal papillary mucinous neoplasm patients, and highlights the urgent need for further clinical studies and the establishment of clear guidelines for this patient group.
Initially developed for diabetes, GLP-1 receptor agonists have gained prominence in obesity treatment due to their efficacy in weight loss and improving metabolic parameters. Early clinical trials raised concerns about potential side effects, notably acute pancreatitis and pancreatic cancer. Acute pancreatitis remains a possible adverse effect in Wegovy® (the only GLP-1 receptor agonist approved for obesity in several countries), yet no direct correlation between GLP-1 receptor agonists and pancreatitis has been demonstrated [1–3]. Most clinical trials exclude patients with a history of acute pancreatitis. When acute pancreatitis occurs, it typically develops after 2–6 months of therapy at varying doses, suggesting that the weight loss itself – potentially causing gallstones – could be the trigger, rather than GLP-1 receptor agonist therapy [4].
A recent meta-analysis by Masson et al. [1], which included 21 trials and 34,721 patients on semaglutide, found no increased risk of acute pancreatitis. Similarly, a further meta-analysis from Nreu et al. [5] failed to show a significant correlation between GLP-1 receptor agonists and pancreatic cancer.
Studies conducted on rodents with GLP-1 receptor agonists have produced inconsistent findings. These range from worsening pancreatitis [6] and triggering inflammation in pancreatic acinar cells [7], to promoting the growth of pancreatic duct glands [8, 9] or reducing chemically induced pancreatitis while increasing levels of anti-inflammatory cytokines [10].
Additionally, there has been limited research on nonhuman primates that indicates any impact on the exocrine pancreas. In studies where a GLP-1 receptor agonist was administrated at doses exceeding normal levels for more than 10 weeks, no alterations in pancreatic structure were identified [11, 12].
Intraductal papillary mucinous neoplasm is one of the most common cystic neoplasms affecting the pancreas, characterised by its potential for malignant transformation. The incidence of intraductal papillary mucinous neoplasms has been increasing significantly, largely due to the enhanced detection capabilities offered by cross-sectional imaging techniques [13]. Chronic pancreatitis is recognised as a relevant risk factor for the development of intraductal papillary mucinous neoplasm, likely due to the inflammatory changes that alter the pancreatic ductal epithelium [14, 15]. Furthermore, a retrospective cohort study and meta-analysis by Xu et al. [16] demonstrated an association between acute pancreatitis and high-grade dysplasia in patients with intraductal papillary mucinous neoplasms, emphasising the importance of closely monitoring patients with these conditions.
Moreover, intraductal papillary mucinous neoplasms can be classified into different types, such as main-duct and branch-duct intraductal papillary mucinous neoplasms, which vary in their risk of progression to invasive cancer. Understanding these classifications is crucial when considering treatments like GLP-1 receptor agonists, as patients with main-duct intraductal papillary mucinous neoplasms may have a higher risk of malignant transformation [17, 18]. MRI along with physical examination, assessment of serum tumour markers and new-onset diabetes are the preferred ways to provide surveillance for non-resected intraductal papillary mucinous neoplasm [18].
A case reported by Shi [19] involved a woman in her 60s with diabetes, treated with dulaglutide for 16 months. Routine screening revealed elevated serum CA19-9 and CA242 levels, but no evidence of hepatobiliary, gastrointestinal or pancreatic neoplasms. Discontinuation of dulaglutide normalised her markers within 6 weeks. This elevation in a patient under surveillance for intraductal papillary mucinous neoplasm and treated with GLP-1 receptor agonists could complicate the differentiation between benign conditions and malignant transformation, making clinical interpretation challenging.
Despite the controversial link between acute pancreatitis and use of GLP-1 receptor agonists, we were unable to find any literature that specifically addresses the use of GLP-1 receptor agonists in patients diagnosed with intraductal papillary mucinous neoplasms. Further research is essential to elucidate the safety profile of GLP-1 receptor agonists in this context, particularly in light of intraductal papillary mucinous neoplasm’s characteristics that may influence treatment outcomes and risk assessments.
While GLP-1 receptor agonists have shown promise in the management of obesity and diabetes, their potential risks, particularly regarding pancreatitis and pancreatic cancer, remain contentious. Despite numerous studies and meta-analyses indicating no significant correlation between GLP-1 receptor agonist therapy and the incidence of acute pancreatitis or pancreatic cancer, gaps in the literature persist regarding their effects in patients with existing pancreatic conditions, such as intraductal papillary mucinous neoplasms. The notable simultaneous rise in intraductal papillary mucinous neoplasm and obesity incidence, alongside the established link between chronic pancreatitis and intraductal papillary mucinous neoplasm development, emphasises the need for further investigation into the safety profile of GLP-1 receptor agonists in this population. The potential growth of pancreatic duct glands associated with GLP-1 RA usage, reported in rodent models, could also have implications in intraductal papillary mucinous neoplasm patients. Further rigorous clinical studies addressing the safety of GLP-1 receptor agonists in patients with existing pancreatic conditions, such as intraductal papillary mucinous neoplasms, should be conducted to better understand the potential risks and benefits, establish clear guidelines for clinical practice and ultimately ensure the safety of these medications in this potentially vulnerable patient population.
The initial idea for the manuscript was conceived by ML and LB. ML was responsible for searching the available literature, drafting the manuscript and, along with LB, directly accessed and verified the data. PI, JLF, MA and LB contributed to the revision of the manuscript. All authors had full access to the data, take responsibility for accuracy and integrity and approved the final version of the manuscript submitted for publication.
This article project has not received any funding.
All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflict of interest related to the content of this manuscript was disclosed.
1.Masson W, Lobo M, Barbagelata L, Lavalle-Cobo A, Nogueira JP. Acute pancreatitis due to different semaglutide regimens: an updated meta-analysis. Endocrinol Diabetes Nutr (Engl Ed). 2024 Mar;71(3):124–32.
2.Tan HC, Dampil OA, Marquez MM. Efficacy and Safety of Semaglutide for Weight Loss in Obesity Without Diabetes: A Systematic Review and Meta-Analysis. J ASEAN Fed Endocr Soc. 2022;37(2):65–72.
3. Pinto LC, Falcetta MR, Rados DV et al. Glucagon-like peptide-1 receptor agonists and pancreatic cancer: a meta-analysis with trial sequential analysis. Sci Rep. 2019;9(1):2375. Published 2019 Feb 20. doi:
4.Lomeli LD, Kodali AM, Tsushima Y, Mehta AE, Pantalone KM. The incidence of acute pancreatitis with GLP-1 receptor agonist therapy in individuals with a known history of pancreatitis. Diabetes Res Clin Pract. 2024 Sep;215:111806.
5.Nreu B, Dicembrini I, Tinti F, Mannucci E, Monami M. Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials. Minerva Endocrinol (Torino). 2023 Jun;48(2):206–13.
6.Rouse R, Xu L, Stewart S, Zhang J. High fat diet and GLP-1 drugs induce pancreatic injury in mice. Toxicol Appl Pharmacol. 2014 Apr;276(2):104–14.
7.Nachnani JS, Bulchandani DG, Nookala A, Herndon B, Molteni A, Pandya P, et al. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia. 2010 Jan;53(1):153–9.
8.Deng H, Yang F, Ma X, Wang Y, Chen Q, Yuan L. Long-Term Liraglutide Administration Induces Pancreas Neogenesis in Adult T2DM Mice. Cell Transplant. 2020;29:963689720927392.
9.Gier B, Matveyenko AV, Kirakossian D, Dawson D, Dry SM, Butler PC. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model [published correction appears in Diabetes. 2012 Aug;61(8):2195]. Diabetes. 2012 May;61(5):1250–62.
10.Tatarkiewicz K, Smith PA, Sablan EJ, Polizzi CJ, Aumann DE, Villescaz C, et al. Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. Am J Physiol Endocrinol Metab. 2010 Dec;299(6):E1076–86.
11.Nyborg NC, Mølck AM, Madsen LW, Knudsen LB. The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species. Diabetes. 2012 May;61(5):1243–9.
12.Vahle JL, Byrd RA, Blackbourne JL, Martin JA, Sorden SD, Ryan T, et al. Effects of the GLP-1 Receptor Agonist Dulaglutide on the Structure of the Exocrine Pancreas of Cynomolgus Monkeys. Toxicol Pathol. 2015 Oct;43(7):1004–14.
13.Klibansky DA, Reid-Lombardo KM, Gordon SR, Gardner TB. The clinical relevance of the increasing incidence of intraductal papillary mucinous neoplasm. Clin Gastroenterol Hepatol. 2012 May;10(5):555–8.
14.Capurso G, Boccia S, Salvia R, Del Chiaro M, Frulloni L, Arcidiacono PG, et al.; Italian Association for Study of Pancreas (AISP); Intraductal Papillary Mucinous Neoplasm (IPMN) Study Group. Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. Am J Gastroenterol. 2013 Jun;108(6):1003–9.
15.Aronsson L, Andersson R, Ansari D. Intraductal papillary mucinous neoplasm of the pancreas - epidemiology, risk factors, diagnosis, and management. Scand J Gastroenterol. 2017 Aug;52(8):803–15.
16. Xu JH, Ni CY, Zhuang YY, et al. Acute pancreatitis in intraductal papillary mucinous neoplasm: a single-center retrospective cohort study with systematic review and meta-analysis. BMC Gastroenterol. 2023;23(1):424. Published 2023 Dec 1. doi:
17.Ohtsuka T, Fernandez-Del Castillo C, Furukawa T, Hijioka S, Jang JY, Lennon AM, et al. International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas. Pancreatology. 2024 Mar;24(2):255–70.
18.Tanaka M, Fernández-Del Castillo C, Kamisawa T, Jang JY, Levy P, Ohtsuka T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17(5):738–53.
19. Shi X. Significant elevation of serum CA19-9 and CA242 levels induced by dulaglutide. BMJ Case Rep. 2024;17(5):e257657. Published 2024 May 6. doi: