Abstract
OBJECTIVES: To assess whether initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) rather than sulfonylureas is associated with all cause acute pancreatitis and cause specific acute pancreatitis and to characterise temporal risk patterns of the various causes of acute pancreatitis associated with GLP-1RA use. DESIGN: Target trial using the electronic healthcare databases of the US Department of Veterans Affairs healthcare system. SETTING: US Department of Veterans Affairs. PARTICIPANTS: 333 687 users of the Veterans Affairs healthcare system with type 2 diabetes initiating GLP-1RA (n=132 551) or sulfonylureas (n=201 136) between 1 January 2017 and 31 December 2023. EXPOSURE: Initiation of GLP-1RA or sulfonylureas, and separately, continued use of GLP-1RA or sulfonylureas during follow-up. MAIN OUTCOME MEASURES: Risks of acute pancreatitis during 12 months' follow-up including all cause acute pancreatitis and cause specific acute pancreatitis (eg, pancreatitis that is suspected drug induced, alcohol induced, hypertriglyceridaemia associated, biliary, and idiopathic or other cause). The risks were measured through discrete time survival models after application of inverse probability weighting. RESULTS: In intention-to-treat analyses, participants who initiated GLP-1RAs had similar rates of all cause pancreatitis at one year compared with participants who initiated sulfonylureas (rate difference -3.64, 95% confidence interval (CI) -30.76 to 23.48 per 100 000 persons at one year). However, the overall null finding was the net result of countervailing effects across various causes of acute pancreatitis. GLP-1RA was associated with an increased risk of suspected drug induced acute pancreatitis (23.45 (14.27 to 33.85)) and decreased risks of hypertriglyceridaemia associated (-16.96 (-27.41 to -7.34)) and alcohol induced pancreatitis (-10.32 (-18.12 to -3.17)). Similar rates of biliary and idiopathic or other causes of acute pancreatitis were observed in the two groups. In per protocol analyses, drug induced acute pancreatitis attributable to GLP-1RA clustered early (42% of GLP-1RA attributable events over one year of follow-up occurred in the first three months), whereas reductions in alcohol related acute pancreatitis concentrated between months four and six and hypertriglyceridaemia associated acute pancreatitis concentrated between months 10 and 12. Cumulatively, these divergent temporal trends resulted in a net increase in risk of all cause pancreatitis during the first two months of treatment, with similar monthly risk observed for the remainder of follow-up. CONCLUSIONS: In this nationwide cohort, similar rates of all cause acute pancreatitis in GLP-1RA and sulfonylurea users were observed at one year. Increased risk of suspected drug induced pancreatitis during the early period was offset by later reductions in alcohol induced and hypertriglyceridaemia associated acute pancreatitis. Clinicians should counsel patients on early risk while recognising the overall neutral long term effect.