Differential Biliary Adverse Event Signals Among Glp-1 Receptor Agonists: A FAERS Disproportionality Analysis

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Methods: We conducted a disproportionality analysis of FAERS comparing biliary outcomes (cholelithiasis, cholecystitis, biliary colic, bile duct stone, and cholangitis) across semaglutide, tirzepatide, liraglutide, exenatide, and dulaglutide; semaglutide was used as the reference agent. Proportional reporting ratios (PRR), reporting odds ratios (ROR), 95% confidence intervals, and Fisher exact tests were calculated. Subgroup analyses and sensitivity analyses were performed. Results: After deduplication, 3,460 reports were analyzed: semaglutide 1,797, tirzepatide 1,363, liraglutide 1,033, exenatide 999, and dulaglutide 574. Compared with semaglutide, exenatide (PRR 0.39 (0.23–0.65) p<0.001) and tirzepatide (PRR 0.58 (0.39–0.84), p= 0.004) showed lower reporting for bile duct stone, while dulaglutide (PRR 0.50 (0.30–0.82), p=0.003) and exenatide (PRR 0.30 (0.19–0.47), p<0.001) showed lower reporting for biliary colic (PRR 0.30 and 0.50). Dulaglutide showed higher reporting for cholangitis (PRR 1.65 (1.05–2.60), p=0.045). Exenatide (PRR 1.12 (1.08–1.16), p<0.001), liraglutide (PRR 1.07 (1.03–1.12), p<0.001), and tirzepatide (PRR 1.05 (1.01–1.09), p=0.018) showed higher reporting for cholecystitis . Exenatide (PRR 1.33 (1.23–1.44), p<0.001), liraglutide (PRR 1.21 (1.11–1.31), p<0.001) and tirzepatide (PRR 1.15 (1.06–1.25), p<0.001) also showed higher reporting for cholelithiasis . Subgroup findings were consistent with heterogeneity mainly observed for bile duct stone and biliary colic. Sensitivity analyses were largely concordant, although rarer outcomes lost significance. Conclusions: Biliary AE reporting varies across GLP-1RAs, highlighting agent-specific differences within class and the need for individualized prescribing and counseling. Biliary adverse events Disproportionality analysis FDA Adverse Event Reporting System Glucagon-like peptide-1 receptor agonists Obesity Type 2 diabetes Introduction Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a cornerstone in the management of type 2 diabetes mellitus and obesity due to their demonstrated efficacy in glycemic control, weight reduction and lowering risk of cardiovascular diseases 1 . Concurrent to the increase in the prescription and use of these agents, attention has shifted to evaluate safety concerns, including gallbladder-related adverse events. Biliary complications such as cholelithiasis, cholecystitis, biliary colic and biliary cancer have been reported in GLP-1RA users in randomized controlled trials and observational studies 2 – 5 . Semaglutide is now one of the most widely prescribed GLP-1RAs for both diabetes and obesity and represents the most extensively studied GLP-1RA in clinical practice 6 . Several trials and studies have identified the effects of GLP-1RAs on the biliary system, however there is limited evidence available when comparing within class differences in biliary related adverse events in semaglutide versus other GLP-1RA agents 2 , 4 , 7 Given its widespread use, it serves as an important reference point and prompts further evaluation about whether these biliary adverse events (AE) differ across agents. Using semaglutide as the reference agent therefore provides a stable anchor to evaluate within-class differences and allows interpretation of biliary AEs in the context of current prescribing patterns. The FDA Adverse Event Reporting System (FAERS) is a useful system for detecting real-world safety signals for medications, as it stores and allows analysis of post-marketing adverse event reports submitted to the FDA 8 . Given the growing clinical use of GLP-1RAs and the evolving literature linking them to biliary complications, it is essential to evaluate and compare biliary adverse events across individual agents to help guide physicians in having informed risk-benefit discussions with patients. Therefore, in this study, we conducted a FAERS-based disproportionality analysis to assess relative reporting of biliary adverse events among individual GLP-1RAs, comparing semaglutide with dulaglutide, exenatide, liraglutide, and tirzepatide. Methods We conducted a retrospective analysis using data from the FDA Adverse Event Reporting System (FAERS), a publicly available database that collects post-marketing adverse event reports submitted by healthcare professionals, manufacturers, and consumers 8 . FAERS data from January 1st, 2005, to February 17th, 2026, was included. The analysis focused on GLP-1 receptor agonists approved for the treatment of type 2 diabetes mellitus and obesity. We evaluated dulaglutide, exenatide, liraglutide, and tirzepatide, and used semaglutide as the reference agent given its widespread clinical use. Biliary adverse events were grouped into the following clinically relevant categories; cholelithiasis, cholecystitis, biliary colic, bile duct stone and cholangitis. Reports listing one of the study drugs and containing one of the mentioned biliary adverse events were included in the analysis. ADRs are categorized using standardized medical terminology from the Medical Dictionary for Regulatory Activities (MedDRA). Deduplication of reports was performed by conditional formatting for variables including patient age, sex, active drug ingredient, country, date of report and drug reactions. A disproportionality analysis was performed using Proportional Reporting Ratios (PRRs) to assess the relative reporting frequency of biliary adverse events associated with each GLP-1 receptor agonist compared with semaglutide. For each adverse event category, PRRs were calculated by comparing the proportion of reports for a given event among users of an individual GLP-1RA with the proportion of the same adverse event reported among semaglutide users. Additionally, Reporting Odds Ratios (RORs) was performed on the same data to validate the findings. We used the standard error of the log-PRR to calculate 95% confidence intervals (CIs). A 2-sided Fisher exact p test was used to determine statistical significance, with p < 0.05 considered significant. We performed a sub-group analysis on the deduplicated data on age, sex and indication for use. Unknown values were excluded from the analysis. Breslow–Day heterogeneity tests were used to detect heterogeneity across strata with p < 0.05 considered a signal for heterogeneity. To assess robustness of results, we performed a sensitivity analysis. We repeated the disproportionality analysis by (i) excluding reports with unknown indication for use, (ii) restricting to U.S. reports geographically. This study did not require Institutional Review Board (IRB) approval, as it utilized the publicly available, open-access FAERS database, which does not contain any identifiable health information. We adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist in preparing our report 9 . (Supplementary material table 1) Results There were 27 duplicates reports of cholecystitis, 14 of cholelithiasis, 1 each of bile duct stone and biliary colic and 0 of cholangitis removed from the analysis. (Table 2) We analyzed a total of 3,460 de-duplicated adverse event reports across 5 biliary conditions for five GLP-1RA drugs. Of these, semaglutide accounted for 1797 reports, tirzepatide 1363, liraglutide 1033, exenatide 999 and dulaglutide 574. (Table 1) Semaglutide was used as the reference drug. We stratified the data based on reporter type, route and indication for use. 3219 (93.3%) reports were from manufacturers, 103 (3%) from healthcare providers, 102 (2.9%) from patients and 36 (1%) unknown. There were 3162 (91.4%) reports of injection use, 81(2.3 %) of oral, 20 (0.6%) of mixed and 197(5.7%) unknown. 1448 (41.8%) reports of use for type 2 diabetes, 835 (24.1%) for obesity, 122 (3.5%) for both and 1055 (30.5%) unknown. Data was also stratified based on age and sex, the most common age group for GLP-1RA ADR reports was 45-64 years (1153 reports, 33.3%) followed by 18-44 years (653 reports, 18.9%). Females had a higher number of ADR reports as compared to males (2094, [60.5%]vs 1129 [32.6%] reports). For bile duct stone, exenatide (PRR 0.39 (0.23–0.65), ROR 0.37 (0.22–0.63), p<0.001) and tirzepatide (PRR 0.58 (0.39–0.84), ROR 0.56 (0.37–0.83), p= 0.004) showed significantly lower reporting compared to semaglutide. Dulaglutide (PRR 0.81 (0.49–1.34), ROR 0.80 (0.47–1.37), p=0.518) and liraglutide (PRR 0.75 (0.51–1.10), ROR 0.73 (0.48–1.10), p=0.136) showed no significant differences. For biliary colic , dulaglutide (PRR 0.50 (0.30–0.82), ROR 0.46 (0.27–0.79), p=0.003) and exenatide (PRR 0.30 (0.19–0.47), ROR 0.27 (0.17–0.44), p<0.001) demonstrated significantly lower relative reporting compared to semaglutide. Tirzepatide (PRR 0.89 (0.69–1.15), ROR 0.88 (0.66–1.17), p=0.383) and Liraglutide (PRR 0.87 (0.65–1.16), ROR 0.85 (0.62–1.18), p=0.376) showed no significant differences. For cholangitis, dulaglutide (PRR 1.65 (1.05–2.60), ROR 1.71 (1.04–2.81), p=0.045) showed significantly higher reporting relative to semaglutide. Tirzepatide (PRR 1.24 (0.87–1.78), ROR 1.26 (0.86–1.84), p=0.240), Liraglutide (PRR 0.82 (0.52–1.29), ROR 0.81 (0.51–1.30), p=0.416) and Exenatide (PRR 0.99 (0.65–1.52), ROR 0.99 (0.63–1.56), p=1.000) showed no significant differences. For cholecystitis , exenatide (PRR 1.12 (1.08–1.16), ROR 2.39 (1.71–3.33), p<0.001), liraglutide (PRR 1.07 (1.03–1.12), ROR 1.60 (1.20–2.14), p<0.001), and tirzepatide (PRR 1.05 (1.01–1.09), ROR 1.36 (1.06–1.74), p=0.018) all demonstrated significantly higher PRRs compared to semaglutide. Dulaglutide (PRR 1.01 (0.95–1.07), ROR 1.06 [0.75–1.51], p=0.792) showed no significant differences. For cholelithiasis , exenatide (PRR 1.33 (1.23–1.44), ROR 2.12 (1.71–2.63), p<0.001), liraglutide (PRR 1.21 (1.11–1.31), ROR 1.58 (1.28–1.94), p<0.001) and tirzepatide (PRR 1.15 (1.06–1.25), ROR 1.39 (1.15–1.67), p<0.001) demonstrated significantly higher reporting relative to semaglutide. Dulaglutide (PRR 1.03 (0.91–1.16), ROR 1.06 (0.81–1.38), p=0.684) showed no significant differences. (Table 3) In the subgroup sex-stratified analysis, for cholelithiasis and cholecystitis, ADR reporting was consistent across age and sex groups. However, for bile duct stone, exenatide and liraglutide demonstrated significant heterogeneity by sex with lower reporting in males (p=0.014 and p=0.031, respectively). (Table 4) (supplementary material table 2) In the age-stratified analysis, exenatide and liraglutide demonstrated heterogeneity for bile duct stone with significantly lower reporting in individuals ≥65 years (p=0.049 and p=0.027, respectively). Exenatide also demonstrated heterogeneity in biliary colic reporting with lower reporting in 0.05), however, for cholelithiasis, tirzepatide showed higher reporting for obesity as compared to semaglutide (p=0.05 ) (supplementary material table 2) We performed sensitivity analysis, by excluding reports with unknown indication for use and restricting to U.S. reports geographically. There was largely no change in the signals of outcomes. However, certain signals particularly for rarer outcomes (e.g., bile duct stone and cholangitis) lost statistical significance likely due to reduced power. (supplementary material table 3) Discussion In our FAERS-based disproportionality analysis, we observed that biliary adverse events are not consistent across all individual GLP-1RAs. Specifically, dulaglutide and exenatide had lower relative reporting of biliary colic and bile duct stone; exenatide, liraglutide, and tirzepatide had higher relative reporting of cholecystitis. Similarly, dulaglutide demonstrated higher relative reporting of cholangitis, and exenatide, liraglutide and tirzepatide showed higher relative reporting of cholelithiasis. These results align with recent studies showing similar variability across individual GLP-1RAs rather than the same pattern across all agents 4 , 7 , 10 . Several biologically plausible mechanisms have been proposed to explain the association between GLP-1RAs and biliary AEs. These mechanisms primarily focus on the effects of GLP-1 signaling on gallbladder physiology. GLP-1RAs reduce cholecystokinin (CCK) secretion, leading to decreased gallbladder emptying, impaired motility, and prolonged bile stasis. These physiological changes increase the risk for gallstone formation and biliary inflammation 7 , 11 . A systematic review and meta-analysis evaluating GLP-1RA-associated biliary complications reported that the risk of adverse events increases with higher doses and longer duration of therapy 2 . Another contributing factor is weight loss induced by GLP-1RAs, as rapid weight reduction is an established risk factor for gallstone disease due to increased bile cholesterol supersaturation and gallbladder hypomotility 2 , 4 , 12 . Our analysis demonstrated a strong signal for semaglutide and biliary colic/bile duct stone. This parallels with the findings seen in multiple systematic reviews and pharmacovigilance analyses showing a similar association 13 – 15 . Cholecystitis and cholelithiasis had higher relative reporting with tirzepatide, exenatide and liraglutide. This is consistent with prior clinical trials 16 . This is also supported by findings of Gameil et al which also showed a higher clinically significant risk with liraglutide compared to semaglutide and dulaglutide 7 and a randomized controlled trial by Lundgren et al., which showed a higher incidence of cholelithiasis with liraglutide compared to placebo 17 . The higher cholangitis signal observed for dulaglutide (vs semaglutide) should be interpreted cautiously. Cholangitis typically occurs in the setting of biliary obstruction and may be influenced by factors not well captured in FAERS (previous ERCP, anatomic abnormalities, malignancy). For tirzepatide, systematic reviews and meta-analyses of RCTs have reported increased risk of gallbladder and biliary outcomes including cholelithiasis supporting biologic plausibility for a post-marketing signal 5 , 18 . Although tirzepatide is slightly different from traditional GLP-1RAs due to its dual GIP and GLP-1 receptor agonism, current evidence does not suggest that this alters the risk of biliary events significantly compared to other GLP-1RAs. Multiple systematic reviews and meta-analyses have shown that the magnitude and pattern of biliary complications observed with tirzepatide fall within the range that is reported for GLP1-RAs 18 , 19 . This supports the interpretation that tirzepatide-associated biliary events are part of a broader incretin class effect instead of its dual GIP/GLP-1 receptor agonism. Our findings, which show comparable relative reporting patterns between tirzepatide and long-acting GLP-1RAs, are also consistent with this interpretation. While FAERS remains an important post-marketing surveillance dataset, it is important to highlight that our study had a few limitations. Firstly, the FAERS database is a voluntary reporting database that can be subject to underreporting or incomplete reports. Secondly, the database does not include patient factors (co-morbidities, BMI, concurrent medication use or lab abnormalities) that could potentially lead to confounding. However, our within-class comparator approach (drug vs the remainder of the GLP-1RA class) aided to partially reduce confounding within the class level, while still allowing detection of drug-specific patterns. Thirdly, the database lacks crucial information on drug dosage, frequency and duration. Lastly, disproportionality reporting, including PRR and ROR is best suited for signal detection rather than measurement of incidence of adverse events 20 , 21 . Despite these, there is consistency noted between our findings and previous trials and studies, which strengthens the credibility of the patterns observed in our study. Our results suggest that biliary AE risks should not be generalized across GLP-1RAs and should be evaluated on an agent-specific basis. In this comprehensive FAERS-based analysis, we observed notable variability in biliary AE reporting across individual GLP-1 receptor agonists. While semaglutide showed higher relative reporting for some biliary outcomes, dulaglutide, exenatide, liraglutide and tirzepatide demonstrated contrasting findings, therefore identifying that biliary AEs are not uniform among all agents. Findings vary based on multiple factors including individual pharmacologic profiles, treatment duration and dose intensity. As the use of GLP-1RAs increases for diabetes, obesity and cardiovascular problems, understanding these differences is important. Further prospective and comparative studies are warranted to clarify these mechanisms and determine how they make meaningful differences in patient care. Declarations Author Contributions (per ICMJE criteria): Alvina, Huda Jaffar, Chidera N Onwuzo, and Abdelkader Chaarcontributed to the conception and drafting of the manuscript and preparation of the tables and figures with the data. Mohamed Eisa provided critical revisions and supervision. All authors meet ICMJE authorship criteria and approve the final manuscript. Article Guarantor: Mohamed Eisa, MD Orcid ID: Alvina-0009-0007-8273-5252 Huda Jaffar- 0000-0003-4805-0691 Chidera N Onwuzo-0009-0008-5674-3424 Abdelkader Chaar-0000-0002-4259-0606 Mohamed Eisa-0000-0001-5120-4060 Financial Support: None. Funding Declaration: No funding was received for this study. Conflicts of Interest: The authors declare no conflicts of interest related to this submission. Prior Presentation: None Data availability statement: The data were obtained from FAERS, a publicly available database. The raw data can be accessed through the FDA website. 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Hosp Pharm. 2019 Apr;54(2):75–7. doi:10.1177/0018578718795271 Tables Tables 1 to 5 are available in the supplementary files section Additional Declarations No competing interests reported. Supplementary Files Tablesonly.docx suppmaterialonly.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 26 Apr, 2026 Reviews received at journal 16 Apr, 2026 Reviews received at journal 09 Apr, 2026 Reviewers agreed at journal 26 Mar, 2026 Reviewers agreed at journal 26 Mar, 2026 Reviewers agreed at journal 25 Mar, 2026 Reviewers agreed at journal 25 Mar, 2026 Reviewers invited by journal 24 Mar, 2026 Editor assigned by journal 23 Mar, 2026 Submission checks completed at journal 23 Mar, 2026 First submitted to journal 22 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9192889","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":612363804,"identity":"735a51d4-596a-40dc-8a71-207b541558f6","order_by":0,"name":"Alvina FNU","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYDACdgaGA0CKh5+9+eADEIOPoBZmiBYZyZ5jyQYgLWzEaAEBG4MbOWYSIBZBLfzNPIaHC2oYeCRnpKVVfs2xk2FjYH746AYeLRKHeQwOzzgG9AvP42O3ZbclAx3GZmycg8+aw2wJh4HKeCTb09JuS25jBrHZpPFpkQdr+cfAY3Agx6xYcls9YS0Gh5kPHOZtA2o5kWPG+HHbYcJaDMFa+iR4QIEszbjtOA8bMwG/yB1vbP7M883GHhSVH39uqwYxHj7G630IAMcIAzMPmCSsHAEYf5CiehSMglEwCkYMAAAPCUI7ew2zhwAAAABJRU5ErkJggg==","orcid":"","institution":"SUNY Upstate Medical University","correspondingAuthor":true,"prefix":"","firstName":"Alvina","middleName":"","lastName":"FNU","suffix":""},{"id":612363809,"identity":"98b90b59-fba6-4045-a911-ac3cc21040bc","order_by":1,"name":"Huda Jaffar","email":"","orcid":"","institution":"SUNY Upstate Medical University","correspondingAuthor":false,"prefix":"","firstName":"Huda","middleName":"","lastName":"Jaffar","suffix":""},{"id":612363811,"identity":"4ec0b698-8746-47ae-b013-a38aa37b7795","order_by":2,"name":"Chidera N Onwuzo","email":"","orcid":"","institution":"SUNY Upstate Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chidera","middleName":"N","lastName":"Onwuzo","suffix":""},{"id":612363812,"identity":"1663a2e9-7d18-438c-a94e-1f4b00470bd6","order_by":3,"name":"Abdelkader Chaar","email":"","orcid":"","institution":"SUNY Upstate Medical University","correspondingAuthor":false,"prefix":"","firstName":"Abdelkader","middleName":"","lastName":"Chaar","suffix":""},{"id":612363814,"identity":"52e1a7b9-8710-4b95-8254-9c0b654f9e7f","order_by":4,"name":"Mohamed Eisa","email":"","orcid":"","institution":"SUNY Upstate Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"Eisa","suffix":""}],"badges":[],"createdAt":"2026-03-22 17:23:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9192889/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9192889/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105566797,"identity":"755c95cd-806c-4b65-8e93-cf97a5221a59","added_by":"auto","created_at":"2026-03-27 12:57:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":546912,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9192889/v1/821306ed-32ef-4de7-8317-9b4d740f06ed.pdf"},{"id":105491569,"identity":"123ea2a0-d14c-47a2-9a4d-a5a8d42ade3e","added_by":"auto","created_at":"2026-03-26 15:37:12","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":21229,"visible":true,"origin":"","legend":"","description":"","filename":"Tablesonly.docx","url":"https://assets-eu.researchsquare.com/files/rs-9192889/v1/c59842b7b0bcda395af1adbd.docx"},{"id":105491567,"identity":"aea232fd-9e46-4029-93a4-f82938a79037","added_by":"auto","created_at":"2026-03-26 15:37:12","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":87192,"visible":true,"origin":"","legend":"","description":"","filename":"suppmaterialonly.docx","url":"https://assets-eu.researchsquare.com/files/rs-9192889/v1/1593295372a8c3379d2517df.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Differential Biliary Adverse Event Signals Among Glp-1 Receptor Agonists: A FAERS Disproportionality Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are a cornerstone in the management of type 2 diabetes mellitus and obesity due to their demonstrated efficacy in glycemic control, weight reduction and lowering risk of cardiovascular diseases\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Concurrent to the increase in the prescription and use of these agents, attention has shifted to evaluate safety concerns, including gallbladder-related adverse events.\u003c/p\u003e \u003cp\u003eBiliary complications such as cholelithiasis, cholecystitis, biliary colic and biliary cancer have been reported in GLP-1RA users in randomized controlled trials and observational studies\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSemaglutide is now one of the most widely prescribed GLP-1RAs for both diabetes and obesity and represents the most extensively studied GLP-1RA in clinical practice\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Several trials and studies have identified the effects of GLP-1RAs on the biliary system, however there is limited evidence available when comparing within class differences in biliary related adverse events in semaglutide versus other GLP-1RA agents\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Given its widespread use, it serves as an important reference point and prompts further evaluation about whether these biliary adverse events (AE) differ across agents. Using semaglutide as the reference agent therefore provides a stable anchor to evaluate within-class differences and allows interpretation of biliary AEs in the context of current prescribing patterns.\u003c/p\u003e \u003cp\u003eThe FDA Adverse Event Reporting System (FAERS) is a useful system for detecting real-world safety signals for medications, as it stores and allows analysis of post-marketing adverse event reports submitted to the FDA\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Given the growing clinical use of GLP-1RAs and the evolving literature linking them to biliary complications, it is essential to evaluate and compare biliary adverse events across individual agents to help guide physicians in having informed risk-benefit discussions with patients. Therefore, in this study, we conducted a FAERS-based disproportionality analysis to assess relative reporting of biliary adverse events among individual GLP-1RAs, comparing semaglutide with dulaglutide, exenatide, liraglutide, and tirzepatide.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe conducted a retrospective analysis using data from the FDA Adverse Event Reporting System (FAERS), a publicly available database that collects post-marketing adverse event reports submitted by healthcare professionals, manufacturers, and consumers\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. FAERS data from January 1st, 2005, to February 17th, 2026, was included.\u003c/p\u003e \u003cp\u003eThe analysis focused on GLP-1 receptor agonists approved for the treatment of type 2 diabetes mellitus and obesity. We evaluated dulaglutide, exenatide, liraglutide, and tirzepatide, and used semaglutide as the reference agent given its widespread clinical use. Biliary adverse events were grouped into the following clinically relevant categories; cholelithiasis, cholecystitis, biliary colic, bile duct stone and cholangitis. Reports listing one of the study drugs and containing one of the mentioned biliary adverse events were included in the analysis. ADRs are categorized using standardized medical terminology from the Medical Dictionary for Regulatory Activities (MedDRA). Deduplication of reports was performed by conditional formatting for variables including patient age, sex, active drug ingredient, country, date of report and drug reactions.\u003c/p\u003e \u003cp\u003eA disproportionality analysis was performed using Proportional Reporting Ratios (PRRs) to assess the relative reporting frequency of biliary adverse events associated with each GLP-1 receptor agonist compared with semaglutide. For each adverse event category, PRRs were calculated by comparing the proportion of reports for a given event among users of an individual GLP-1RA with the proportion of the same adverse event reported among semaglutide users. Additionally, Reporting Odds Ratios (RORs) was performed on the same data to validate the findings. We used the standard error of the log-PRR to calculate 95% confidence intervals (CIs). A 2-sided Fisher exact p test was used to determine statistical significance, with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered significant.\u003c/p\u003e \u003cp\u003eWe performed a sub-group analysis on the deduplicated data on age, sex and indication for use. Unknown values were excluded from the analysis. Breslow\u0026ndash;Day heterogeneity tests were used to detect heterogeneity across strata with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered a signal for heterogeneity.\u003c/p\u003e \u003cp\u003eTo assess robustness of results, we performed a sensitivity analysis. We repeated the disproportionality analysis by (i) excluding reports with unknown indication for use, (ii) restricting to U.S. reports geographically.\u003c/p\u003e \u003cp\u003eThis study did not require Institutional Review Board (IRB) approval, as it utilized the publicly available, open-access FAERS database, which does not contain any identifiable health information. We adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist in preparing our report\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. \u003cb\u003e(Supplementary material table 1)\u003c/b\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThere were 27 duplicates reports of cholecystitis, 14 of cholelithiasis, 1 each of bile duct stone and biliary colic and 0 of cholangitis removed from the analysis. \u003cstrong\u003e(Table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analyzed a total of 3,460 de-duplicated adverse event reports across 5 biliary conditions for five GLP-1RA drugs. Of these, semaglutide accounted for 1797 reports, tirzepatide 1363, liraglutide 1033, exenatide 999 and dulaglutide 574. \u003cstrong\u003e(Table 1)\u003c/strong\u003e Semaglutide was used as the reference drug. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe stratified the data based on reporter type, route and indication for use. 3219 (93.3%) reports were from manufacturers, 103 (3%) from healthcare providers, 102 (2.9%) from patients and 36 (1%) unknown. There were 3162 (91.4%) reports of injection use, 81(2.3 %) of oral, 20 (0.6%) of mixed and 197(5.7%) unknown. 1448 (41.8%) reports of use for type 2 diabetes, 835 (24.1%) for obesity, 122 (3.5%) for both and 1055 (30.5%) unknown.\u003c/p\u003e\n\u003cp\u003eData was also stratified based on age and sex, the most common age group for GLP-1RA ADR reports was 45-64 years (1153 reports, 33.3%) followed by 18-44 years (653 reports, 18.9%). Females had a higher number of ADR reports as compared to males (2094, [60.5%]vs 1129 [32.6%] reports).\u003c/p\u003e\n\u003cp\u003eFor \u003cstrong\u003ebile duct stone,\u003c/strong\u003e exenatide (PRR\u0026nbsp;0.39 (0.23–0.65), ROR 0.37 (0.22–0.63), p\u0026lt;0.001)\u0026nbsp;and tirzepatide (PRR\u0026nbsp;0.58 (0.39–0.84), ROR 0.56 (0.37–0.83), p= 0.004)\u0026nbsp;showed significantly lower reporting compared to semaglutide. Dulaglutide (PRR 0.81 (0.49–1.34), ROR 0.80 (0.47–1.37), p=0.518) and liraglutide (PRR 0.75 (0.51–1.10), ROR 0.73 (0.48–1.10), p=0.136) showed no significant differences.\u003c/p\u003e\n\u003cp\u003eFor \u003cstrong\u003ebiliary colic\u003c/strong\u003e, dulaglutide (PRR\u0026nbsp;0.50 (0.30–0.82), ROR\u0026nbsp;0.46 (0.27–0.79),\u0026nbsp;p=0.003) and exenatide (PRR\u0026nbsp;0.30 (0.19–0.47), ROR\u0026nbsp;0.27 (0.17–0.44),\u0026nbsp;p\u0026lt;0.001) demonstrated significantly lower relative reporting compared to semaglutide. Tirzepatide (PRR 0.89 (0.69–1.15), ROR 0.88 (0.66–1.17), p=0.383) and Liraglutide (PRR 0.87 (0.65–1.16), ROR 0.85 (0.62–1.18), p=0.376) showed no significant differences.\u003c/p\u003e\n\u003cp\u003eFor \u003cstrong\u003echolangitis,\u003c/strong\u003e dulaglutide (PRR\u0026nbsp;1.65 (1.05–2.60), ROR\u0026nbsp;1.71 (1.04–2.81),\u0026nbsp;p=0.045) showed significantly higher reporting relative to semaglutide. Tirzepatide (PRR 1.24 (0.87–1.78), ROR 1.26 (0.86–1.84), p=0.240), Liraglutide (PRR 0.82 (0.52–1.29), ROR 0.81 (0.51–1.30), p=0.416) and Exenatide (PRR 0.99 (0.65–1.52), ROR 0.99 (0.63–1.56), p=1.000) showed no significant differences.\u003c/p\u003e\n\u003cp\u003eFor \u003cstrong\u003echolecystitis\u003c/strong\u003e, exenatide (PRR\u0026nbsp;1.12 (1.08–1.16), ROR\u0026nbsp;2.39 (1.71–3.33),\u0026nbsp;p\u0026lt;0.001), liraglutide (PRR\u0026nbsp;1.07 (1.03–1.12), ROR\u0026nbsp;1.60 (1.20–2.14),\u0026nbsp;p\u0026lt;0.001), and tirzepatide (PRR\u0026nbsp;1.05 (1.01–1.09), ROR\u0026nbsp;1.36 (1.06–1.74),\u0026nbsp;p=0.018) all demonstrated significantly higher PRRs compared to semaglutide. Dulaglutide (PRR 1.01 (0.95–1.07), ROR 1.06 [0.75–1.51], p=0.792) showed no significant differences.\u003c/p\u003e\n\u003cp\u003eFor \u003cstrong\u003echolelithiasis\u003c/strong\u003e, exenatide (PRR\u0026nbsp;1.33 (1.23–1.44), ROR\u0026nbsp;2.12 (1.71–2.63),\u0026nbsp;p\u0026lt;0.001), liraglutide (PRR\u0026nbsp;1.21 (1.11–1.31), ROR\u0026nbsp;1.58 (1.28–1.94),\u0026nbsp;p\u0026lt;0.001) and tirzepatide (PRR\u0026nbsp;1.15 (1.06–1.25), ROR\u0026nbsp;1.39 (1.15–1.67),\u0026nbsp;p\u0026lt;0.001) demonstrated significantly higher reporting relative to semaglutide. Dulaglutide (PRR 1.03 (0.91–1.16), ROR 1.06 (0.81–1.38), p=0.684) showed no significant differences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(Table 3)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the subgroup sex-stratified analysis, for cholelithiasis and cholecystitis, ADR reporting was consistent across age and sex groups. However, for bile duct stone, exenatide and liraglutide demonstrated significant heterogeneity by sex with lower reporting in males (p=0.014 and p=0.031, respectively). \u003cstrong\u003e(Table 4) (supplementary material table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the age-stratified analysis, exenatide and liraglutide demonstrated heterogeneity for bile duct stone with significantly lower reporting in individuals ≥65 years (p=0.049 and p=0.027, respectively). Exenatide also demonstrated heterogeneity in biliary colic reporting with lower reporting in \u0026lt;65 age group (p=0.005).\u003cstrong\u003e\u0026nbsp;(Table 5) (supplementary material table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the indication for use stratified analysis (Type 2 diabetes vs obesity vs both), most strata did not demonstrate heterogeneity (p\u0026gt;0.05), however, for cholelithiasis, tirzepatide showed higher reporting for obesity as compared to semaglutide (p=0.05\u003cstrong\u003e) (supplementary material table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe performed sensitivity analysis, by excluding reports with unknown indication for use and restricting to U.S. reports geographically. There was largely no change in the signals of outcomes. However, certain signals particularly for rarer outcomes (e.g., bile duct stone and cholangitis) lost statistical significance likely due to reduced power. \u003cstrong\u003e(supplementary material table 3)\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our FAERS-based disproportionality analysis, we observed that biliary adverse events are not consistent across all individual GLP-1RAs. Specifically, dulaglutide and exenatide had lower relative reporting of biliary colic and bile duct stone; exenatide, liraglutide, and tirzepatide had higher relative reporting of cholecystitis. Similarly, dulaglutide demonstrated higher relative reporting of cholangitis, and exenatide, liraglutide and tirzepatide showed higher relative reporting of cholelithiasis. These results align with recent studies showing similar variability across individual GLP-1RAs rather than the same pattern across all agents\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral biologically plausible mechanisms have been proposed to explain the association between GLP-1RAs and biliary AEs. These mechanisms primarily focus on the effects of GLP-1 signaling on gallbladder physiology. GLP-1RAs reduce cholecystokinin (CCK) secretion, leading to decreased gallbladder emptying, impaired motility, and prolonged bile stasis. These physiological changes increase the risk for gallstone formation and biliary inflammation\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. A systematic review and meta-analysis evaluating GLP-1RA-associated biliary complications reported that the risk of adverse events increases with higher doses and longer duration of therapy\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Another contributing factor is weight loss induced by GLP-1RAs, as rapid weight reduction is an established risk factor for gallstone disease due to increased bile cholesterol supersaturation and gallbladder hypomotility\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur analysis demonstrated a strong signal for semaglutide and biliary colic/bile duct stone. This parallels with the findings seen in multiple systematic reviews and pharmacovigilance analyses showing a similar association\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Cholecystitis and cholelithiasis had higher relative reporting with tirzepatide, exenatide and liraglutide. This is consistent with prior clinical trials\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. This is also supported by findings of Gameil et al which also showed a higher clinically significant risk with liraglutide compared to semaglutide and dulaglutide\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and a randomized controlled trial by Lundgren et al., which showed a higher incidence of cholelithiasis with liraglutide compared to placebo\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe higher cholangitis signal observed for dulaglutide (vs semaglutide) should be interpreted cautiously. Cholangitis typically occurs in the setting of biliary obstruction and may be influenced by factors not well captured in FAERS (previous ERCP, anatomic abnormalities, malignancy).\u003c/p\u003e \u003cp\u003eFor tirzepatide, systematic reviews and meta-analyses of RCTs have reported increased risk of gallbladder and biliary outcomes including cholelithiasis supporting biologic plausibility for a post-marketing signal\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Although tirzepatide is slightly different from traditional GLP-1RAs due to its dual GIP and GLP-1 receptor agonism, current evidence does not suggest that this alters the risk of biliary events significantly compared to other GLP-1RAs. Multiple systematic reviews and meta-analyses have shown that the magnitude and pattern of biliary complications observed with tirzepatide fall within the range that is reported for GLP1-RAs\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. This supports the interpretation that tirzepatide-associated biliary events are part of a broader incretin class effect instead of its dual GIP/GLP-1 receptor agonism. Our findings, which show comparable relative reporting patterns between tirzepatide and long-acting GLP-1RAs, are also consistent with this interpretation.\u003c/p\u003e \u003cp\u003eWhile FAERS remains an important post-marketing surveillance dataset, it is important to highlight that our study had a few limitations. Firstly, the FAERS database is a voluntary reporting database that can be subject to underreporting or incomplete reports. Secondly, the database does not include patient factors (co-morbidities, BMI, concurrent medication use or lab abnormalities) that could potentially lead to confounding. However, our within-class comparator approach (drug vs the remainder of the GLP-1RA class) aided to partially reduce confounding within the class level, while still allowing detection of drug-specific patterns. Thirdly, the database lacks crucial information on drug dosage, frequency and duration. Lastly, disproportionality reporting, including PRR and ROR is best suited for signal detection rather than measurement of incidence of adverse events\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite these, there is consistency noted between our findings and previous trials and studies, which strengthens the credibility of the patterns observed in our study. Our results suggest that biliary AE risks should not be generalized across GLP-1RAs and should be evaluated on an agent-specific basis.\u003c/p\u003e \u003cp\u003eIn this comprehensive FAERS-based analysis, we observed notable variability in biliary AE reporting across individual GLP-1 receptor agonists. While semaglutide showed higher relative reporting for some biliary outcomes, dulaglutide, exenatide, liraglutide and tirzepatide demonstrated contrasting findings, therefore identifying that biliary AEs are not uniform among all agents. Findings vary based on multiple factors including individual pharmacologic profiles, treatment duration and dose intensity. As the use of GLP-1RAs increases for diabetes, obesity and cardiovascular problems, understanding these differences is important. Further prospective and comparative studies are warranted to clarify these mechanisms and determine how they make meaningful differences in patient care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions (per ICMJE criteria):\u003c/strong\u003e Alvina, Huda Jaffar, Chidera N Onwuzo, and Abdelkader Chaarcontributed to the conception and drafting of the manuscript and preparation of the tables and figures with the data. Mohamed Eisa provided critical revisions and supervision. All authors meet ICMJE authorship criteria and approve the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eArticle Guarantor:\u003c/strong\u003e Mohamed Eisa, MD\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOrcid ID:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eAlvina-0009-0007-8273-5252\u003c/li\u003e\n \u003cli\u003eHuda Jaffar- 0000-0003-4805-0691\u003c/li\u003e\n \u003cli\u003eChidera N Onwuzo-0009-0008-5674-3424\u003c/li\u003e\n \u003cli\u003eAbdelkader Chaar-0000-0002-4259-0606\u003c/li\u003e\n \u003cli\u003eMohamed Eisa-0000-0001-5120-4060\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Support:\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration:\u003c/strong\u003e No funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflicts of interest related to this submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrior Presentation: \u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e The data were obtained from FAERS, a publicly available database. The raw data can be accessed through the FDA website.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement:\u003c/strong\u003e Ethics approval was not required as de-identified patient data was used through the publicly available FAERS database.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDrucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metabolism. 2018 Apr;27(4):740\u0026ndash;56. doi:10.1016/j.cmet.2018.03.001\u003c/li\u003e\n\u003cli\u003eHe L, Wang J, Ping F, Yang N, Huang J, Li Y, et al. Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2022 May 1;182(5):513. doi:10.1001/jamainternmed.2022.0338\u003c/li\u003e\n\u003cli\u003eRam\u0026iacute;rez-Mej\u0026iacute;a MM, Ponciano-Rodriguez G, Eslam M, M\u0026eacute;ndez-S\u0026aacute;nchez N. GLP-1 receptor agonists and gallbladder disease risk: insights into molecular mechanisms and clinical implications. Endocrinology and Metabolism. 16.\u003c/li\u003e\n\u003cli\u003eTao C, Zhang Y, Wan T, Zhao W, Chen J, Wang K, et al. Glucagon-like peptide-1 receptor agonist-induced cholecystitis and cholelithiasis: a real-world pharmacovigilance analysis using the FAERS database. Front Pharmacol. 2025 Jul 8;16:1557691. doi:10.3389/fphar.2025.1557691\u003c/li\u003e\n\u003cli\u003eZeng Q, Xu J, Mu X, Shi Y, Fan H, Li S. Safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes and obesity: a systematic review and meta-analysis. Front Endocrinol. 2023 Oct 16;14:1214334. doi:10.3389/fendo.2023.1214334\u003c/li\u003e\n\u003cli\u003eUkhanova M, Wozny JS, Truong CN, Ghosh L, Krause TM. Trends in Glucagon-Like Peptide 1 Receptor Agonist Prescribing Patterns. Am J Manag Care. 2025 Aug 15;31(8):e228\u0026ndash;34. doi:10.37765/ajmc.2025.89778\u003c/li\u003e\n\u003cli\u003eGameil MA, Yousef EAAM, Marzouk RE, Emara MH, Abdelkader AH, Salama RI. The relative risk of clinically relevant cholelithiasis among glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus, real-world study. Diabetol Metab Syndr. 2024 Dec 4;16(1):293. doi:10.1186/s13098-024-01526-2\u003c/li\u003e\n\u003cli\u003ePotter E, Reyes M, Naples J, Dal Pan G. FDA Adverse Event Reporting System ( FAERS ) Essentials: A Guide to Understanding, Applying, and Interpreting Adverse Event Data Reported to FAERS. Clin Pharma and Therapeutics. 2025 Sep;118(3):567\u0026ndash;82. doi:10.1002/cpt.3701\u003c/li\u003e\n\u003cli\u003eVon Elm E, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Journal of Clinical Epidemiology. 2008 Apr;61(4):344\u0026ndash;9. doi:10.1016/j.jclinepi.2007.11.008\u003c/li\u003e\n\u003cli\u003eLiu L, Chen J, Wang L, Chen C, Chen L. Association between different GLP-1 receptor agonists and gastrointestinal adverse reactions: A real-world disproportionality study based on FDA adverse event reporting system database. Front Endocrinol. 2022 Dec 7;13:1043789. doi:10.3389/fendo.2022.1043789\u003c/li\u003e\n\u003cli\u003eShaddinger BC, Young MA, Billiard J, Collins DA, Hussaini A, Nino A. Effect of Albiglutide on Cholecystokinin‐Induced Gallbladder Emptying in Healthy Individuals: A Randomized Crossover Study. The Journal of Clinical Pharma. 2017 Oct;57(10):1322\u0026ndash;9. doi:10.1002/jcph.940\u003c/li\u003e\n\u003cli\u003eNreu B, Dicembrini I, Tinti F, Mannucci E, Monami M. Cholelithiasis in patients treated with Glucagon-Like Peptide-1 Receptor: An updated meta-analysis of randomized controlled trials. Diabetes Research and Clinical Practice. 2020 Mar;161:108087. doi:10.1016/j.diabres.2020.108087\u003c/li\u003e\n\u003cli\u003eDu Y, Zhang M, Wang Z, Hu M, Xie D, Wang X, et al. A real‐world disproportionality analysis of semaglutide: Post‐marketing pharmacovigilance data. J of Diabetes Invest. 2024 Oct;15(10):1422\u0026ndash;33. doi:10.1111/jdi.14229\u003c/li\u003e\n\u003cli\u003eKommu S, Berg RL. Efficacy and safety of once‐weekly subcutaneous semaglutide on weight loss in patients with overweight or obesity without diabetes mellitus\u0026mdash;A systematic review and meta‐analysis of randomized controlled trials. Obesity Reviews. 2024 Sep;25(9):e13792. doi:10.1111/obr.13792\u003c/li\u003e\n\u003cli\u003eXiong S, Gou R, Liang X, Wu H, Qin S, Li B, et al. Adverse Events of Oral GLP-1 Receptor Agonist (Semaglutide Tablets): A Real-World Study Based on FAERS from 2019 to 2023. Diabetes Ther. 2024 Aug;15(8):1717\u0026ndash;33. doi:10.1007/s13300-024-01594-7\u003c/li\u003e\n\u003cli\u003eNauck MA, Muus Ghorbani ML, Kreiner E, Saevereid HA, Buse JB, the LEADER Publication Committee on behalf of the LEADER Trial Investigators. Effects of Liraglutide Compared With Placebo on Events of Acute Gallbladder or Biliary Disease in Patients With Type 2 Diabetes at High Risk for Cardiovascular Events in the LEADER Randomized Trial. Diabetes Care. 2019 Oct 1;42(10):1912\u0026ndash;20. doi:10.2337/dc19-0415\u003c/li\u003e\n\u003cli\u003eLundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021 May 6;384(18):1719\u0026ndash;30. doi:10.1056/NEJMoa2028198\u003c/li\u003e\n\u003cli\u003eGong J, Gao F, Jiang K, Xie Q, Zhao X, Lei Z. Risk of biliary diseases in patients with type 2 diabetes or obesity treated with tirzepatide: A meta‐analysis. J of Diabetes Invest. 2025 Jan;16(1):83\u0026ndash;92. doi:10.1111/jdi.14340\u003c/li\u003e\n\u003cli\u003eMishra R, Raj R, Elshimy G, Zapata I, Kannan L, Majety P, et al. Adverse Events Related to Tirzepatide. Journal of the Endocrine Society. 2023 Feb 9;7(4):bvad016. doi:10.1210/jendso/bvad016\u003c/li\u003e\n\u003cli\u003eChedid V, Vijayvargiya P, Camilleri M. Advantages and Limitations of the Federal Adverse Events Reporting System in Assessing Adverse Event Reporting for Eluxadoline. Clinical Gastroenterology and Hepatology. 2018 Mar;16(3):336\u0026ndash;8. doi:10.1016/j.cgh.2017.11.025\u003c/li\u003e\n\u003cli\u003eKumar A. The Newly Available FAERS Public Dashboard: Implications for Health Care Professionals. Hosp Pharm. 2019 Apr;54(2):75\u0026ndash;7. doi:10.1177/0018578718795271\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 5 are available in the supplementary files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Biliary adverse events, Disproportionality analysis, FDA Adverse Event Reporting System, Glucagon-like peptide-1 receptor agonists, Obesity, Type 2 diabetes","lastPublishedDoi":"10.21203/rs.3.rs-9192889/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9192889/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Biliary adverse events (AEs) have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs), but within-class differences remain unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We conducted a disproportionality analysis of FAERS comparing biliary outcomes (cholelithiasis, cholecystitis, biliary colic, bile duct stone, and cholangitis) across semaglutide, tirzepatide, liraglutide, exenatide, and dulaglutide; semaglutide was used as the reference agent. Proportional reporting ratios (PRR), reporting odds ratios (ROR), 95% confidence intervals, and Fisher exact tests were calculated. Subgroup analyses and sensitivity analyses were performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After deduplication, 3,460 reports were analyzed: semaglutide 1,797, tirzepatide 1,363, liraglutide 1,033, exenatide 999, and dulaglutide 574. Compared with semaglutide, exenatide (PRR 0.39 (0.23–0.65) p\u0026lt;0.001) and tirzepatide (PRR 0.58 (0.39–0.84), p= 0.004) showed lower reporting for \u003cstrong\u003ebile duct stone, \u003c/strong\u003ewhile dulaglutide (PRR 0.50 (0.30–0.82), p=0.003) and exenatide (PRR 0.30 (0.19–0.47), p\u0026lt;0.001) showed lower reporting for \u003cstrong\u003ebiliary colic\u003c/strong\u003e(PRR 0.30 and 0.50). Dulaglutide showed higher reporting for \u003cstrong\u003echolangitis \u003c/strong\u003e(PRR 1.65 (1.05–2.60), p=0.045). Exenatide (PRR 1.12 (1.08–1.16), p\u0026lt;0.001), liraglutide (PRR 1.07 (1.03–1.12), p\u0026lt;0.001), and tirzepatide (PRR 1.05 (1.01–1.09), p=0.018) showed higher reporting for \u003cstrong\u003echolecystitis\u003c/strong\u003e. Exenatide (PRR 1.33 (1.23–1.44), p\u0026lt;0.001), liraglutide (PRR 1.21 (1.11–1.31), p\u0026lt;0.001) and tirzepatide (PRR 1.15 (1.06–1.25), p\u0026lt;0.001) also showed higher reporting for \u003cstrong\u003echolelithiasis\u003c/strong\u003e. Subgroup findings were consistent with heterogeneity mainly observed for bile duct stone and biliary colic. Sensitivity analyses were largely concordant, although rarer outcomes lost significance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Biliary AE reporting varies across GLP-1RAs, highlighting agent-specific differences within class and the need for individualized prescribing and counseling.\u003c/p\u003e","manuscriptTitle":"Differential Biliary Adverse Event Signals Among Glp-1 Receptor Agonists: A FAERS Disproportionality Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-26 15:37:05","doi":"10.21203/rs.3.rs-9192889/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-26T18:18:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-16T14:09:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-09T09:52:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192932194040738567924628637445227617342","date":"2026-03-27T03:48:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"110027080334902152339826273158148738771","date":"2026-03-26T14:39:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"256668947467307673646892265807249194300","date":"2026-03-26T03:48:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230384272892206930468194938730379074746","date":"2026-03-25T06:10:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-25T03:30:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-23T23:12:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-23T14:12:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2026-03-22T17:13:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"21964b1e-ce20-4a9c-8bef-daf362c0b787","owner":[],"postedDate":"March 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-08T04:08:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-26 15:37:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9192889","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9192889","identity":"rs-9192889","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}