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. 2025 Jun 30.
doi: 10.1007/s40264-025-01558-1. Online ahead of print.

Association of GLP1-Receptor Agonists with Risk of Hepatocellular Carcinoma: A Retrospective Cohort Study

Joane Titus  1   2 , Vinay Katukuri  1   2 , Moheb Boktor #  3 , Ishak A Mansi #  4   5
Affiliations

Association of GLP1-Receptor Agonists with Risk of Hepatocellular Carcinoma: A Retrospective Cohort Study

Joane Titus et al. Drug Saf. .

Abstract

Background: The use of glucagon-like peptide-1 receptor agonists (GLP-1RA) has exponentially increased owing to their favorable cardio-renal-metabolic effects. Some studies have raised concerns about a potential association between GLP-1RA use and malignancy. This study aimed to examine the association between GLP-1RA use and risk of hepatocellular carcinoma (HCC).

Methods: This retrospective propensity score (PS)-matched cohort study used data from the Veterans Health Administration (years 2006-2021). Using a new-user active comparator design, the study included adults who initiated a GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP4i) as an active comparator and had no prior history of HCC or liver transplantation. The primary outcome was incident HCC. We developed a PS that included 133 variables encompassing diabetes severity, hepatic conditions, liver disease scores, vital signs, laboratory investigations, comorbidity scores, and use of other medication classes.

Results: Of 147,969 GLP-1RA and 263,664 DPP4i users, 100,248 pairs of GLP-1RA and DPP4i users were PS-matched. Hepatocellular carcinoma occurred in 302 (0.30%) GLP-1RA users and in 230 (0.23%) DPP4i users (odds ratio [OR]: 1.31, 95% confidence interval [95% CI]: 1.11-1.56). Secondary analysis, which stratified patients by duration of medication use, showed an increased risk of HCC in association with GLP-1RA use > 6 months, but similar HCC risk if medication use was < 6 months (OR: 0.96; 95% CI 0.68-1.35).

Conclusions: Glucagon-like peptide-1 receptor agonists use was associated with a modest but statistically significant increase in HCC risk versus DPP4i use. Although the reported benefits of GLP-1RA seem to far exceed this modest increased risk, further studies are warranted due to exponentially increasing GLP-1RA use and their broadening indications.

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Conflict of interest statement

Declarations. Funding: This material is the result of work supported with resources and the use of facilities at the Orlando Veterans Affairs (VA) Healthcare System (Orlando, Florida). This research was supported, in whole or in part, by HCA Healthcare and/or an HCA Healthcare affiliated entity. Role of Sponsor: None. Conflict of Interest: The authors declared no conflict of interest. Ethics Approval Statement: The Orlando VA Institutional Review Board approved the study (IRB approval number: 1680940-6). Consent to Participate/Consent for publication : The Orlando VA institutional review board waived the requirement for informed consent because only preexisting deidentified data were analyzed. Data Availability Statement: Data are stored in the VA Informatics and Computing Infrastructure (VINCI), the operational platform for health services research at the Veterans Healthcare Administration (VHA). The VINCI acts as a data steward for the VHA Data Systems. The data in VINCI cannot be copied, transferred, or printed. Access to data by other researchers is possible following the VINCI protocols, ascribed to the VINCI Central website: http://vaww.vinci.med.va.gov/VinciCentral . Code Availability: Codes used in the study are provided in Supplementary Material. Authors Contributions: The study concept and design: JT, IM, MB, VK; Acquisition of data and statistical analysis: IM; Interpretation of data: JT, IM, MB, VK; manuscript initial draft: JT, MB; critical revision of the manuscript for important intellectual content: IM, JT, MB, VK; study supervision: IM, MB. All authors have read and approved the final version of the manuscript.

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