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Multicenter Study
. 2025 Apr;19(2):395-404.
doi: 10.1007/s12072-024-10752-9. Epub 2024 Nov 27.

Semaglutide and the risk of adverse liver outcomes in patients with nonalcoholic fatty liver disease and type 2 diabetes: a multi-institutional cohort study

Chia-Chih Kuo  1 , Min-Hsiang Chuang  1 , Chun-Hsien Li  2 , Po-Yu Huang  1 , Hsing-Tao Kuo  3   4 , Chih-Cheng Lai  5   6
Affiliations
Multicenter Study

Semaglutide and the risk of adverse liver outcomes in patients with nonalcoholic fatty liver disease and type 2 diabetes: a multi-institutional cohort study

Chia-Chih Kuo et al. Hepatol Int. 2025 Apr.

Abstract

Background: Semaglutide has shown potential liver benefits in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). However, no direct comparisons have been made between semaglutide and other antidiabetic medications, including sodium-glucose cotransporter-2 inhibitors (SGLT2i), thiazolidinediones (TZD), and dipeptidyl peptidase-4 inhibitors (DPP-4i), regarding liver outcomes in patients with both NAFLD and T2D.

Methods: This retrospective cohort study utilized the TriNetX electronic health record database, a multinational and multi-institutional database. Adults with NAFLD and T2D who received their first prescription for either semaglutide or other antidiabetic medications were included. New users of semaglutide were matched 1:1 via propensity score matching with users of SGLT2i, DPP-4i, and TZD. The primary outcome was major adverse liver outcome (MALO), a composite end point consisting of decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation. Secondary outcomes included the individual components of MALO and all-cause mortality.

Results: A total of 648,070 adult patients with T2D and NAFLD were identified, and patients were categorized into three different comparison groups based on their drug of interest. Semaglutide was associated with a lower risk of MALO compared to SGLT2i (adjusted hazard ratio [aHR], 0.73; 95% CI 0.60-0.88), DPP-4i (aHR, 0.72; 95% CI 0.56-0.86), and TZD (aHR, 0.76; 95% CI 0.56-0.99). Additionally, semaglutide was linked to a lower risk of all-cause mortality compared to SGLT2i (aHR, 0.62; 95% CI 0.53-0.72), DPP-4i (aHR, 0.42; 95% CI 0.36-0.49), and TZD (aHR, 0.67; 95% CI 0.54-0.83).

Conclusion: Semaglutide is associated with better liver outcomes and a lower risk of all-cause mortality compared to SGLT2i, DPP-4i, and TZD in patients with NAFLD and T2D.

Keywords: Diabetes mellitus; Major adverse liver outcomes; Nonalcoholic fatty liver disease; Semaglutide.

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Conflict of interest statement

Declarations. Competing interests: The authors state that they have no conflicts of interest. Ethics approval and consent to participate: The Institutional Review Board of the Chi Mei Medical Center approved the study protocol. Written informed consent was not required because TriNetX contains anonymized data. Consent for publication: All authors consent to the publishing of this article.

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