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Letter to the Editor

Letter to the editor on “Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study”

Xingyu Yaoorcid
Clinical and Molecular Hepatology 2026;32(2):e165-e166.
Published online: July 21, 2025

Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China

Corresponding author : Xingyu Yao Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China Tel:+86-079186311630, E-mail: ndefy_yxy@163.com

Editor: Gi-Ae Kim, Kyung Hee University, Korea

• Received: June 11, 2025   • Revised: July 8, 2025   • Accepted: July 21, 2025

Copyright © 2026 by The Korean Association for the Study of the Liver

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the reply "Correspondence to letter to the editor 2 on “Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study”" in Volume 32 on page e249.
See the article "Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study" on page 1084.
  • Keywords: Methodological; GLP-1RA; MASLD
    • Dear Editor,
    I read with great interest the study by Mao et al. [1] examining the association between glucagon-like peptide-1 receptors (GLP-1RAs) and DPP-4i in relation to hepatic and extra-hepatic complications in adults with T2DM and metabolic dysfunction-associated steatotic liver disease (MASLD). The study provides valuable real-world evidence, yet several methodological aspects merit further consideration to enhance the validity and interpretability of the findings.
    First, the grouping of pharmacologically distinct GLP-1RA formulations may warrant additional nuance. The included weekly formulations (semaglutide) and daily formulations (liraglutide) exhibit markedly different pharmacokinetic profiles, adherence patterns, and clinical effects 单击或点击此处输入文字。 [2]. Recent studies demonstrate that semaglutide provides superior outcomes compared to liraglutide: 32% reduction in all-cause mortality, 3.3-fold greater renal protection (eGFR decline: 0.87 vs. 0.26 mL/min/1.73 m2/year), and superior cardiovascular protection (26% vs. 13% MACE reduction) [3-6].
    Second, Supplementary Table 6 reports a baseline imbalance in sodium-glucose cotransporter-2 (SGLT-2) inhibitor use in hepatocellular carcinoma (HCC) cohort (23.1% vs. 7.6%, SMD 0.442). SGLT-2 inhibitors exert significant hepatoprotective effects comparable to GLP-1RAs and produce synergistic cardiovascular benefits in combined therapy [7,8]. While IPTW adjustment is a reasonable choice under existing conditions, this methodology may not fully account for time-varying confounding when treatment decisions are influenced by intermediate outcomes affected by prior treatment. Combining marginal structural models would be more precise for capturing independent and synergistic effects [9,10].
    Third, the follow-up duration would appear insufficient relative to MASLD natural history. Mean follow-up periods for primary outcomes were HCC (25.9 months) and cirrhosis (24.7 months). However, MASLD progression typically requires 5–10 years from steatosis to NASH, and 10–20 years from NASH to cirrhosis [11]. Observing an HCC risk reduction (HR 0.53, 95% CI 0.39–0.71) around 2 years of follow-up would more likely reflects differences in diagnostic timing of pre-existing subclinical lesions or baseline risk heterogeneity rather than true tumor prevention effects. Therefore, if HCC is the primary outcome, it would be ideal to set an 8–15 years follow-up duration for MASLD patients and 5-year for those with cirrhosis. However, considering the practical constraints and patient follow-up, the existing follow-up duration has certain reasonableness in real-world studies, but it remains to be improved relative to MASLD natural history [12].
    In conclusion, this study provides valuable real-world evidence for GLP-1RA use in MASLD patients. While there are some methodological considerations, these do not affect the core value of the research.

    Conflicts of Interest

    The author has no conflicts to disclose.

    GLP-1RA

    glucagon-like peptide-1 receptor

    HCC

    hepatocellular carcinoma

    MASLD

    metabolic dysfunction-associated steatotic liver disease

    SGLT-2

    sodium-glucose cotransporter-2
    • 1. Mao X, Zhang X, Lai R, Cheung KS, Yuen MF, Cheung R, et al. Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study. Clin Mol Hepatol 2025;31:1084-1099.
    • 2. Sattar N, Lee MMY, Kristensen SL, Branch KRH, Del Prato S, Khurmi NS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 2021;9:653-662.
    • 3. Kuo CC, Li CH, Chuang MH, Huang PY, Kuo HT, Lai CC. Semaglutide versus other GLP-1 receptor agonists in patients with MASLD. Hepatol Commun 2025;9:e0747.
    • 4. Shaman AM, Bain SC, Bakris GL, Buse JB, Idorn T, Mahaffey KW, et al. Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: Pooled analysis of SUSTAIN 6 and LEADER. Circulation 2022;145:575-585.
    • 5. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-1844.
    • 6. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-322.
    • 7. Bea S, Ko HY, Bae JH, Cho YM, Chang Y, Ryu S, et al. Risk of hepatic events associated with use of sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists, and thiazolidinediones among patients with metabolic dysfunction-associated steatotic liver disease. Gut 2025;74:284-294.
    • 8. Dave CV, Kim SC, Goldfine AB, Glynn RJ, Tong A, Patorno E. Risk of cardiovascular outcomes in patients with type 2 diabetes after addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-1RA therapy. Circulation 2021;143:770-779.
    • 9. Robins JM, Hernán MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology 2000;11:550-560.
    • 10. Mansournia MA, Etminan M, Danaei G, Kaufman JS, Collins G. Handling time varying confounding in observational research. BMJ 2017;359:j4587.
    • 11. Hagström H, Shang Y, Hegmar H, Nasr P. Natural history and progression of metabolic dysfunction-associated steatotic liver disease. Lancet Gastroenterol Hepatol 2024;9:944-956.
    • 12. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024;81:492-542.

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    Letter to the editor on “Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study”
    Clin Mol Hepatol. 2026;32(2):e165-e166.   Published online July 21, 2025
    DOI: https://doi.org/10.3350/cmh.2025.0620
    Download Citation

    Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.
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    Letter to the editor on “Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study”
    Clin Mol Hepatol. 2026;32(2):e165-e166.   Published online July 21, 2025
    DOI: https://doi.org/10.3350/cmh.2025.0620
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