Background/Aims Information about the association of glucagon-like peptide-1 receptor (GLP-1RA) with liver and non-liver complications is insufficient in patients with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). We conducted a target trial emulation study to evaluate whether GLP-1RA decreases the risk of liver and non-liver outcomes.
Methods Patients with T2D and MASLD initiating GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP-4i) were included from 2013 to 2022 in Merative™ Marketscan® Research Databases. Primary outcomes included incidences of (1) hepatocellular carcinoma (HCC) and cirrhosis, and (2) cardiovascular disease (CVD), chronic kidney disease (CKD), and non-liver cancer. Inverse probability of treatment weighting was applied to balance baseline characteristics and Cox regression models were conducted to estimate hazard ratio (HR) and 95% confidence interval (CI).
Results In the intention-to-treat design, GLP-1RA, compared with DPP-4i, had a significantly lower incidence (per 1,000 person-years) of HCC (0.8 vs. 1.7; HR 0.53, 95% CI 0.39–0.71), of cirrhosis (29.3 vs. 32.9; HR 0.91, 95% CI 0.86–0.96), of CVD (57.2 vs. 73.9; HR 0.90, 95% CI 0.86–0.95), of CKD (4.5 vs. 6.8; HR 0.73, 95% CI 0.64–0.84), and of non-liver cancer (16.9 vs. 22.9; HR 0.82, 95% CI 0.77–0.89). In the per-protocol design, significant inverse associations for these study outcomes still were observed, with HR 0.60–0.77.
Conclusions In this emulated target trial of nationwide patients with T2D and MASLD, GLP-1RA use, when compared with DPP-4i, was associated with a significantly lower risk of liver and non-liver complications.
Citations
Citations to this article as recorded by
Tirzepatide versus SGLT2 inhibitors for MASLD: a multi-institutional propensity score-matched cohort study Jheng-Yan Wu, Yu-Min Lin, Wan-Hsuan Hsu, Ting-Hui Liu, Ya-Wen Tsai, Po-Yu Huang, Min-Hsiang Chuang, Tsung Yu, Chih-Cheng Lai Hepatology International.2026; 20(2): 292. CrossRef
Impact of newer antihyperglycemic agents on hepatic complications: A systematic review and meta-analysis of data from 5.3 million patients with type 2 diabetes mellitus Jiwon Yang, Yeongseok Hwang, Jin-Sung Ju, Seungbong Han, Jihyun An, Ju Hyun Shim Hepatology.2026; 84(3): 851. CrossRef
Association of Semaglutide Treatment With Liver Cirrhosis and Hepatocellular Carcinoma in Type 2 Diabetes: A Population‐Based Cohort Study Assaf Issachar, Talish Razi, Ilya Borochov, Hadar Duskin Bitan, Ronen Arbel Diabetes, Obesity and Metabolism.2026; 28(7): 5704. CrossRef
Early cancer risk reduction after GLP-1RA use: Signal or bias?: 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 l Shio-Shin Jean, Chih-Cheng Lai Clinical and Molecular Hepatology.2026; 32(2): e163. CrossRef
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” Chunyan Wang, Xu Han, Yinyan Li Clinical and Molecular Hepatology.2026; 32(2): e167. CrossRef
Correspondence to letter to the editor 1 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 Xianhua Mao, Mindie H. Nguyen Clinical and Molecular Hepatology.2026; 32(2): e231. CrossRef
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 Xianhua Mao, Mindie H. Nguyen Clinical and Molecular Hepatology.2026; 32(2): e249. CrossRef
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 Yao Clinical and Molecular Hepatology.2026; 32(2): e165. CrossRef
Correspondence to editorial 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” Xianhua Mao, Mindie H. Nguyen Clinical and Molecular Hepatology.2026; 32(2): e219. CrossRef
Reply to correspondence 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 Yao Clinical and Molecular Hepatology.2026; 32(2): e267. CrossRef
GLP-1RA may open a new era for MASLD treatment: Editorial 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 tria Ye Feng, Chengfu Xu Clinical and Molecular Hepatology.2026; 32(2): 924. CrossRef
Metabolic Dysfunction‐Associated Steatotic Liver Disease and Obesity: Pathogenesis, Diagnostics, Risk Stratification, and Therapeutic Approach Beom Kyung Kim The Kaohsiung Journal of Medical Sciences.2026;[Epub] CrossRef
Secular Trend in Glycaemic Management in Type 2 Diabetes Patients With and Without Cirrhosis Between 2000 and 2023: A Territory‐Wide Cohort Study Mary Yue Wang, Sherlot Juan Song, Nana Peng, Grace Lai‐Hung Wong, Vincent Wai‐Sun Wong, Jimmy Che‐To Lai, Terry Cheuk‐Fung Yip Alimentary Pharmacology & Therapeutics.2026; 64(3): 356. CrossRef
GLP-1 receptor agonist–SGLT-2 inhibitor combination and risk of major adverse liver and cardiovascular outcomes in adults with MASLD and type 2 diabetes Xianhua Mao, Hong Fan, Man-Fung Yuen, Ramsey Cheung, Wai-Kay Seto, Mindie H. Nguyen Hepatology.2026;[Epub] CrossRef
Tumor microenvironment and metabolic reprogramming in MASLD-related hepatocellular carcinoma Vanilla X. Zhang, Tiffany C.-Y. Yu, Yu M. Tsui, Irene O.-L. Ng Trends in Molecular Medicine.2026;[Epub] CrossRef
Hepatic Events Prevention by Antihyperglycemic Therapies and Intervention Comparisons in Type 2 Diabetes: The HEPATIC-T2DM Network Meta-analysis Pedro Robson Costa Passos, Rodrigo Motta, Valbert Oliveira Costa Filho, Mariana Macambira Noronha, Roberto Cavalcante Venâncio, Guilherme Grossi Lopes Cançado, Amanda Adler, Jeremy F. Cobbold, Jeremy W. Tomlinson Diabetes Care.2026; 49(6): 1144. CrossRef
Predictors of Discordance Between Controlled Attenuation Parameter and Magnetic Resonance-Proton Density Fat Fraction in Hepatic Steatosis Dong Yun Kim, Hyung-Jin Rhee, Beom Kyung Kim Clinical and Translational Gastroenterology.2026; 17(7): e01042. CrossRef
Glucagon-Like Peptide-1 Receptor Agonist Use and Liver-Related Outcomes in Metabolic Dysfunction-Associated Steatotic Liver Disease and Type 2 Diabetes in the All of Us Research Program Erik Almazan, Jonggi Choi, Tushar Kamath, Vy H. Nguyen, Eric Przybyszewski, Jiunn Song, Allison Carroll, Megan Michta, Tracey G. Simon, Raymond T. Chung American Journal of Gastroenterology.2026;[Epub] CrossRef
Association between hemoglobin glycation index and new-onset diabetes mellitus in individuals with chronic liver disease: Findings from a prospective cohort study using CHARLS data Yanyan Mao, Hui Kong, Li Wang, Fangyan Liao, Xiangwen Li Medicine.2026; 105(27): e49567. CrossRef
Glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors after liver resection for hepatocellular carcinoma in patients with type 2 diabetes: a target trial emulation study Yan-Jun Xiang, Zong-Han Liu, Jin-Kai Feng, Ying-Yi Qin, Hong-Ming Yu, Yu-Qiang Cheng, Gang Chen, Jia-Yi Wu, Yong-Yi Zeng, Yu-Fu Tang, Jian-Hua Rao, Feng-Min Zhang, Shi-Ye Yang, Gui-Ran Wang, Lin-Sen Ye, Ren Lang, Jian-Hua Lin, Yi-Tao Zheng, Ye-Fan Mao, Ho Gut.2026; : gutjnl-2026-338462. CrossRef
How Negative Controls Are Used in Pharmacoepidemiology: A Methodological Scoping Review of Real‐World Observational Studies of Glucagon‐Like Peptide‐1 Receptor Agonists Zhengxuan Li, Yinan Huang, Hua Chen, Jieni Li Pharmacoepidemiology and Drug Safety.2026;[Epub] CrossRef
Cancer outcomes and biological mechanisms among patients with type 2 diabetes mellitus using glucagon-like peptide-1 receptor agonists: a systematic review and meta-analysis Ejike Daniel Eze, Leopold Ntakirutimana, Swase Dominic Terkimbi, Muluken Walle, Abdullahi Hussein Umar, Diresibachew Haile Wondimu, Makinde Vincent Olubiyi, Onyinye Cynthia Okeke, Olufunke Onaadepo, Jimoh Abdulazeez, David Chibuike Ikwuka, Elemi John Ani, Frontiers in Oncology.2026;[Epub] CrossRef
GLP-1 receptor agonists at the crossroads of diabetes, hepatic steatosis, and hepatocellular carcinoma Alfredo Vozza, Filippo Biagi, Chiara Raggi, Francesco Vizzutti, Fabio Marra Internal and Emergency Medicine.2026;[Epub] CrossRef
Comparative risk of hepatocellular carcinoma and mortality among initiators of GLP-1 receptor agonists versus other glucose-lowering therapies: a target trial emulation Jesus Gibran Hernández-Pérez, Omer Abdelgadir, Subin Jang, Deepali K. Ernest, Xiaotao Zhang, Dimpy Shah, Arthur S. Hong, Jaime P. Almandoz, Lindsay G. Cowell, Sarah E. Messiah, David S. Lopez Hepatology International.2026;[Epub] CrossRef
Gestational Diabetes and Postpartum Cardiovascular, Kidney, and Metabolic Disorders Lili Liu, Junjie Anderson Lu, Esther E. Velasquez, Cande V. Ananth, Mindie H. Nguyen, Michelle A. Williams JAMA Network Open.2026; 9(8): e2628578. CrossRef
Associations Between Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and Cancer Risk: A Systematic Review and Meta-Analysis Isha Lalani, Reynaldo Nambayan, Chantelle Carbonell, Yibing Ruan, Dylan E. O’Sullivan, Igor Stukalin, Robert J. Hilsden, Darren R. Brenner Cancer Control.2026;[Epub] CrossRef
Associations between glucagon-like peptide-1 receptor agonists and respiratory outcomes in chronic obstructive pulmonary disease and diabetes Kuang-Ming Liao, Ya-Wen Tsai, Konstantinos Kostikas, Gerard J Criner, Jheng-Yan Wu, Chih-Cheng Lai QJM: An International Journal of Medicine.2026;[Epub] CrossRef
Evaluating causal protective effect of dual GLP-1R/GIPR agonists on MASLD: A Mendelian randomization and colocalization study Yangke Cai, Siyuan Xie, Liyi Xu, Jiamin Chen, Jianting Cai European Journal of Pharmacology.2025; 1005: 178088. CrossRef
Impaired Thyroid Hormone Sensitivity is Associated with Increased
Risk of Liver Fibrosis in Euthyroid Population: A Cross-Sectional Analysis of
NHANES Xingyu Yao, Kaiwen Xiao, Hein Ko Oo Hormone and Metabolic Research.2025; 57(09): 511. CrossRef
First
Prev
