Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of progressive steatotic liver conditions, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), accompanied by varying degrees of liver fibrosis that may progress to cirrhosis. The global prevalence of MASLD among adults is approximately 30%, and it is estimated that there are approximately 1.66 billion prevalent cases of MASLD worldwide [
1]. MASLD is associated not only with an increased risk of liver-related complications such as cirrhosis, end-stage liver disease, and hepatocellular carcinoma but also with an increased risk of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), chronic kidney disease (CKD), and certain types of extrahepatic cancers [
2]. The increasing prevalence and significant clinical importance of this disease have led MASLD to evolve from medical curiosity to the most prevalent chronic liver disease worldwide, imposing a substantial health care burden.
Unlike T2DM, which has numerous therapeutic options, the most widely accepted approach for managing MASLD is lifestyle intervention. Over several decades, substantial progress has been made in understanding the pathogenic mechanisms of MASLD and MASH. On the basis of this evidence, two main therapeutic approaches have emerged as central focuses [
3]. One approach is to directly target hepatocytes with agents that allow the liver to function better in a toxic metabolic environment. These agents include thyroid hormone receptor-β (THRβ) agonists and fatty acid synthase inhibitors. The THRβ agonist resmetirom was approved by the US FDA as the first drug specifically for MASH in 2024. Although the main results from the phase III clinical trial of resmetirom revealed MASH resolution with improvement in fibrosis at least once after 52 weeks of treatment, the overall response rate was less than 30%, which is considered unsatisfactory [
4]. Other therapeutic options, such as agonists for the fibroblast growth factor 21 receptor and peroxisome proliferator-activated receptors, have diverse effects on the brain, adipose tissue and liver cells, thus modulating related pathways to improve hepatic steatosis [
3]. Another approach is to improve the metabolic environment of the liver. Mimetics of incretin hormones are typical drugs of this type and can act in the brain to reduce appetite and reverse overnutrition without directly targeting the liver. This results in a negative energy balance and metabolic autoregulation, as well as improvements in insulin resistance, hepatic steatosis and inflammation [
3]. In addition, several genetic polymorphisms that increase the risk of MASH have been identified, and they provide information on disease susceptibility as well as therapeutic approaches [
5].
Glucagon-like peptide-1 (GLP-1) is the most extensively studied gut hormone and was initially characterized as an incretin hormone that potentiates meal-stimulated insulin secretion. The action of GLP-1 is mediated by a GLP-1 receptor (GLP-1R) located in the bowel, pancreatic alpha and beta cells and the central nervous system. GLP-1R agonist (GLP-1RA) is a synthetic analog of GLP-1 that is resistant to degradation by dipeptidyl peptidase-4 (DPP-4) enzymes; thus, it has a long half-life in the circulation. Compared with traditional pharmacological treatments such as sulfonylureas and insulins, GLP-1RA not only results in comparative glycemic control but also has fewer drawbacks, such as low hypoglycemia and weight gain [
6]. Furthermore, GLP-1RA has been demonstrated to be extraordinarily effective in reducing future risk or preventing the progression of existing CVD and CKD [
7]. In addition to its cardio- and nephroprotective effects, GLP-1RA also benefits from MASLD and MASH on the basis of increasing evidence. Clinical trials evaluating liraglutide and semaglutide have demonstrated significant benefits in decreasing hepatic lipid content, suppressing inflammatory responses, and enhancing insulin sensitivity [
8]. Notably, recent findings from the phase III ESSENCE trial of semaglutide further underscore the potential of GLP-1RAs in improving fibrosis. Mechanistically, GLP-1 ameliorates hepatic steatosis and fibrosis likely through indirect pathways, given the absence of canonical GLP-1R expression in any type of liver cell [
8]. Specifically, hypothalamic GLP-1R signaling reduces food intake, leading to subsequent weight loss and reductions in glucose and fatty acid levels. Furthermore, GLP-1R activation in beta-cells enhances insulin secretion, which promotes the uptake of fatty acids and glucose into insulin-sensitive tissues. This process reduces the macronutrient-induced expression of genes associated with fatty acid synthesis and limits lipid accumulation in the liver, thereby inhibiting
de novo lipogenesis and intrahepatic triglyceride formation. Systemic and hepatic inflammation are also attenuated, and fibrosis is improved, potentially through the activation of liver-resident GLP-1R-positive γδ T cells and endothelial cells.
Although substantial research supports the benefits of MASLD, the effects of GLP-1RA on the long-term outcomes of MASLD patients remain unclear. In this issue of
Clinical and Molecular Hepatology, Mao and colleagues [
9] evaluated the associations of GLP-1RA with liver and nonliver complications in patients with T2DM and MASLD. They conducted a target trial emulation study by including relevant information from 2013–2022 in the Merative
TM Marketscan
® Research Database. They reported that, compared with DPP-4 inhibitors, GLP-1RA had a significantly lower incidence (per 1,000 person-years) of hepatocellular carcinoma (0.8 vs. 1.7; hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.39–0.71), cirrhosis (29.3 vs. 32.9; HR 0.91, 95% CI 0.86–0.96), CVD (57.2 vs. 73.9; HR 0.90, 95% CI 0.86–0.95), CKD (4.5 vs. 6.8; HR 0.73, 95% CI 0.64–0.84), and nonliver 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 remained significant. Overall, Mao’s work demonstrated that GLP-1RA administration not only ensures long-term safety but also may reduce the risk of adverse outcomes in patients with T2DM and MASLD. This finding highlights the potential and feasibility of expanding GLP1-RA therapy to a broader population, particularly those with MASLD and MASH.
Recently, considerable progress has been made toward improving the therapeutic efficacy of GLP-1RA via the development of incretin co-agonists or the use of GLP-1RAbased combination therapy in MASLD. As another type of incretin, glucose-dependent insulinotropic polypeptide (GIP) activation can synergistically amplify insulin secretion with GLP-1 and increase adipocyte triglyceride storage, diverting free fatty acids away from ectopic hepatic deposition [
10]. A MASH clinical trial revealed that tirzepatide, a GLP-1/GIP dual agonist, achieved MASH resolution in 44–62% of patients and improved fibrosis in 51–55% of patients [
11]. Glucagon directly targets hepatocytes, suppresses lipogenesis and enhances the mitochondrial β-oxidation of FFAs while also increasing energy expenditure via brown adipose tissue activation [
12]. Both the glucagon agonist and the glucagon receptor (GCGR)/GLP-1R co-agonist cotadutide reduced
de novo lipogenesis in mouse hepatocytes [
12]. A subsequent study revealed that the same drugs benefitted MASH mice by restoring mitochondrial respiration [
12]. GLP-1/glucagon receptor (GCGR) dual agonists, including lowered hepatic lipids, liver weight, biomarkers of liver injury and NAS scores in pre- and clinical studies, have been shown to improve MASH resolution and ameliorate fibrosis [
13]. In another clinical study evaluating GLP-1/FGF21 dual agonists in MASLD and T2DM, HEC88473 significantly reduced the hepatic fat fraction, as assessed via MRI, and improved glycemic control and lipid profiles with only 5 weeks of treatment, with general safety and good tolerance [
14]. Moreover, triple agonists such as retatrutide (GLP-1/GIP/glucagon) have resulted in unprecedented weight loss (24.2%) and hepatic fat reduction in phase 2 trials, with 90% of participants achieving normal liver triglyceride content [
15].
It may be reasonable to explore the utility of GLP-1RA combination therapies, where the second component of the regimen directly targets fibrosis. In addition to the combination therapy achieved through the use of the co-agonists mentioned above, pre- and clinical studies in MASLD have demonstrated the feasibility of combining GLP-1RA with farnesoid X receptor agonists [
16], sodium-dependent glucose transporter 2 inhibitors [
17], and cannabinoid receptor antagonists [
18]. Complementary mechanisms also suggest that combining GLP-1RA with mimetics may be a viable option for MASH therapeutics [
19]. GLP-1RA appears to be well suited for combination therapy in MASH, as most of its mechanisms do not directly target the liver.
FOOTNOTES
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Authors’ contributions
YF initiated the concept and complete the paper. CX initiated the concept, revised and approved the final version.
-
Conflicts of Interest
The authors have no conflicts of interest to declare.
Abbreviations
glucose-dependent insulinotropic polypeptide
glucagon-like peptide-1 receptor
glucagon-like peptide-1 agonist
metabolic dysfunction-associated steatohepatitis
metabolic dysfunction-associated steatotic liver disease
thyroid hormone receptor-β
REFERENCES
- 1. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 2023;77:1335-1347.
- 2. Huang DQ, Terrault NA, Tacke F, Gluud LL, Arrese M, Bugianesi E, et al. Global epidemiology of cirrhosis - aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol 2023;20:388-398.
- 3. Do A, Zahrawi F, Mehal WZ. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat Rev Drug Discov 2025;24:171-189.
- 4. Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med 2024;390:497-509.
- 5. Lindén D, Romeo S. Therapeutic opportunities for the treatment of NASH with genetically validated targets. J Hepatol 2023;79:1056-1064.
- 6. Shi Q, Nong K, Vandvik PO, Guyatt GH, Schnell O, Rydén L, et al. Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 2023;381:e074068.
- 7. Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med 2024;391:109-121.
- 8. Yabut JM, Drucker DJ. Glucagon-like peptide-1 receptor-based therapeutics for metabolic liver disease. Endocr Rev 2023;44:14-32.
- 9. 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.
- 10. Samms RJ, Christe ME, Collins KA, Pirro V, Droz BA, Holland AK, et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest 2021;131:e146353.
- 11. Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, et al. Tirzepatide for metabolic dysfunctionassociated steatohepatitis with liver fibrosis. N Engl J Med 2024;391:299-310.
- 12. Boland ML, Laker RC, Mather K, Nawrocki A, Oldham S, Boland BB, et al. Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat Metab 2020;2:413-431.
- 13. Sanyal AJ, Bedossa P, Fraessdorf M, Neff GW, Lawitz E, Bugianesi E, et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med 2024;391:311-319.
- 14. Xiang L, Wang G, Zhuang Y, Luo L, Yan J, Zhang H, et al. Safety and efficacy of GLP-1/FGF21 dual agonist HEC88473 in MASLD and T2DM: A randomized, double-blind, placebocontrolled study. J Hepatol 2025;82:967-978.
- 15. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. Triple-Hormone-Receptor agonist retatrutide for obesity - A phase 2 trial. N Engl J Med 2023;389:514-526.
- 16. Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A, et al. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J Hepatol 2022;77:607-618.
- 17. Hupa-Breier KL, Dywicki J, Hartleben B, Wellhöner F, Heidrich B, Taubert R, et al. Dulaglutide alone and in combination with empagliflozin attenuate inflammatory pathways and microbiome dysbiosis in a non-diabetic mouse model of NASH. Biomedicines 2021;9:353.
- 18. Zizzari P, He R, Falk S, Bellocchio L, Allard C, Clark S, et al. CB1 and GLP-1 receptors cross talk provides new therapies for obesity. Diabetes 2021;70:415-422.
- 19. Harrison SA, Bashir M, Moussa SE, McCarty K, Pablo Frias J, Taub R, et al. Effects of resmetirom on noninvasive endpoints in a 36-week phase 2 active treatment extension study in patients with NASH. Hepatol Commun 2021;5:573-588.
Citations
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- 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
