Dear Editor,
I would like to express my appreciation to Prof. Xianhua Mao and Prof. Mindie H. Nguyen for their comprehensive Reply addressing the “Methodological concerns regarding GLP-1RA effects on MASLD outcomes” [
1,
2,
3]. Their insightful response is particularly engaging and provides valuable evidence regarding the role of GLP-1RAs on MASLD patients management.
Beyond the traditional GLP-1RAs examined in their study, the novel multi-target agonists could present promising therapeutic opportunities on metabolic dysfunction-associated steatotic liver disease (MASLD) that deserve further investigation. Tirzepatide, a dual GLP-1/GIP receptor agonist, and mazdutide, a dual GLP-1/GCG receptor agonist, represent next-generation therapies that could offer enhanced metabolic benefits through dual-pathway activation [
4-
6]. These multi-target approaches could potentially provide synergistic effects on liver and non-liver complications compared to single-target glucagon-like peptide-1 receptor agonists (GLP-1RAs) alone, though comparative investigations are needed.
Prof. Xianhua Mao, Prof. Mindie H. Nguyen and I all agree that long-term real-world evidence is essential to accurately evaluate the benefits of GLP-1RAs on MASLD patients, particularly regarding progression to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Additionally, extended follow-up research would allow for comprehensive assessment of cardiovascular and all-cause mortality effects, which represent significant and clinically relevant endpoints for patients with MASLD and diabetes.
In conclusion, I would like to express my gratitude to Prof. Mao and Prof. Nguyen for their thoughtful response and scientific rigor in addressing the methodological concerns previously raised. Their work contributes profoundly to our understanding of GLP-1RA effects on hepatic and non-hepatic outcomes in patients with MASLD and diabetes, thereby providing a solid foundation for clinical therapeutic decision making.
FOOTNOTES
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Conflicts of Interest
The author has no conflicts to disclose.
Abbreviations
glucagon-like peptide-1 receptor
metabolic dysfunction-associated steatotic liver disease
REFERENCES
- 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. Yao X. 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:e165-e166.
- 3. Mao X, Nguyen MH. Correspondence to 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:e250-e251.
- 4. Ji L, Jiang H, Bi Y, Li H, Tian J, Liu D, et al. Once-weekly Mazdutide in Chinese adults with obesity or overweight. N Engl J Med 2025;392:2215-2225.
- 5. Aronne LJ, Horn DB, le Roux CW, Ho W, Falcon BL, Gomez Valderas E, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med 2025;393:26-36.
- 6. Lee B, Ghumman U, Pedicone LD, Aldana AG, Lawitz E. Prospects of late-stage development agents in the treatment of metabolic dysfunction-associated steatohepatitis. Clin Mol Hepatol 2025;31:1167-1196.
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