Dear Editor,
We appreciate Drs Feng and Xu’s editorial on our recent study regarding the impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on the incidence of liver and non-liver outcomes among patients with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) [
1,
2]. As mentioned in the editorial, the health burden of MASLD has increased over the past several decades, especially in those with concomitant T2D. Many studies have explored the effect of pharmacological therapy on adverse outcomes to reduce the clinical burden in this high-risk population.
Although the U.S. Food and Drug Administration has approved resmetirom for the first and only treatment for MASLD in 2024, its relatively low rate of fibrosis improvement limits its application [
3]. GLP-1RA is regarded as a promising treatment option, and several clinical studies have reported its benefits in improving liver health in MASLD [
4]. However, the information regarding its long-term impact on advanced liver disease in T2D and MASLD remains largely unknown. In addition, cardiovascular disease (CVD), chronic kidney disease (CKD), and non-liver cancer are the leading causes of death in MASLD [
5,
6]. Thus, it would be valuable to examine the impact of GLP-1RA on these complications. As such, we conducted a target emulation trial and found that GLP-1RA could decrease the incidence of hepatocellular carcinoma, cirrhosis, CVD, CKD, and non-liver cancer in patients with T2D and MASLD. Of note, both intention-to-treat and per-protocol designs strengthen the reliability of our findings.
We agree with Drs Feng and Xu that the combined therapy of GLP-1RA and other potential anti-MASLD medications may outperform single therapy. For example, GLP-1/glucose-dependent insulinotropic polypeptide dual agonists, especially tirzepatide, have shown a greater weight loss compared to semaglutide.7 In this light, Drs Feng and Xu have highlighted the reasonability of the utility of GLP-1RA combination therapies in their mechanisms. Nonetheless, our current research has provided encouraging findings on the long-term benefits of GLP-1RA to liver and nonliver complications among adults with T2D and MASLD, which provides a reference for GLP-1RA combination therapies in future studies.
FOOTNOTES
-
Authors’ contribution
Xianhua Mao and Mindie H. Nguyen: Conceptualization; Data acquisition and analysis; Writing—original draft; Writing—review and editing.
-
Conflicts of Interest
Mindie H. Nguyen received research grants via Stanford University from Pfizer, Enanta, Astra Zeneca, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Vir Biotech, Helio Health, National Cancer Institute, Glycotest and personal fees from consulting/advisory board from Intercept, Exact Science, Gilead, GSK. Xianhua Mao has nothing 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. Feng Y, Xu C. 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 trial emulation study”. Clin Mol Hepatol 2026;32:924-927.
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- 4. Sanyal AJ, Newsome PN, Kliers I, Østergaard LH, Long MT, Kjær MS, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med 2025;392:2089-2099.
- 5. Issa G, Shang Y, Strandberg R, Hagström H, Wester A. Causespecific mortality in 13,099 patients with metabolic dysfunctionassociated steatotic liver disease in Sweden. J Hepatol 2025;83:643-651.
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- 7. Ghusn W, Hurtado MD. Glucagon-like Receptor-1 agonists for obesity: Weight loss outcomes, tolerability, side effects, and risks. Obes Pillars 2024;12:100127.
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