Rebranding NAFLD/NASH → MASLD/MASH: Why the New Terminology Matters
In 2023, a major nomenclature shift redefined the landscape of fatty liver disease: NAFLD (nonalcoholic fatty liver disease) became MASLD (metabolic dysfunction-associated steatotic liver disease), and NASH (nonalcoholic steatohepatitis) was renamed MASH (metabolic dysfunction-associated steatohepatitis). This reclassification, endorsed by hepatology societies including the AASLD in its 2024 guidance, reflects a growing consensus that metabolic dysfunction is the central driver of liver fat accumulation and inflammation in these conditions.
The previous terminology, especially the “nonalcoholic” label, was criticized for being reductionist and stigmatizing, as it defined disease by what it is not, rather than what it is. MASLD explicitly recognizes the common metabolic risk factors such as obesity, insulin resistance, dyslipidemia, and type 2 diabetes. MASH, in turn, identifies patients with hepatic inflammation and ballooning in the context of MASLD. This change has implications beyond semantics. It affects clinical trial inclusion criteria, billing codes, drug approvals, and patient understanding. The shift aligns nomenclature with the evolving therapeutic landscape, which increasingly targets cardiometabolic pathways, and supports a more holistic view of liver disease within the broader spectrum of metabolic syndrome. As new pharmacologic treatments emerge, this terminology provides a clearer framework for identifying patients most likely to benefit.
Mode of Action of GLP-1 Receptor Agonists in Liver Disease
GLP-1 receptor agonists (GLP-1 RAs) were originally developed for type 2 diabetes and obesity, but they also show significant promise in MASLD and MASH due to their effects on metabolic and inflammatory pathways. These agents enhance insulin secretion, reduce appetite, and promote weight loss factors that indirectly improve hepatic steatosis and insulin resistance. Though hepatocytes lack GLP-1 receptors, the liver benefits from systemic improvements in metabolism, including reduced de novo lipogenesis and hepatic fat content.
GLP-1 RAs also appear to have weight-independent effects, such as lowering hepatic inflammation and ballooning, likely via changes in gut hormones, adipokines, and the gut–liver axis. Some studies report liver histology improvements even in patients with minimal weight change.
Additionally, GLP-1 RAs may improve intestinal barrier function and reduce microbial translocation, indirectly lessening hepatic inflammation.
Altogether, their metabolic benefits, favorable safety profile, and potential for hepatic histologic improvement make GLP-1 RAs attractive candidates in the treatment of MASLD/MASH.
Semaglutide Phase 3 Data and Weight-Independent Effects
In 2025, a pivotal phase 3 trial published in the New England Journal of Medicine evaluated semaglutide, a once-weekly GLP-1 receptor agonist, in patients with histologically confirmed MASH and fibrosis. The trial enrolled over 1,000 participants and assessed the ability of semaglutide to induce MASH resolution without worsening fibrosis, as well as to improve fibrosis staging independently.
Results showed that semaglutide significantly increased rates of MASH resolution compared to placebo (59% vs. 17%), particularly in patients with early-stage fibrosis. While weight loss contributed to these outcomes, exploratory subgroup analyses demonstrated histologic improvement even in patients with less than 5% weight reduction, suggesting direct hepatic and systemic anti-inflammatory effects. However, the trial did not meet its secondary endpoint of statistically significant fibrosis regression, which remains a limitation. Liver stiffness by elastography improved modestly, but biopsy-confirmed fibrosis stage did not significantly differ between groups.
Semaglutide was well tolerated, with gastrointestinal symptoms being the most common adverse events. Its favorable metabolic effects, along with early liver-specific benefits, reinforce its role in managing metabolically driven liver disease.
While not yet FDA-approved specifically for MASH, semaglutide is widely used in patients with overlapping obesity, diabetes, and MASLD, and likely to become part of combination treatment strategies.
Thyroid Hormone β Agonist Resmetirom: First FDA-Approved Drug for MASH
In 2024, the FDA approved resmetirom, a selective thyroid hormone receptor β (THR-β) agonist, as the first drug specifically indicated for MASH with fibrosis. Resmetirom acts by targeting hepatocyte nuclear receptors that regulate lipid metabolism, promoting hepatic fat oxidation and reducing lipogenesis without affecting systemic thyroid hormone activity. The approval was based on a phase 3 randomized, placebo-controlled trial published in the New England Journal of Medicine involving over 1,000 adults with biopsy-confirmed MASH and stage F2–F3 fibrosis. Resmetirom met both histologic and metabolic endpoints. At 52 weeks, significantly more patients in the treatment group achieved a ≥1-stage improvement in fibrosis without worsening of MASH, compared to placebo.
Secondary outcomes included meaningful reductions in ALT, LDL cholesterol, and triglycerides, reflecting the drug’s broader cardiometabolic benefit. MRI-PDFF imaging also demonstrated a marked reduction in hepatic fat content. Importantly, these effects were observed without clinically significant changes in bone density, heart rate, or thyroid axis parameters, underscoring resmetirom’s targeted hepatic action and tolerability.
Resmetirom is administered orally, once daily, with food, and does not require injection or complex titration. This improves its accessibility and real-world usability, especially for patients who are not candidates for GLP-1 receptor agonists due to tolerability or insurance barriers.
As the first agent to show anti-fibrotic efficacy in MASH, resmetirom sets a new standard for pharmacologic intervention and may serve as a backbone therapy in future combination regimens aimed at halting or reversing fibrotic progression in metabolic liver disease.
Practical Prescribing Issues: Patient Selection, Monitoring, Cost
As pharmacologic options for MASLD and MASH expand, clinicians must navigate complex decisions regarding who to treat, how to monitor response, and how to manage access barriers.
Patient Selection
Current guidelines prioritize treatment for patients with biopsy-confirmed MASH with significant fibrosis (F2–F3) or those with noninvasive evidence of progressive disease, such as elevated FibroScan stiffness, FAST score, or NFS. For patients with early-stage disease, lifestyle modification remains first-line, but those with T2DM, obesity, or cardiometabolic comorbidities may benefit from earlier pharmacologic intervention.
Monitoring Requirements
Treatment with GLP-1 RAs or resmetirom requires regular follow-up. For semaglutide, monitor weight, HbA1c, and GI tolerance; for resmetirom, track liver enzymes, lipid panels, and fibrosis markers. Noninvasive imaging (e.g., MRI-PDFF or transient elastography) may be useful for gauging hepatic response, though liver biopsy remains the gold standard for definitive histologic endpoints.
Cost and Access
Both resmetirom and GLP-1 RAs come with significant cost, and may require prior authorization, specialty pharmacy dispensing, and step therapy documentation. Coverage can vary by insurer and indication. Semaglutide, widely used for diabetes and obesity, may be reimbursed more readily than resmetirom, which is newly approved and narrowly indicated for MASH with fibrosis.
Clinicians should work closely with pharmacists and case managers to optimize access, and educate patients on the long-term value of treatment in preventing cirrhosis and liver-related complications.
Unmet Needs & Investigational Agents on the Horizon
Despite major advances, significant therapeutic gaps remain in the management of MASLD and MASH. Current agents like semaglutide and resmetirom offer improvements in steatosis, inflammation, and early fibrosis, but their efficacy in reversing advanced fibrosis or cirrhosis is limited. Many patients still progress despite metabolic improvements, especially those with fibrotic-predominant phenotypes or comorbid conditions that complicate weight loss.
There is an urgent need for therapies that target fibrogenesis directly, particularly hepatic stellate cell activation and extracellular matrix remodeling. Multiple investigational compounds are in development:
- FXR agonists (e.g., cilofexor) show anti-inflammatory and anti-fibrotic effects but raise lipid safety concerns.
- PPAR agonists, particularly pan-agonists like lanifibranor, modulate lipid metabolism, insulin sensitivity, and fibrotic signaling.
- FGF21 analogs (e.g., pegozafermin) have shown rapid reduction in liver fat and improvement in histology, though long-term outcomes are under investigation.
- Dual and triple incretin receptor agonists (targeting GLP-1, GIP, and glucagon) are being evaluated for enhanced metabolic and hepatic benefits beyond current GLP-1 monotherapy.
A major direction of research is phenotype-driven therapy tailoring treatment based on patient subtypes: metabolic-dominant, inflammatory, or fibrotic. Combination regimens, such as GLP-1 RA plus FXR or THR-β agonists, may enhance response rates while minimizing side effects. Finally, biomarker-guided treatment using noninvasive tools like ELF, PRO-C3, and multi-omics profiling could enable precision dosing and early prediction of response.
The next generation of MASH therapies aims to move beyond liver fat toward true disease modification, with fibrosis regression, cirrhosis prevention, and improved long-term survival.
Key Practice Points
- GLP-1 receptor agonists and resmetirom are reshaping the treatment landscape of MASH, offering histologic benefits alongside weight loss and metabolic improvement.
- Patient selection, affordability, and long-term safety monitoring are central to implementing these agents in routine care.
- Continued clinical trial data and integration with lifestyle and metabolic risk management will be essential as newer therapies emerge.
References
1. Newsome, P. N., Ratziu, V., Harrison, S. A., et al. (2025). Semaglutide in patients with MASH: A phase 3 trial. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2413258
2. Rinella, M. E., Sanyal, A. J., Loomba, R., et al. (2024). Resmetirom for treatment of NASH with fibrosis: A phase 3 trial. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2309000
3. American Association for the Study of Liver Diseases. (2024). Clinical assessment and management of MASLD/MASH: Practice guidance. https://www.aasld.org/practice-guidelines/clinical-assessment-and-management-metabolic-dysfunction-associated-steatotic
4. Newsome, P. N., Ratziu, V., Harrison, S. A., Francque, S., Van Gaal, L., Linder, M., … & Sanyal, A. J. (2021). Effect of semaglutide on liver histology in patients with nonalcoholic steatohepatitis: A randomized clinical trial. JAMA, 324(21), 2173–2184. https://doi.org/10.1001/jama.2020.22938
5. Rinella, M. E., Loomba, R., Caldwell, S. H., Kowdley, K. V., Charlton, M., Tetri, B. A., … & Sanyal, A. J. (2023). Expert panel recommendations on the management of metabolic dysfunction-associated steatohepatitis. Hepatology, 78(2), 639–654. https://doi.org/10.1002/hep.32801
6. Loomba, R., Neuschwander-Tetri, B. A., Sanyal, A. J., Lavine, J. E., & Chalasani, N. (2022). Novel therapeutic targets in MASLD: Beyond metabolic risk. Nature Reviews Gastroenterology & Hepatology, 19(8), 533–547. https://doi.org/10.1038/s41575-022-00630-9
7. Francque, S., Verrijken, A., Caron, S., Prawitt, J., Paumelle, R., Derudas, B., … & Staels, B. (2021). PPAR agonists in the treatment of NAFLD/NASH. Journal of Hepatology, 75(6), 1369–1385. https://doi.org/10.1016/j.jhep.2021.07.015
8. Sanyal, A. J., Loomba, R., Kowdley, K. V., McCullough, A., Ren, W., Goodman, Z., … & Harrison, S. A. (2023). Safety and efficacy of lanifibranor, a pan-PPAR agonist, in NASH: A phase 2b randomized trial. Gastroenterology, 164(2), 383–397. https://doi.org/10.1053/j.gastro.2022.10.003