GLP-1 RAs Improve MASLD, MASH Markers, but Long-Term Benefits Unclear

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with improvements in hepatic steatosis, liver enzymes, body weight, and glycated hemoglobin (HbA1c) in adults with metabolic dysfunction–associated steatotic liver disease (MASLD) or metabolic dysfunction–associated steatohepatitis (MASH), according to a systematic review and meta-analysis published in Medicine.¹

Evolving Treatment Options Highlight Unmet Needs in MASLD, MASH Care

Lifestyle modification remains the foundation of care for MASLD and MASH, but long-term adherence is often poor, and sustained histologic improvement is difficult to achieve. Pioglitazone and vitamin E have also demonstrated benefit in select patients but are limited by safety concerns and inconsistent antifibrotic effects.

However, in recent years the treatment landscape has shifted. Resmetirom (Rezdiffra; Madrigal Pharmaceuticals) became the first FDA-approved therapy for noncirrhotic MASH with liver fibrosis on March 14, 2024.² On August 15, 2025, the FDA granted accelerated approval to semaglutide 2.4 mg (Wegovy; Novo Nordisk) for adults with MASH and moderate to advanced fibrosis.³ Still, the authors described a continued unmet need for therapies that target both metabolic dysfunction and fibrotic progression.¹

To assess the efficacy and safety of GLP-1 RAs in adults with MASLD or MASH, the researchers searched 5 databases for English-language studies published between January 2019 and December 2025. They included 9 studies with 795 participants, comprising 8 randomized trials and 1 single-arm trial conducted in the US, China, India, Denmark, the United Kingdom, and multinational settings.

GLP-1 RAs Improve Liver and Metabolic Outcomes

Across 3 studies, GLP-1 RA therapy was associated with a greater reduction in liver fat content vs control (mean difference [MD], −3.17; 95% CI, −4.06 to −2.29), with no heterogeneity observed (I² = 0%). Liver enzymes also improved, as pooled data from 2 studies showed greater reductions in alanine aminotransferase (MD, −15.17; 95% CI, −21.29 to −9.05) and aspartate aminotransferase (MD, −9.89; 95% CI, −13.65 to −6.13), with no heterogeneity for either outcome.

On the metabolic side, HbA1c declined more with GLP-1 RAs (MD, −0.78; 95% CI, −1.07 to −0.49; I² = 38%). Body weight also declined across 4 studies (MD, −4.68; 95% CI, −6.88 to −2.47), with substantial heterogeneity (I² = 82%); despite this, the effect remained significant in leave-one-out sensitivity analyses, with pooled MDs ranging from −3.64 to −5.48.

Any adverse event (AE) was modestly more frequent with GLP-1 RAs across 3 studies (risk ratio [RR], 1.13; 95% CI, 1.02-1.25). Nausea (RR, 1.96; 95% CI, 1.34-2.86) and vomiting (RR, 2.34; 95% CI, 1.20-4.56) were significantly more common, whereas the increase in diarrhea did not reach statistical significance (RR, 1.77; 95% CI, 0.93-3.38). Serious AEs did not differ significantly between groups (RR, 1.37; 95% CI, 0.52-3.62), the researchers noted.

The results are consistent with a separate meta-analysis of 4 placebo-controlled semaglutide trials, which found that semaglutide more than doubled the likelihood of MASH resolution without worsening fibrosis but did not significantly improve fibrosis stage.⁴ The analysis also reported more gastrointestinal AEs without a significant increase in serious events.

Clinical Benefits of GLP-1 RAs Remain Promising, but Evidence Gaps Persist

Based on current evidence, the authors said GLP-1 RAs are best suited for patients with MASLD or MASH who also meet established indications for the therapy, such as type 2 diabetes or obesity, where liver benefits may be considered an added-value outcome rather than the sole treatment objective.¹

Tolerability remains a key barrier in practice, with Naim Alkhouri, MD, telling The American Journal of Managed Care^® that an estimated 20% to 30% of patients discontinue GLP-1 therapy within a year, primarily because of AEs and, in some cases, insurance coverage challenges.⁵ The researchers advised managing tolerability proactively through counseling and gradual dose escalation.¹

At the same time, they acknowledged their limitations, including that the meta-analyses were based on a limited number of studies for several outcomes, which may reduce the precision and generalizability of the estimates. The included studies also varied in design, population, treatment duration, comparator, and outcome assessment methods.

Still, the researchers noted that current evidence supports improvements in steatotic, biochemical, and metabolic surrogate outcomes among adults with MASLD or MASH rather than definitive histological or disease-modifying benefits. However, they cautioned that evidence regarding MASH resolution, fibrosis regression, and long-term liver-related clinical outcomes remains limited.

“Larger, adequately powered randomized controlled trials with longer follow-up and standardized histological or validated non-fibrosis end points are needed to determine whether these short- to medium-term improvements translate into sustained antifibrotic effects and meaningful long-term liver-related clinical benefits,” the authors concluded.

References

1. Alfawaz M, Bajamaan D, Alghamdi L, et al. Efficacy and safety of GLP-1 receptor agonists in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH): a systematic review and meta-analysis. Medicine (Baltimore). 2026;105(43):e51306. doi:10.1097/MD.0000000000051306
2. Joszt L. FDA approves resmetirom, first treatment for NASH with liver fibrosis. AJMC^®. March 14, 2024. Accessed November 5, 2026. https://www.ajmc.com/view/fda-approves-resmetirom-first-treatment-for-nash-with-liver-fibrosis
3. Klein H. FDA approves semaglutide for MASH with fibrosis. AJMC. August 18, 2025. Accessed November 5, 2026. https://www.ajmc.com/view/fda-approves-semaglutide-for-mash-with-fibrosis
4. McCormick B. Semaglutide more than doubled likelihood of MASH resolution. AJMC. July 28, 2026. Accessed November 5, 2026. https://www.ajmc.com/view/semaglutide-more-than-doubled-likelihood-of-mash-resolution
5. Munz K. Semaglutide shows promise for MASH resolution, severe fibrosis: Naim Alkhouri, MD. AJMC. May 9, 2025. Accessed November 5, 2026. https://www.ajmc.com/view/semaglutide-set-to-benefit-patients-with-mash-severe-fibrosis-naim-alkhouri-md