MASLD treatment: what a 2026 review found

A review published in Gut and Liver on 31 August 2026 (PMID 42670691)^[1] takes stock of where pharmacological treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) stands after two years of landmark approvals. The picture is one of genuine progress alongside clear limits: two drugs are available for a subset of patients with active steatohepatitis and significant fibrosis, a pipeline is advancing, and hard long-term endpoints such as liver-related mortality remain unproven for any approved agent.

MASLD affects an estimated 30 to 38 percent of adults worldwide^[1]. Its more severe form, metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), involves liver cell inflammation and injury alongside fat accumulation. MASH can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Most patients also carry obesity, type-2 diabetes, or both, which is why treatments developed for metabolic disease have emerged as the most promising liver therapies.

Why lifestyle change remains foundational

Before drugs entered the picture, the standard of care for MASLD was lifestyle modification. A sustained reduction of 7 to 10 percent of body weight reduces liver fat, can resolve active steatohepatitis histologically, and improves fibrosis stage. Clinical trial populations for both approved drugs received structured lifestyle support alongside pharmacotherapy, so the drug benefits observed in trials add to rather than substitute for dietary and activity changes.

The challenge is sustainability. Most people who achieve meaningful weight loss regain a significant portion within two to three years without continued support. For patients with F2 or F3 fibrosis who cannot sustain sufficient weight loss, the risk of progressive fibrosis is real. It is that population for whom pharmacotherapy now offers an option^[1].

The two approved pharmacological agents

Resmetirom (brand name Rezdiffra) was the first drug to reach regulatory approval specifically for MASH. It is an oral, liver-directed thyroid hormone receptor-beta (THR-beta) agonist taken once daily. The MAESTRO-NASH phase 3 trial, published in the New England Journal of Medicine in February 2024, showed that both the 80 mg and 100 mg daily doses produced histological MASH resolution and at least one-stage fibrosis improvement significantly more often than placebo in non-cirrhotic patients with F2 or F3 fibrosis^[3]. The FDA granted conditional approval on the basis of those histological surrogate endpoints. Resmetirom does not produce meaningful body-weight reduction; its liver benefits appear to be largely independent of weight loss, working through direct hepatic lipid metabolism and fatty acid oxidation pathways.

The second approved agent is semaglutide 2.4 mg weekly, a GLP-1 receptor agonist already approved for obesity and type-2 diabetes. The phase 3 ESSENCE trial (Sanyal et al., NEJM 2025) enrolled 1,197 adults with biopsy-confirmed MASH and F2 or F3 fibrosis. At the 72-week interim analysis, 62.9 percent of participants on semaglutide achieved MASH resolution without fibrosis worsening, compared with 34.3 percent on placebo, a difference of 28.7 percentage points (p less than 0.001)^[2]. Fibrosis improved by at least one stage in 36.8 percent versus 22.4 percent. Mean body weight fell by 10.5 percent on semaglutide versus 2.0 percent on placebo.

A 2026 meta-analysis (Peng TR et al., British Journal of Clinical Pharmacology) pooled 10 randomised controlled trials of semaglutide in MASLD covering 1,908 patients. The pooled odds ratio for steatohepatitis resolution was 3.48 (95% CI 2.68 to 4.53; p less than 0.00001) and for achieving a 30 percent or greater reduction in liver fat was 7.16 (95% CI 3.08 to 16.64)^[4]. Pooled histological fibrosis improvement did not reach statistical significance (OR 1.17; p 0.72), consistent with the observation that fibrosis reversal may require longer treatment duration and is most pronounced in non-cirrhotic disease stages.

In November 2025, the American Association for the Study of Liver Diseases (AASLD) updated its practice guidance to include semaglutide as a treatment option for MASH with F2 to F3 fibrosis^[5]. The guidance also shifted toward non-invasive test-based patient selection rather than mandatory biopsy, which lowers the barrier to identifying eligible patients in clinical practice.

The treatment gap: cirrhotic MASH and beyond F3

Both approved drugs apply to non-cirrhotic MASH. Patients who have already reached cirrhosis (fibrosis stage F4) have no approved pharmacological option as of late 2026^[1]. That population faces distinct risks: portal hypertension, oesophageal varices, ascites, and hepatic decompensation. The biology at F4 differs from earlier stages in ways that make existing trial endpoints harder to interpret and regulatory pathways harder to navigate. Cirrhotic MASH remains one of the most explicitly stated unmet needs in the field.

Novel therapies in the pipeline

The Gut and Liver review gives attention to the pipeline agents beyond the two approved drugs^[1]. The most advanced class in clinical development includes fibroblast growth factor-21 (FGF-21) analogues such as pegozafermin and efruxifermin. FGF-21 is a hormone involved in energy expenditure, fatty acid metabolism, and insulin sensitivity; its analogues aim to reduce hepatic steatosis and fibrosis while also improving metabolic parameters. Several FGF-21 candidates have reported promising phase 2 data showing both liver fat reduction and fibrosis improvement, though none has yet received regulatory approval.

Dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonists (dual GIP/GLP-1 agonists), most notably tirzepatide, are also under investigation for MASH. Tirzepatide's superior weight-loss profile over semaglutide in obesity trials has generated interest in whether its liver effects might also exceed those of the GLP-1 class alone. Phase 3 data in MASH are expected in the coming years^[1]. Additional pipeline mechanisms under study include farnesoid X receptor (FXR) agonists, which target bile acid metabolism and hepatic inflammation, and combinations pairing a GLP-1 receptor agonist with a fibrosis-targeted agent. No combination regimen has yet produced key trial data.

What the evidence cannot yet settle

The conditional approvals for both resmetirom and semaglutide rest on histological surrogate endpoints, specifically MASH resolution and fibrosis stage, rather than long-term clinical outcomes such as rates of cirrhosis, liver transplant, hepatocellular carcinoma incidence, or liver-related mortality^[1]. Surrogates are accepted by regulators when they are reasonably likely to predict clinical benefit, but that prediction remains to be confirmed in outcome trials. The ESSENCE trial is ongoing to a 240-week primary endpoint, and longer-term MAESTRO-NASH data are also pending. Until those results read out, the clinical case for either drug relies on mechanistic plausibility and the assumption that histological improvement translates to reduced disease progression.

Secondary analyses of the ESSENCE data suggest that liver benefits occurred across all body-weight-reduction thresholds, pointing to a direct hepatic component of semaglutide's action beyond weight loss. Resmetirom's weight-independent mechanism already establishes a proof of principle that direct hepatic targeting is sufficient for histological improvement without requiring systemic metabolic change^[3].

This article is for informational purposes only and does not constitute medical advice. Consult a healthcare provider before making any treatment decisions.