MASH drugs: resmetirom and semaglutide

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, ^[1] and for most of the past two decades, doctors had no approved drugs to treat it. That changed in 2024 and 2025, when two agents cleared regulatory hurdles for its more advanced form: metabolic dysfunction-associated steatohepatitis (MASH). Understanding what these drugs are, what the clinical evidence shows, and where the gaps remain matters for anyone tracking the MASLD field.

What MASLD and MASH are

MASLD is a spectrum. At the mild end, fat accumulates in liver cells (steatosis) with little or no inflammation. When inflammation and cell injury are present alongside the fat, the condition is called MASH. Left untreated, MASH can progress to fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related death. ^[1] Behavioral weight loss, specifically a reduction of 7 to 10 percent of body weight, reduces liver fat and can resolve MASH histologically, but achieving and sustaining that level of weight loss is a substantial challenge for most patients. This is what has driven pharmaceutical development.

The two conditionally approved drugs

Resmetirom (Rezdiffra)

Resmetirom is an oral, liver-directed, selective thyroid hormone receptor-beta (THR-beta) agonist. 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 were superior to placebo for MASH resolution and for improvement in liver fibrosis by at least one stage. ^[2] Based on these histological outcomes, the US Food and Drug Administration granted conditional approval for resmetirom for adults with non-cirrhotic MASH and moderate to severe fibrosis (stages F2 and F3). It is the first oral agent approved for this indication.

Semaglutide (Wegovy)

Semaglutide is a GLP-1 receptor agonist delivered as a once-weekly 2.4 mg subcutaneous injection. The ESSENCE phase 3 trial enrolled 1,197 patients and reported interim results at 72 weeks in June 2025: 62.9 percent of patients in the semaglutide group achieved MASH resolution without fibrosis worsening, compared with 34.3 percent in the placebo group. ^[3] Fibrosis improved by at least one stage in 36.8 percent of the semaglutide group versus 22.4 percent with placebo. ^[3] Body weight fell by a mean of 10.5 percent with semaglutide versus 2.0 percent with placebo. Gastrointestinal adverse events (nausea, vomiting, diarrhoea) were more common in the semaglutide group but were generally mild and transient, consistent with the known safety profile of the GLP-1 class.

The FDA granted accelerated approval for semaglutide for MASH with moderate to advanced fibrosis (F2 to F3) in August 2025, based on these interim histological endpoints. Full approval awaits longer-term outcome data from the ongoing ESSENCE trial. ^[4]

How these drugs differ in mechanism

Resmetirom acts directly in the liver by activating THR-beta receptors, which regulate fatty acid oxidation and lipid metabolism in hepatocytes. The liver-directed design is intended to produce hepatic effects while limiting systemic thyroid hormone signalling that could affect the heart or bone. Semaglutide acts via GLP-1 receptors in the gut, pancreas, and brain to reduce appetite, slow gastric emptying, and improve insulin sensitivity. Its liver benefit appears to be driven largely by weight loss and the downstream reduction in hepatic fat influx, though direct GLP-1 receptor effects in the liver may also contribute.

The difference in mechanism means the two drugs are not head-to-head competitors in the same pharmacological sense. A patient with MASH and type-2 diabetes or obesity may be a candidate for semaglutide for multiple reasons; resmetirom addresses the liver more specifically. Whether combining them adds benefit over either alone is an active research question.

Emerging therapies: FGF-21 analogues and others

Beyond the two approved agents, the MASLD pipeline includes fibroblast growth factor-21 (FGF-21) analogues and other incretin-based therapies. ^[1] FGF-21 analogues aim to improve both metabolic and hepatic endpoints by acting on adipose tissue and liver simultaneously. Several candidates are in phase 2 or phase 3. None has reached approval as of mid-2026, so their place in clinical practice remains to be established.

The remaining gap: MASH-related cirrhosis

Both approved drugs have been studied primarily in non-cirrhotic MASH (F1 to F3). Effective pharmacological therapy for MASH-related cirrhosis (stage F4) remains an unmet need identified explicitly in the 2026 state-of-the-art review. ^[1] Patients who have already reached cirrhosis face different biology, different complications (portal hypertension, varices, hepatic decompensation), and a higher bar for clinical-trial endpoints. Regulatory pathways and trial designs for this population are still being worked out.

What this means for people tracking the field

The 2024 to 2025 period marked a genuine shift for MASLD pharmacology. Having two conditionally approved drugs with different mechanisms gives clinicians a starting framework for matching therapy to patient profile. The semaglutide data are particularly notable given that many patients with MASH also have obesity or type-2 diabetes, conditions for which the drug was already approved. That overlap means the ESSENCE results carry clinical weight beyond the liver disease community.

What neither drug has yet proven is a reduction in hard clinical outcomes: liver-related mortality, rates of transplant, or all-cause mortality. The conditional approvals are based on histological surrogate endpoints (MASH resolution, fibrosis stage). Longer follow-up from the ongoing ESSENCE and MAESTRO-NASH extension studies is needed to answer that harder question.