MASH (Metabolic-Associated Steatohepatitis): The New Treatment Landscape

From NASH to MASH: Nomenclature and Disease Burden

For the gastroenterologist or hepatologist managing patients with fatty liver disease, 2024 marked a watershed: after decades of lifestyle counseling as the only evidence-based intervention, the field finally has an FDA-approved pharmacotherapy for MASH. For the primary care physician or endocrinologist managing the upstream metabolic drivers — obesity, type 2 diabetes, metabolic syndrome — the GLP-1 agonist data in MASH add yet another indication to an already expanding list of reasons to prescribe these agents. This review covers where the evidence stands, which patients are candidates for treatment, and how the emerging therapeutic landscape is likely to evolve.

The transition from NASH (nonalcoholic steatohepatitis) to MASH (metabolic-associated steatohepatitis) reflects the updated nomenclature adopted in 2023, emphasizing the metabolic drivers of the disease. MASH affects an estimated 5% of the global adult population, with progression to cirrhosis, hepatocellular carcinoma, and liver-related mortality representing the primary clinical concerns.

Why the Name Change Matters Clinically

The shift from NASH to MASH is more than a labeling exercise. The old terminology — "nonalcoholic" — defined the disease by what it was not rather than what it was, and it carried an implicit message that modest alcohol use excluded the diagnosis. The new nomenclature centers on the metabolic dysfunction that drives the disease: insulin resistance, visceral adiposity, and the downstream inflammatory cascade that produces steatohepatitis and progressive fibrosis. This reframing encourages clinicians to think about MASH as a metabolic disease with hepatic manifestations rather than a liver disease with metabolic associations. That distinction matters because it points treatment toward addressing the metabolic root causes — not just the liver pathology in isolation.

Resmetirom: The First Approved MASH Therapy

Resmetirom (Rezdiffra), a thyroid hormone receptor beta agonist, received FDA approval in March 2024 for adults with noncirrhotic MASH and moderate to advanced fibrosis (stages F2-F3)[3]. The MAESTRO-NASH trial demonstrated MASH resolution without worsening fibrosis in 25.9% of patients at 80 mg and 29.9% at 100 mg versus 9.7% with placebo[1]. Fibrosis improvement of one or more stages occurred in 24.2% (80 mg) and 25.9% (100 mg) versus 14.2% with placebo[2].

What These Numbers Mean for Your Patients

The MAESTRO-NASH results should be interpreted with realistic expectations. A 29.9% MASH resolution rate at the highest dose versus 9.7% with placebo means roughly one in five patients on resmetirom achieves histologic resolution who would not have resolved on their own. That is clinically meaningful — but it also means the majority of treated patients will not achieve complete resolution. For the patient in front of you, the conversation should frame resmetirom as a tool that meaningfully improves the odds of histologic improvement, not a guaranteed cure. Fibrosis improvement of one or more stages in approximately a quarter of patients is equally important, because fibrosis stage is the strongest predictor of liver-related mortality in MASH. Moving a patient from F3 to F2 changes their long-term prognosis substantially.

Practical Prescribing Considerations

Resmetirom works through selective activation of thyroid hormone receptor beta in the liver, which reduces hepatic fat content and improves lipid metabolism without the systemic thyroid effects that would accompany non-selective thyroid hormone receptor activation. The most common side effects are gastrointestinal — diarrhea, nausea — and are generally mild and self-limited. Thyroid function should be monitored, though clinically significant thyroid dysfunction has been uncommon in trials. The approved indication is specifically for noncirrhotic MASH with F2-F3 fibrosis, meaning the drug is not indicated for patients with steatosis alone, MASH without significant fibrosis, or those who have already progressed to cirrhosis. Confirming fibrosis stage before prescribing is therefore essential.

GLP-1 Agonists in MASH: Semaglutide and Tirzepatide

Semaglutide at the highest tested dose (0.4 mg daily subcutaneous) demonstrated MASH resolution in 59% of patients versus 17% with placebo in Phase 2 data. The SYNERGY trial showed tirzepatide achieved MASH resolution in up to 74% of patients[4], representing potentially the highest response rate of any investigational MASH therapy. Both agents address the metabolic comorbidities (obesity, diabetes) that drive disease progression.

GLP-1 Agonists vs. Resmetirom: How to Think About the Choice

The response rates for GLP-1 agonists in MASH — particularly tirzepatide at 74% — are substantially higher than resmetirom's 29.9%. However, direct comparison is premature: the GLP-1 agonist MASH data come from Phase 2 trials with smaller sample sizes and different patient populations, while resmetirom has Phase 3 data and FDA approval. The more practical consideration for current clinical decision-making is that GLP-1 agonists address the metabolic root causes of MASH (obesity, insulin resistance) while resmetirom addresses the hepatic pathology more directly. For the patient with MASH, obesity, and type 2 diabetes, a GLP-1 agonist treats all three conditions simultaneously — making it an attractive choice regardless of whether a formal MASH indication exists. For the patient with MASH and F2-F3 fibrosis who is not obese and does not have diabetes, resmetirom is the more targeted option. And for the sickest patients — those with advanced fibrosis, significant metabolic comorbidities, and rapidly progressive disease — combination therapy with both a GLP-1 agonist and resmetirom is a logical approach, though the combination has not been studied in a dedicated trial.