Semaglutide shows promise in MASH

The phase 3 ESSENCE trial, published in NEJM, reports that once-weekly semaglutide 2.4 mg achieves significant histologic improvements in patients with MASH and stage F2–F3 fibrosis.

The ESSENCE trial

Metabolic dysfunction–associated steatohepatitis (MASH), which has replaced the term nonalcoholic steatohepatitis (NASH), is the progressive, inflammatory form within the spectrum of metabolic dysfunction–associated steatotic liver disease (MASLD). It can silently progress to cirrhosis, hepatocellular carcinoma, and liver-related death, while most excess mortality in this population remains cardiovascular. This dual burden, hepatic and cardiometabolic, has made the search for effective therapies especially urgent. Until recently, treatment options were limited to lifestyle interventions and management of comorbidities.

ESSENCE is a landmark phase 3, multicenter, randomized, placebo-controlled trial enrolling 1,197 adults with biopsy-confirmed MASH and stage F2–F3 fibrosis across 37 countries and 253 centers. Patients were randomized 2:1 to once-weekly semaglutide 2.4 mg or placebo, with liver biopsies at baseline and week 72. The co-primary endpoints were resolution of steatohepatitis without fibrosis worsening and at least one stage of fibrosis regression without steatohepatitis worsening.

The trial is designed in two parts: this interim analysis reports 72-week histology; the ongoing part 2 will follow patients up to 240 weeks for hard clinical outcomes such as cirrhosis-free survival. Stratification at randomization accounted for diabetes status, fibrosis stage, and geography, ensuring balance across key risk groups.

Results at 72 weeks

Semaglutide significantly outperformed placebo on both primary endpoints: 62.9% of treated patients achieved resolution of steatohepatitis without fibrosis worsening, compared with 34.3% in the placebo group. Fibrosis regression of at least one stage occurred in 36.8% versus 22.4%, respectively. Importantly, about one third of patients receiving semaglutide met both endpoints simultaneously, twice the proportion observed with placebo.

Secondary endpoints painted a consistent picture: non-invasive fibrosis markers, liver stiffness by elastography, aminotransferases, and composite risk scores all favored semaglutide. The metabolic benefits were equally robust: an average 10% reduction in body weight compared to just 2% in controls, alongside improvements in glycemia, blood pressure, and lipid parameters. These findings are consistent with the drug’s known metabolic effects, suggesting that hepatic improvements are closely linked to systemic changes in weight, insulin resistance, and cardiometabolic risk factors.

Safety profile

As expected, gastrointestinal adverse events were more common with semaglutide, including nausea, diarrhea, constipation and vomiting. However, discontinuation rates were low (2.6% in the semaglutide arm vs 3.3% in placebo), and serious adverse events occurred at comparable rates. Acute pancreatitis was rare and similar across groups. No new hepatic safety signals emerged during the study period, reinforcing the established safety profile of GLP-1 receptor agonists.

Broader implications

These interim results should be interpreted with caution: histologic improvements remain surrogate endpoints, and prior trials in this field have shown histologic gains that failed to translate into meaningful clinical outcomes. Nevertheless, the magnitude and consistency of benefit across histology, non-invasive measures, and systemic metabolism set semaglutide apart.

Commentators have emphasized the holistic value of GLP-1 therapy: not only modifying liver histology, but also improving cardiovascular outcomes, as demonstrated in the SELECT trial (obese patients without diabetes) and SUSTAIN-6 (patients with diabetes). In contrast, resmetirom has demonstrated histologic efficacy but has not yet shown cardiovascular benefit in outcome trials. Given that most MASH patients die from cardiovascular causes, semaglutide may ultimately offer a more comprehensive therapeutic profile.

Regulatory momentum and future directions

The ESSENCE trial provides the strongest evidence to date that a GLP-1 receptor agonist can modify the histologic course of MASH. By targeting both hepatic pathology and systemic metabolic dysfunction, semaglutide may become a cornerstone therapy for this highly prevalent condition with substantial morbidity and mortality. For now, clinicians should view semaglutide as a promising disease-modifying agent, while awaiting confirmation that these histologic gains translate into long-term clinical benefit.

In August 2025, the FDA granted accelerated approval for semaglutide (Wegovy) in adults with biopsy-confirmed MASH and moderate-to-advanced fibrosis, marking the first GLP-1 therapy authorized for this indication. Approval is conditional, requiring confirmation of clinical outcomes in the ongoing extension of ESSENCE.

Looking ahead, several questions remain. Will histologic improvements translate into reduced progression to cirrhosis, hepatic decompensation, or liver-related mortality? How will clinicians choose between semaglutide and resmetirom, or consider them in combination? And how will access and cost influence real-world adoption?

Sources and Further Reading
  1. Sanyal AJ, Neuschwander-Tetri BA, Ratziu V, et al. Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. N Engl J Med. 2025;393:251-263. doi:10.1056/NEJMoa2413258
  2. Simon TG. Semaglutide for Metabolic Dysfunction–Associated Steatohepatitis. N Engl J Med. 2025;393:. doi:10.1056/NEJMe2504717
  3. FDA. Wegovy (semaglutide) accelerated approval for MASH with fibrosis (press release, Aug 2025).
  4. Harrison SA, et al. Resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497-509.
  5. SELECT trial investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med.2023;389:2221-2234.
  6. Mandrola J. Perhaps the strongest benefit of GLP-1 agonists is… Sensible Medicine (Substack), May 2025.