ESSENCE: Semaglutide Improves Liver Markers in MASH Without Obesity

Semaglutide 2.4 mg (Wegovy) improved liver enzymes and noninvasive fibrosis biomarkers compared with placebo in participants with metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and a body mass index (BMI) below 27 kg/m², according to a post hoc analysis of the phase 3 ESSENCE trial presented at AASLD The Liver Meeting 2026.¹ The findings build on earlier evidence of histologic benefit in this subgroup.¹

Jörn Schattenberg, MD, of University Medical Center Homburg and Saarland University, presented the analysis and discussed it in an interview with HCPLive. He emphasized obesity is a major driver of MASH but not a prerequisite for disease, and noted a weight paradox in which some patients with a BMI above 40 have less severe liver disease for reasons not yet understood.

“MASH is not equivalent to obesity, but it’s one of the driving forces behind it,” Schattenberg said.

How Did Semaglutide Perform in Patients With MASH and a BMI Below 27?

ESSENCE is an ongoing phase 3 trial of once-weekly subcutaneous semaglutide 2.4 mg vs placebo in adults with MASH and F2-F3 fibrosis.² In the 72-week interim analysis of 800 participants, resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% with semaglutide compared with 34.3% with placebo, supporting accelerated approval from the US Food and Drug Administration in August 2025.²,³ Part 2 of the trial continues to evaluate liver-related clinical outcomes through 240 weeks.²

Of the 800 participants, 106 had a baseline BMI below 27 kg/m².¹ In this subgroup, 67.9% were female, 68.9% were Asian, and 52.8% had type 2 diabetes, reflecting what investigators described as the metabolic and ethnic heterogeneity of nonobese MASH. Semaglutide previously improved both primary histologic endpoints in this subgroup.¹

At Week 72, semaglutide improved alanine aminotransferase (estimated treatment ratio [ETR], 0.61; 95% CI, 0.48-0.77) and aspartate aminotransferase (ETR, 0.66; 95% CI, 0.56-0.79) compared with placebo.¹ The FibroScan-AST score also favored semaglutide (estimated treatment difference [ETD], −0.15; 95% CI, −0.27 to −0.02).¹

Do Fibrosis Biomarkers Improve With Semaglutide in Nonobese MASH?

Noninvasive fibrosis biomarkers favored semaglutide, including enhanced liver fibrosis score (ETD, −0.48; 95% CI, −0.76 to −0.20) and PRO-C3 (ETR, 0.82; 95% CI, 0.70-0.95).¹ Liver stiffness by vibration-controlled transient elastography trended in favor of semaglutide, though the confidence interval crossed 1 (ETR, 0.83; 95% CI, 0.68-1.02). Investigators also reported improvement in cardiometabolic risk factors.¹

According to Schattenberg, the analysis addressed whether a drug developed for obesity might be less effective in patients with a lower BMI.

“In this post hoc analysis, we looked at the BMI below 27 and compared it to the other BMI categories, and the efficacy is actually the same,” he said.

Schattenberg said the findings support the concept of metabolic disease independent of BMI, which he attributed largely to adipose tissue dysfunction and insulin resistance. He noted clinicians may favor weight-reducing agents for patients with obesity and weight-neutral options such as resmetirom for others, and suggested these data support considering semaglutide in patients without obesity. He added the analysis showed no difference in safety signals between lower and higher BMI categories.

Editors’ note: Schattenberg has relevant disclosures with Boehringer Ingelheim, Gilead Sciences, Intercept, Ipsen, Madrigal Pharmaceuticals, Novartis, Novo Nordisk, and others.

References:

1. Schattenberg J, Armstrong M, Bakulin I, et al. Semaglutide improves liver health in non-obese participants with MASH: a post hoc analysis from the phase 3 ESSENCE trial. Presented at: The Liver Meeting 2026; November 5-9, 2026; Denver, CO.

2. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258

3. Brooks A. FDA approves semaglutide (Wegovy) injection 2.4 mg for noncirrhotic MASH. HCPLive. Published August 15, 2025. Accessed November 8, 2026. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash