Jörn Schattenberg, MD, is a professor of medicine and director of the Metabolic Liver Research Program at the University Medical Center Mainz in Germany.

Jörn Schattenberg, MD

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 

.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 

. 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.

Does Semaglutide Work for MASH in Patients Without Obesity?

“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.

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.

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

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

Videos

Jörn Schattenberg, MD, discusses ESSENCE data showing semaglutide 2.4 mg improved liver markers in patients with MASH and a BMI below 27 kg/m².

ESSENCE: Semaglutide Improves Liver Markers in MASH Without Obesity

Jörn Schattenberg, MD: Preventing MASH Cirrhosis Progression with Pegozafermin

Findings from a posthoc analysis of the phase 2b ENLIVEN trial suggest pegozafermin, an FGF21 analog, may play an important role in preventing progression to cirrhosis in patients with 

The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD)

 in San Diego, California, by Jörn Schattenberg, MD, a professor of medicine and director of the Metabolic Liver Research Program at the University Medical Center Mainz in Germany.

Pegozafermin received Breakthrough Therapy Designation for MASH with fibrosis from the US Food and Drug Administration on September 21, 2023. The decision was supported by data from the ENLIVEN trial demonstrating both the 44 mg every 2 weeks and 30 mg weekly doses met the primary histology endpoints and also had statistically significant and clinically meaningful improvements in liver fat, noninvasive markers of liver fibrosis and inflammation, and meaningful improvements in other metabolic and lipid markers.

In an interview with HCPLive, Schattenberg reviewed key findings from the posthoc analysis, which focused on patients with F3 fibrosis who progressed to cirrhosis within the study’s 24-week duration. Although he noted cirrhosis was not an endpoint that was predefined in the phase 2b ENLIVEN study, this data was still collected in the trial and he indicated it was something he and other investigators were interested in exploring.

In total, 13 of 106 patients with F3 fibrosis at baseline were determined to have progressed to cirrhosis after 24 weeks of treatment. While both placebo and pegozafermin groups experienced some progression, Schattenberg pointed out treatment with pegozafermin led to a reduction in the proportion of patients with baseline F3 fibrosis who progressed to cirrhosis. Additionally, pegozafermin-treated patients demonstrated significant histological improvements and improvement in noninvasive tests, suggesting the drug’s potential clinical benefit in patients with histological fibrosis progression.

“Even in patients who hit cirrhosis, treatment with pegozafermin led to favorable anti-inflammatory responses in these patients… I'm fairly confident that these improvements in NITs will translate into a clinically meaningful benefit,” he said.

Schattenberg also called attention to pegozafermin’s safety and tolerability, even in patients with more advanced disease. He highlighted a lack of side effects or treatment-emergent adverse events that led to treatment discontinuation.

Editors’ note: Schattenberg has relevant disclosures with Boehringer Ingelheim, Gilead Sciences, Intercept, Ipsen, Inventiva Pharma, Madrigal Pharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sanofi, Astra Zeneca, 89Bio, and others.

Schattenberg J, Hartsfield C, Sanyal A, et al. Pegozafermin reduced progression to cirrhosis: A post-hoc analysis from the Phase 2b ENLIVEN study. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.

Brooks A. Pegozafermin Enters Phase 3 Clinical Trial Program for MASH, Fibrosis. HCPLive. March 12, 2024. 

https://www.hcplive.com/view/pegozafermin-enters-phase-3-clinical-trial-program-mash-fibrosis

Pegozafermin, an FGF21 analog, shows promise in preventing cirrhosis progression in patients with metabolic dysfunction-associated steatohepatitis (MASH), as indicated by a posthoc analysis of the phase 2b ENLIVEN trial. The study, presented at The Liver Meeting 2024, revealed that pegozafermin significantly reduced the progression to cirrhosis in patients with F3 fibrosis. The drug demonstrated histological improvements and favorable anti-inflammatory responses, with no significant adverse events leading to discontinuation. Pegozafermin has received Breakthrough Therapy Designation from the FDA for MASH with fibrosis.

Schattenberg reviews results from a posthoc analysis of the ENLIVEN study suggesting pegozafermin’s impact on preventing progression to cirrhosis. 

Jörn Schattenberg, MD: Pegozafermin and Preventing Progression to Cirrhosis in MASH

Pegozafermin, an FGF21 analog, may play an important role in preventing progression to cirrhosis in patients with 

, according to findings from a posthoc analysis of the phase 2b ENLIVEN trial.

Pegozafermin was granted Breakthrough Therapy Designation for MASH with fibrosis by the US Food and Drug Administration on September 21, 2023, based on data from the ENLIVEN trial demonstrating both the 44 mg every 2 weeks and 30 mg weekly doses met the primary histology endpoints and also had statistically significant and clinically meaningful improvements in liver fat, non-invasive markers of liver fibrosis and inflammation, and meaningful improvements in other metabolic and lipid markers.

, Schattenberg highlighted FGF21 as a "metabolic master regulator," describing its influence on multiple organs and tissues to correct metabolic imbalances. As an FGF21 analog, he noted pegozafermin’s potential to prevent progression to cirrhosis in patients with MASH.

The posthoc findings he presented at AASLD showed treatment with pegozafermin led to a reduction in the proportion of patients with baseline F3 fibrosis who progressed to cirrhosis. Of note, relative to F3 progressors on placebo, progressors receiving pegozafermin demonstrated improvement in histological disease activity and liver-related noninvasive tests, suggesting pegozafermin may have clinical benefits in patients with histological fibrosis progression.

“I see these patients with cirrhosis in my clinic every day. I see them in end-stage, with ascites, bleeding, varices, cancer, and that's really something that we could have prevented, because the disease is slowly progressive,” Schattenberg explained.

Beyond preventing these complications, he also cited the importance of preventing progression to cirrhosis for preserving patients’ quality of life and their ability to function on a daily basis.

Pegozafermin, an FGF21 analog, shows promise in preventing cirrhosis progression in patients with metabolic dysfunction-associated steatohepatitis (MASH), as demonstrated in a posthoc analysis of the phase 2b ENLIVEN trial. The study, presented at The Liver Meeting 2024, highlighted pegozafermin's ability to improve liver histology and non-invasive fibrosis markers. The US FDA granted it Breakthrough Therapy Designation for MASH with fibrosis. Pegozafermin's potential to enhance patients' quality of life by preventing cirrhosis progression underscores its clinical significance.

Schattenberg explains pegozafermin’s mechanism of action and describes the importance of preventing progression to cirrhotic MASH.

Jörn Schattenberg, MD

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