Narrative Review | Non-communicable Diseases | Hepatobiliary
Tackling the Silent Burden: Semaglutide Offers Hope for MASH Amidst Rising Global and Regional Prevalence
Time to read: 03:48
Time to listen: 06:52
Originally Published: 30 April 2025
Source: NEJM
Type of article: Narrative Review
MedED Catalogue Reference: MNC003
Category: Non-Communicable Diseases
Cross Reference: Hepatobiliary
Keywords: MASH, NASH, MASLD semaglutide, burden of disease, NCDs
This article is a review of recent studies originally published in the NEJM, 30 April 2025. This article does not represent the original research, nor is it intended to replace the original research. Access the full Disclaimer Information.
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Study Context and Purpose
Metabolic dysfunction–associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), has emerged as a major driver of chronic liver disease, particularly when associated with advancing liver fibrosis. It falls under the broader umbrella of metabolic dysfunction–associated steatotic liver disease (MASLD), which is now the most prevalent chronic liver condition worldwide, affecting over 30% of the adult population.1
The health and economic implications of this growing burden are significant. According to recent data from the Global Burden of Disease (GBD) study, MASLD-related mortality and disability are rising rapidly, with the heaviest burden observed in regions such as Latin America and the Middle East. Projections suggest that the global incidence of MASLD could reach 56% by 2040, underscoring its growing public health impact.1,2
Despite this, no pharmacological treatments are currently approved for MASH.
About this Study
This week, we look at a recent study published in the NEJM in April 2025, which presented the findings of a planned interim analysis of an ongoing study aimed at determining whether once-weekly semaglutide (2.4 mg subcutaneously) improved liver histological features in patients with biopsy-confirmed MASH and fibrosis stage F2 or F3.
The study is registered on ClinicalTrials.gov under the number NCT04822181
Study Methodology
The multicentre phase 3 trial is an ongoing, randomised, double-blind, placebo-controlled study designed to evaluate the efficacy of semaglutide in patients with metabolic dysfunction–associated steatohepatitis (MASH). A total of 1,197 participants were enrolled and randomly assigned in a 2:1 ratio to receive either 2.4 mg of semaglutide or placebo once weekly over a 240-week period.
The findings reported in the current analysis are based on a pre-specified interim review conducted at 72 weeks, which included data from the first 800 participants enrolled in the trial.
The co-primary endpoints for this interim analysis—referred to as part 1 of the study—were 1) the resolution of steatohepatitis without progression of liver fibrosis, and 2) the improvement in fibrosis without worsening of steatohepatitis.
These endpoints were selected to capture meaningful histological changes relevant to disease modification in MASH.
Study Findings
Among the 534 patients treated with semaglutide, nearly two-thirds (62.9%) achieved resolution of steatohepatitis without any worsening of liver fibrosis. This was notably higher than the 34.3% seen in the placebo group of 266 patients—a difference of 28.7 percentage points (95% CI, 21.1 to 36.2; P < 0.001).
When specifically examining liver fibrosis, 36.8% of patients in the semaglutide group showed improvement, without any accompanying worsening of steatohepatitis. In contrast, only 22.4% of those receiving the placebo experienced a similar histological benefit, yielding a difference of 14.4 percentage points (95% CI, 7.5 to 21.3; P < 0.001).
A combined outcome—requiring both resolution of steatohepatitis and improvement in fibrosis—was achieved in 32.7% of patients receiving semaglutide. This was double the rate observed in the placebo group (16.1%) (95% CI, 10.2-22.8; P < 0.001).
Weight reduction, a known effect of GLP-1 receptor agonists, was also observed: patients receiving semaglutide lost an average of 10.5% of their baseline body weight by week 72, compared to 2.0% in the placebo group (difference −8.5 percentage points; 95% CI, −9.6 to −7.4; P<0.001).
There was no significant difference between groups in self-reported pain scores. However, gastrointestinal side effects were reported more frequently among patients receiving semaglutide.
A combined outcome—requiring both resolution of steatohepatitis and improvement in fibrosis—was achieved in 32.7% of patients receiving semaglutide. This was double the rate observed in the placebo group (16.1%) (95% CI, 10.2-22.8; P < 0.001).
Discussion
While metabolic dysfunction-associated steatohepatitis (MASH), formerly known as NAFLD, is not explicitly identified within South Africa's "quadruple burden of disease," its growing prevalence—particularly in the context of non-communicable diseases (NCDs)—is undeniable. The increasing rates of obesity and type 2 diabetes, both key drivers of metabolic dysfunction, suggest that MASH represents a significant and under-recognised component of the country's NCD landscape.
As MASH progresses, it can lead to advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma, further compounding the strain on an already burdened healthcare system. Addressing MASH, therefore, is not simply a concern for hepatology practitioners —it is a broader public health imperative.
The interim results from this phase 3 trial provide encouraging evidence that semaglutide, administered once weekly at a dose of 2.4 mg, offers clinically meaningful histological improvements in patients with MASH and moderate to advanced fibrosis. Significant rates of steatohepatitis resolution, reduction in fibrosis, and substantial weight loss were observed. Although gastrointestinal side effects were more frequently reported, the overall safety profile was acceptable, supporting the continued investigation of semaglutide as a potential disease-modifying therapy.
However, the cost of GLP-1 receptor agonists, such as semaglutide, remains a significant barrier to widespread use in low- and middle-income countries. As evidence accumulates regarding the efficacy of these agents, there is an urgent need for policy-level discussions on access, affordability, and integration into public health strategies.
MASH may not yet be fully visible in South Africa's disease policy frameworks, but studies like this point to both the scale of the problem and a potential way forward.
Original Study
Sanyal, A. J., Newsome, P. N., Kliers, I., Østergaard, L. H., Long, M. T., Kjær, M. S., Cali, A. M. G., Bugianesi, E., Rinella, M. E., Roden, M., Ratziu, V., & ESSENCE Study Group (2025). Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. The New England journal of medicine, 392(21), 2089–2099. https://doi.org/10.1056/NEJMoa2413258
Additional References
1. Miao, L., Targher, G., Byrne, C. D., Cao, Y. Y., & Zheng, M. H. (2024). Current status and future trends of the global burden of MASLD. Trends in endocrinology and metabolism: TEM, 35(8), 697–707. https://doi.org/10.1016/j.tem.2024.02.007
2. Clinical World Trials. Metabolic dysfunction-associated steatohepatitis (MASH): A growing cardiovascular concern [Infographic]. Retrieved 30 June 2025, Cardiovascular-Infographic-Metabolic-Dysfuction-Associated-MASH.pdf
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