A Milestone in MASH Therapeutics
The U.S. Food and Drug Administration’s August 2025 decision to grant accelerated approval to Wegovy® (semaglutide 2.4 mg weekly) for metabolic dysfunction associated steatohepatitis (MASH) represents a watershed moment in hepatology. Until this ruling, there had been no officially sanctioned pharmacologic treatment for MASH in the United States, despite the fact that the disease is one of the most common chronic liver disorders, estimated to affect millions of Americans with obesity and type 2 diabetes as key drivers.
MASH, formerly referred to as nonalcoholic steatohepatitis (NASH), is characterized by fatty liver infiltration plus inflammation and fibrosis. It is considered the aggressive form of metabolic-associated steatotic liver disease (MASLD, formerly NAFLD), and it carries a risk of progression to cirrhosis, hepatocellular carcinoma, and ultimately liver transplantation. For decades, hepatologists have been limited to recommending weight reduction, glycemic control, lipid management, and blood pressure control. While lifestyle interventions remain critical, they rarely lead to consistent histological improvement in fibrosis, particularly in patients with advanced disease.
By approving Wegovy in this setting, the FDA has effectively acknowledged that pharmacotherapy now has a defined role in modifying disease progression. Semaglutide is already widely known as a GLP-1 receptor agonist approved for obesity and type 2 diabetes. Its ability to induce significant weight loss and improve insulin sensitivity hinted strongly at liver benefits. The pivotal ESSENCE trial demonstrated that semaglutide treatment resulted in histologic resolution of MASH without worsening of fibrosis in a meaningful proportion of patients, satisfying the surrogate endpoints that underpin accelerated approval.
It is important to stress that the FDA’s decision is conditional77: approval is based on improvement in liver histology, and the sponsor will need to verify longer-term clinical outcomes such as reduced rates of cirrhosis, liver failure, and transplantation. Nevertheless, the precedent is powerful. Wegovy is among the first therapies to be officially recognized as changing the natural history of MASH, not merely alleviating risk factors.
According to Dr. Rohit Loomba, MD, MHSc, Director of Hepatology at UC San Diego, this moment should be seen as “a genuine turning point.” He explains: “For the first time in the United States, patients with MASH and significant fibrosis can be offered a drug that has been shown to improve liver histology. This validates years of research and signals that liver specialists now have pharmacologic tools in their armamentarium.”
Indication and Patient Population
The FDA’s label for Wegovy in MASH is precise: the drug is approved for adults with noncirrhotic MASH who have moderate to advanced fibrosis (F2 F3 on the fibrosis scale). Patients with cirrhosis were excluded from pivotal trials and remain outside the indication. Similarly, those with only simple steatosis or mild fibrosis do not qualify. This makes patient selection critical and requires that hepatologists use noninvasive fibrosis assessment tools, such as transient elastography (FibroScan), magnetic resonance elastography, or blood-based fibrosis panels, to confirm disease stage before prescribing.
This targeted population reflects both the potential benefits and the risks of pharmacologic intervention. In individuals with established but not end-stage fibrosis, halting progression or ideally inducing regression can prevent the cascade toward cirrhosis, portal hypertension, and liver-related complications. By contrast, patients with cirrhosis face risks that outweigh the expected benefit in current data, and clinical trials have not yet demonstrated safety and efficacy in that group.
The requirement that therapy be combined with dietary and lifestyle modification remains central. The FDA’s approval notes that semaglutide should be used “as an adjunct to a reduced-calorie diet and increased physical activity.” This stipulation reflects decades of evidence showing that weight loss of 7 10% can independently improve histology in MASH. What semaglutide offers is pharmacologic leverage for patients who cannot achieve or sustain that target on lifestyle measures alone.
From the clinician’s perspective, this approval is especially relevant for patients with obesity, insulin resistance, and type 2 diabetes, i.e., groups disproportionately affected by MASH and also those most likely to benefit metabolically from GLP-1 receptor agonist therapy. These are the same populations in which Wegovy is already widely prescribed for weight management, which may facilitate real-world uptake in hepatology.
According to Dr. Rohit Loomba, patient identification will be the first test of implementation: “We need to ensure that those with clinically significant fibrosis are prioritized, because these are the patients at highest risk of progression to cirrhosis. Noninvasive testing should be integrated into primary care and endocrinology, so we can identify patients earlier and channel them into hepatology care.”
Loomba also points out that patient counseling must stress that Wegovy is not approved for cirrhosis. “There is a temptation to extrapolate, but the safety and efficacy in cirrhosis are not established. We must adhere to the population studied,” he notes.
This approval therefore creates a new framework: identifying at-risk patients before cirrhosis develops, offering pharmacologic therapy alongside lifestyle modification, and carefully monitoring both liver and metabolic outcomes.
Impact on Hepatology and Gastroenterology Practice
For decades, physicians treating patients with metabolic-associated fatty liver disease have been limited to advising diet, exercise, and cardiometabolic risk reduction—strategies that, while important, were notoriously difficult to sustain at scale. Now, hepatologists have access to a pharmacologic therapy with proven histologic benefit, shifting the conversation from “we can only recommend lifestyle” to “we can offer a drug that directly modifies disease activity.”
In day-to-day practice, this means a greater emphasis on systematic screening and fibrosis staging. Patients with diabetes or obesity who present with elevated liver enzymes or imaging evidence of steatosis may now be referred earlier for noninvasive fibrosis testing. The presence of F2 or F3 fibrosis could trigger not only closer follow-up but also discussion of Wegovy as a therapeutic option. Gastroenterologists and endocrinologists, often the first to encounter these patients, will play an expanded role in multidisciplinary care pathways.
Clinicians will also need to prepare for new monitoring requirements. While semaglutide is familiar from the obesity and diabetes context, in hepatology it must be evaluated not only for weight and glycemic effects but also for histologic and noninvasive markers of fibrosis. This may lead to closer coordination between hepatologists, radiologists, and primary care physicians who can facilitate ongoing assessments.
For patients, the impact is potentially transformative. MASH has long been an under-recognized disease, often diagnosed late when cirrhosis is already established. The availability of an approved therapy may encourage both earlier detection and better adherence to treatment plans, especially as semaglutide also improves metabolic comorbidities.
As Dr. Rohit Loomba observes, “This is not just a hepatology story. It will affect how endocrinologists, obesity medicine specialists, and primary care physicians approach liver health. We are entering an era where liver disease management must be woven into the broader fabric of metabolic care.”
Differentiation vs. Resmetirom
When discussing Wegovy’s approval, it is impossible not to compare it with resmetirom (Rezdiffra™), the thyroid hormone receptor-β agonist that received accelerated FDA approval in 2024 for noncirrhotic MASH with fibrosis. Both are landmark approvals, but they represent different therapeutic philosophies.
According to Dr. Rohit Loomba, the contrast is instructive: “Resmetirom is a liver-directed drug. It reduces hepatic fat content, alters lipid metabolism, and improves fibrosis through mechanisms focused squarely on the liver. Semaglutide, by contrast, is a systemic therapy. It reduces body weight, improves insulin sensitivity, and lowers inflammation across the body. The liver benefits are significant, but they are part of a broader metabolic effect.”
This divergence has important clinical implications. For patients whose primary driver of disease is obesity and insulin resistance, semaglutide may provide the greatest overall benefit—improving not only liver histology but also glycemic control and cardiovascular risk. For those without significant metabolic syndrome but with high hepatic fat burden and fibrosis, resmetirom may be a better fit. Loomba emphasizes that the future may not be about choosing one or the other, but rather understanding which patient subgroups benefit most from each agent, and potentially sequencing or combining therapies.
Another critical distinction lies in the side effect profile. Resmetirom carries lipid effects that require monitoring, including reductions in LDL cholesterol that may necessitate dose adjustments in patients on statins. Semaglutide’s tolerability is dominated by gastrointestinal side effects—nausea, vomiting, diarrhea—which are familiar to clinicians prescribing it for diabetes and obesity. Long-term safety signals differ as well: thyroid receptor modulation raises theoretical concerns about off-target effects, while GLP-1 agonists are more closely scrutinized for gastrointestinal and gallbladder complications.
Loomba underlines the importance of mechanistic diversity in drug development: “We do not want every therapy for MASH to work through the same pathway. Having both a GLP-1 agonist and a thyroid hormone receptor-β agonist gives us complementary tools. One targets systemic metabolic dysfunction; the other targets intrahepatic lipid metabolism. Together, they represent the beginnings of a therapeutic toolbox that we can expand and refine.”
He cautions, however, that both approvals are accelerated and hinge on confirmatory trials. “Neither resmetirom nor semaglutide has yet shown reduction in liver-related mortality in randomized controlled trials. That evidence will take years. But what we have now are validated histologic endpoints that give us confidence we are moving in the right direction.”
For hepatologists, this differentiation means individualized therapy is on the horizon. Treatment decisions will involve weighing comorbidities, tolerability, and patient goals something that simply wasn’t possible when lifestyle advice was the only option.
Expert Commentary and Outlook
With semaglutide now joining resmetirom as an FDA-approved therapy for MASH, hepatologists are entering a new clinical era. Yet as Dr. Rohit Loomba emphasizes, this is only the beginning of a much longer journey.
“We must be very clear with patients and colleagues: accelerated approval means we have demonstrated histologic improvement, not definitive evidence of reduced cirrhosis or liver-related mortality. That evidence will take years of follow-up. At the same time, it would be a mistake to underestimate the importance of this milestone. For the first time, we can look our patients in the eye and say there is a drug specifically approved for MASH.”
One of the most pressing challenges now will be access and affordability. Semaglutide is already a high-cost medication, and supply constraints in obesity medicine have shown how demand can quickly outpace manufacturing capacity. Loomba stresses that insurers and policymakers must recognize the scale of the MASH epidemic and prepare reimbursement structures that allow patients with significant fibrosis to receive treatment without prohibitive out-of-pocket costs.
Integration into clinical pathways is another priority. Screening for fibrosis has historically been inconsistent outside specialist centers. Loomba argues that primary care and endocrinology must become active partners: “If we leave identification solely to hepatologists, we will miss millions of patients. Fibrosis screening must be mainstreamed, just as hemoglobin A1c is in diabetes. Only then will therapies like semaglutide reach the right population at the right time.”
The approval also shifts the research landscape. Combination therapy trials are already under discussion, pairing GLP-1 receptor agonists with thyroid hormone receptor agonists, FXR agonists, or antifibrotic candidates. Loomba believes that polytherapy may ultimately mirror oncology, where multiple agents are layered to target disease from different angles.
Finally, he underscores the importance of continued patient education. Many individuals with MASH are unaware of their diagnosis or assume fatty liver disease is benign. “We must change the narrative. MASH is not just extra fat in the liver—it is a progressive disease with real consequences. Having an approved therapy helps bring urgency to diagnosis and management, but we must also educate patients that lifestyle measures remain essential. Semaglutide is not a free pass; it is a tool that works best when combined with diet and physical activity.”
The outlook, then, is cautiously optimistic. For the first time in history, MASH is treatable with FDA-approved drugs. With continued research, broader screening, and equitable access, hepatology may finally begin to alter the natural history of this silent but devastating disease.
References
- Food and Drug Administration. (2025, August 19). FDA approves treatment for serious liver disease known as MASH. U.S. Food & Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash
- Loomba, R., Neuschwander-Tetri, B. A., Anstee, Q. M., Lawitz, E. J., Powell, E. E., Rinella, M. E., … & Harrison, S. A. (2024). Semaglutide in patients with metabolic dysfunction associated steatohepatitis. New England Journal of Medicine, 390(8), 745 757. https://doi.org/10.1056/NEJMoa2413258