Lifestyle modifications and control of cardiometabolic risk factors are foundational to the management of all patients with metabolic dysfunction–associated steatotic liver disease, but those with steatohepatitis and moderate fibrosis who are at risk of developing advanced liver disease may also need more targeted pharmacologic therapy, according to hepatologist Zobair M. Younossi, MD, MPH.
Weight loss is a critical starting point, Dr. Younossi said. For patients who are overweight or obese, he recommended a reduction of 10% or more in total body weight to foster improvement of steatohepatitis and fibrosis. Even patients with MASLD of normal weight should strive for a 3% to 5% reduction of total body weight, according to new global consensus recommendations from the Global NASH/MASH Council (Gastroenterology 2025 Apr 11. doi:10.1053/j.gastro.2025.02.044).
In a presentation at the 2025 Expert Strategies in Endoscopy, Gastrointestinal and Liver Disorders Course, Dr. Younossi, the chairman of the global council, and a professor and the chairman of Beatty Liver and Obesity Research at Inova Health System, in Falls Church, Va., said the council recommended a Mediterranean or similar plant-based diet and calorie reduction.
In addition, he suggested optimizing physical activity, aiming for 150 to 300 minutes of moderate-intensity aerobic activity per week, or 75 to 150 minutes of vigorous-intensity activity weekly, adding that it also is important that patients reduce sedentary time. Other recommendations include avoiding smoking, and the council noted that it is particularly vital that patients with advanced disease abstain from alcohol.
Carrying out this strategy isn’t as simple as it sounds, Dr. Younossi said. “The issue here is that lifestyle recommendations have been made for a long time, but implementation is difficult,” he added, acknowledging that sustaining a healthier lifestyle is challenging. A multidisciplinary team—including a hepatologist, an endocrinologist, a behavioral health expert, a dietitian and an exercise specialist—should guide patients in their efforts.
“Given that fatty liver is so common and increasing in incidence, all practitioners need to know about this disease,” said Prateek Sharma, MD, MASGE, the co-director of the Expert Strategies course and a professor of medicine at the University of Kansas School of Medicine, in Kansas City. “Increasing diabetes, cholesterol and metabolic syndrome are probably contributing to the increase in fatty liver,” Dr. Sharma added, in addition to obesity.
New and Emerging Pharmacologic Options
For patients who have progressed metabolic dysfunction-associated steatohepatitis (MASH) and notable fibrosis, there are now pharmacologic options to directly address liver damage. In March 2024, the FDA approved resmetirom (Rezdiffra, Madrigal) in conjunction with diet and exercise to treat adults who have MASH with moderate to advanced fibrosis but no cirrhosis. The approval followed a phase 3 randomized controlled trial that found both the 80- and the 100-mg doses of resmetirom were superior to placebo in terms of MASH resolution and improvement in liver fibrosis by at least one stage (N Engl J Med 2024;390[6]:497-509).
Another phase 3 trial evaluating semaglutide (Wegovy, Novo Nordisk) in MASH and moderate or advanced liver fibrosis found that a once-weekly dose of 2.4 mg improved liver histologic results (N Engl J Med 2025;392[21]:2089-2099). Several other glucagon-like peptide-1 receptor agonists and dual agonists have shown promise in clinical trials, Dr. Younassi said. ”However, gastrointestinal side effects of these drugs and overall tolerability in real-world settings remain concerns that warrant further investigation. In addition, long-term access and affordability must be evaluated through well-designed health economic analyses,” he added.
Moreover, he noted that investigational agents targeting different mechanisms, such as fibroblast growth factor-21 agonists and pan-peroxisome proliferator–activated receptor agonists, have advanced to phase 3 clinical trials after demonstrating encouraging results in phase 2 studies (Gastroenterology 2025 Apr 11. doi:10.1053/j.gastro.2025.02.044).
“It is highly plausible that these therapies will eventually be used in combination and tailored to individual patients based on their specific risk profiles,” Dr. Younossi said. “For example, patients with severe metabolic abnormalities may benefit from regimens targeting multiple metabolic pathways, while those with advanced fibrosis may require therapies with strong anti-fibrotic activity.
“Given the growing global clinical, economic and humanistic burden of metabolic dysfunction–associated steatotic liver disease and MASH, ongoing research in this area remains both highly relevant and urgently needed.”
—Susan Kreimer
Dr. Sharma reported no relevant financial disclosures. He is a member of the Gastroenterology & Endoscopy News editorial board. Dr. Younossi reported financial relationships with Abbott, Akero, Aligos, Boehringer Ingelheim, Bristol Myers Squibb, CymaBay, GSK, Intercept, Ipsen, Madrigal, Merck, Novo Nordisk, Sanofi and Siemens.
This article is from the August 2025 print issue.