Weight Loss Medications Show Promise in MASLD, MASH

As providers increasingly turn to weight-loss medications for conditions like metabolic dysfunction-associated steatotic liver disease (MASLD), a new review published in the World Journal of Gastroenterology highlights the growing evidence supporting the class of treatment as effective, and often safe, options for managing the complex liver condition formerly known as non-alcoholic fatty liver disease.¹

MASLD now affects nearly 30% of adults worldwide, making it the most prevalent chronic liver disease. Driven primarily by obesity, insulin resistance, and chronic inflammation, the disease can progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis. Left untreated, MASLD not only damages the liver but also increases the risk of heart disease, kidney failure, and cancer. Yet, early-stage MASLD often goes undiagnosed due to its silent symptoms, leaving many patients untreated until liver damage becomes advanced.

“Sustained weight loss has been shown to improve steatosis, inflammation, and even fibrosis, with clinical benefits observed from reductions as modest as 5%, and more profound histological improvement with ≥10% weight loss,” wrote the researchers. “However, achieving and maintaining weight loss through lifestyle modification alone remains challenging for most patients. In this context, anti-obesity medications have emerged as a promising adjunct.”

Among available treatments, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide (Victoza, Saxenda; Novo Nordisk) and semaglutide (Ozempic, Wegovy; Novo Nordisk), currently offer the strongest evidence for improving liver outcomes, while dual and triple incretin agonists represent exciting but still investigational options.

GLP-1 RAs, originally developed for diabetes and obesity, promote weight loss while offering direct liver benefits: reducing hepatic fat, improving liver enzymes, and slowing fibrosis progression. Clinical trials including the LEAN study demonstrated histological improvement and steatohepatitis resolution with liraglutide, while semaglutide has shown similar effects at higher doses.

In August this year, the FDA gave the greenlight to semaglutide, marketed as Wegovy, specifically for MASH, marking the first approval of this kind. Approval was based on the phase 3 ESSENCE trial, which showed that 63% of patients achieved resolution of steatohepatitis without fibrosis worsening and 37% of patients achieved improved fibrosis without steatohepatitis worsening.²

Notably, highlighted the researchers, GLP-1 RAs appear safe in patients with compensated cirrhosis, though their use in more advanced disease requires caution due to limited data and risks like malnutrition or gastrointestinal side effects.

Newer incretin-based agents are showing even more striking results. Tirzepatide (Mounjaro; Zepbound; Eli Lilly), a dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonist, has demonstrated superior weight loss (up to 20%) and marked reductions in liver fat in phase 3 trials, while Eli Lilly’s investigational retatrutide, a triple GLP-1/GIP/glucagon agonist, has reported weight loss exceeding 24% in early studies. However, while these next-generation drugs show metabolic and hepatic benefits, researchers caution that biopsy-confirmed improvements in fibrosis are still lacking.

Meanwhile, FGF-21 analogs such as Akero Therapeutics’s investigational efruxifermin have shown biopsy-confirmed improvements in fibrosis among patients with moderate disease, underscoring their potential as targeted liver therapies.

Centrally acting agents like phentermine/topiramate and naltrexone/bupropion aid weight reduction but lack MASLD-specific data and carry potential risks such as hepatotoxicity, teratogenicity, or neuropsychiatric side effects.

The researchers note that while these therapies mark a milestone in MASLD management, global inequities persist, with high drug costs and limited insurance coverage restricting access in low-resource settings, where obesity and MASLD are often most prevalent. The group urged tiered access strategies and inclusion of high-risk patients in public health programs to avoid widening disparities.

They also emphasized that future research focus on long-term safety, advanced disease, and real-world populations to transform these promising therapies into standard care.

References:

1. Concepción-Zavaleta MJ, Fuentes-Mendoza JM, Gonzáles-Yovera JG, et al. Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review. World J Gastroenterol. 2025;31(37):111435.

2. FDA approves treatment for serious liver disease known as ‘MASH’. FDA. Published August 15, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-liver-disease-known-mash