Currently, resmetirom (Rezdiffra®), a thyroid hormone receptor beta partial agonist, is the only FDA-approved medication for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), formally known as nonalcoholic steatohepatitis or fatty liver disease. MASH is a progressive liver condition with an estimated global prevalence of 4 to 6%. Its strong association with obesity has prompted researchers to evaluate the effects of weight-loss GLP therapies, specifically semaglutide and tirzepatide, on MASH pathology. A 72-week interim analysis from a placebo-controlled semaglutide study (N=800) in MASH patients with stage 2 or 3 fibrosis was recently published. The analysis found that semaglutide (2.4 mg) caused resolution of steatohepatitis without worsening of fibrosis in 62.9% of patients, compared to 34.3% in the placebo group (p<0.001). A reduction in liver fibrosis without worsening of steatohepatitis occurred in 36.8% and 22.4%, respectively (p<0.001). Semaglutide-treated patients lost 10.5% of their body weight compared to 2.0% with placebo (p<0.001). As expected, gastrointestinal adverse events were more frequent in the semaglutide group.

These results are consistent with a previous 52-week study (N=190) involving tirzepatide, where MASH resolution without worsening of fibrosis was observed in 62% of tirzepatide-treated patients (15 mg) and 10% of placebo-treated patients (p<0.001). Weight loss in this study was 15.6% and 0.8%, respectively.

While results from different studies are not comparable linearly, nothing in resmetirom's pivotal trial suggests that it is superior to semaglutide or tirzepatide. Furthermore, it does not cause weight loss, giving it no benefit in other obesity-related conditions. Resmetirom also has drug interactions and requires lab monitoring, while GLP-1 therapies generally do not. The effects of these drugs on long-term clinical outcomes like cirrhosis and liver failure are being evaluated in ongoing studies. MASH indications for semaglutide and tirzepatide are likely forthcoming.

• Semaglutide vs Placebo for MASH, NEJM (2025)
• Tirzepatide vs Placebo for MASH, NEJM (2024)
• Resmetirom (Rezdiffra®) review