Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD). It involves inflammation and damage to the liver, unlike simple fatty liver where only fat accumulates. The global prevalence of NASH has been steadily increasing, mirroring the rise in obesity and type 2 diabetes. Untreated NASH carries significant risks, including progression to advanced liver scarring (cirrhosis) and even liver cancer, making effective treatments a pressing medical need. The treatment landscape for NASH has recently advanced with the approval of the first medication specifically for this condition.
The First Approved NASH Medication
The U.S. Food and Drug Administration (FDA) granted accelerated approval to Rezdiffra (resmetirom) in March 2024 as the first medication specifically indicated for NASH. It functions as a thyroid hormone receptor-beta (THR-β) agonist, targeting a liver pathway. By activating this receptor, resmetirom helps reduce fat accumulation in liver cells and improves their function.
Rezdiffra is prescribed for adults with NASH and moderate to advanced liver fibrosis (F2 to F3). Approval was based on the MAESTRO-NASH clinical trial, which showed a higher percentage of patients on resmetirom achieved NASH resolution without worsening fibrosis, or improved fibrosis by at least one stage without worsening NASH, compared to placebo.
NASH resolution was achieved by 25.9% (80 mg) and 36.6% (100 mg) of resmetirom patients, versus 9.7% on placebo. Fibrosis improved in 24.2% (80 mg) and 25.9% (100 mg) of resmetirom patients, compared to 14.2% on placebo. Common side effects included diarrhea and nausea, which were generally mild to moderate.
Investigational Drugs in Development
A robust pipeline of investigational drugs is currently undergoing late-stage clinical trials for NASH. These emerging therapies explore diverse mechanisms to address the complex pathology of the disease.
Some compounds aim to reduce liver scarring, which is a major driver of disease progression to cirrhosis. These anti-fibrotic agents interfere with the processes that lead to scar tissue formation.
Other experimental drugs focus on metabolic pathways, improving how the body processes fats and sugars. These agents target fatty acid synthesis, glucose metabolism, or insulin sensitivity, reducing fat accumulation and metabolic stress within the liver. Modulating these pathways decreases liver fat, a primary characteristic of NASH.
A third category targets inflammation, a defining feature of NASH that contributes to liver cell damage. These anti-inflammatory agents inhibit various inflammatory pathways or immune cell activation within the liver. Reducing inflammation aims to prevent further liver injury and slow disease progression. The ongoing development of these varied approaches reflects the multifaceted nature of NASH and the hope for more comprehensive treatment options.
Off-Label Treatments and Supplements
Before Rezdiffra’s approval, some medications were prescribed “off-label” for NASH, meaning their use was not explicitly covered by FDA approval. This practice is based on scientific evidence suggesting potential benefits. Two examples are vitamin E and pioglitazone, studied for their effects on liver health in NASH patients.
Vitamin E, an antioxidant, has shown in studies to reduce liver inflammation and fat accumulation in non-diabetic adults with NASH. It neutralizes harmful free radicals that contribute to liver cell damage. Its use is reserved for specific patient profiles, and long-term safety data, especially regarding higher doses, requires careful consideration.
Pioglitazone, primarily used for type 2 diabetes, improves insulin sensitivity, which can reduce liver fat and decrease inflammation. It has demonstrated effectiveness in improving liver histology in NASH patients, with or without diabetes. Despite its benefits, pioglitazone can cause side effects like weight gain and fluid retention, necessitating close medical supervision.
Lifestyle Interventions as a Cornerstone of Therapy
Even with approved medications, lifestyle interventions remain a foundational component of NASH management. Gradual and sustained weight loss is the most effective strategy for reducing liver fat, inflammation, and improving fibrosis in NASH patients. A 5-7% body weight reduction can improve liver fat, while 7-10% or more often leads to NASH resolution and fibrosis improvement.
Dietary modifications play a significant role in achieving and maintaining weight loss. Adopting a Mediterranean-style eating pattern, rich in fruits, vegetables, whole grains, lean proteins, and healthy fats, is particularly beneficial. Reducing processed foods, sugary beverages, and unhealthy saturated and trans fats is also crucial for improving liver health.
Regular physical activity complements dietary changes by contributing to weight loss, improving insulin sensitivity, and reducing liver fat independently. Aiming for at least 150 minutes of moderate-intensity aerobic activity per week, along with strength training, provides significant benefits. These lifestyle changes are indispensable for managing NASH, regardless of pharmacologic treatment.