Nonalcoholic steatohepatitis (NASH) is a form of liver disease characterized by fat accumulation, inflammation, and liver cell damage. As an advanced stage of non-alcoholic fatty liver disease (NAFLD), it can progress to cirrhosis and liver cancer. Glucagon-like peptide-1 (GLP-1) receptor agonists, medications used for type 2 diabetes and obesity, are now showing potential for treating NASH. This suggests a new therapeutic avenue for a condition with limited treatment options.
The Relationship Between NASH, Diabetes, and Obesity
Nonalcoholic steatohepatitis (NASH) is intertwined with metabolic disorders like type 2 diabetes and obesity and is often described as the liver’s manifestation of metabolic syndrome. The prevalence of NAFLD is around 75% in patients with type 2 diabetes and 90% in the obese population. This relationship is bidirectional, as NAFLD increases the risk of developing type 2 diabetes, while diabetes worsens the progression of NAFLD to NASH and fibrosis.
The primary driver of this connection is insulin resistance, where the body’s cells do not respond well to insulin. In obesity and type 2 diabetes, dysfunctional fat tissue releases excess fatty acids into the bloodstream. This overflow, combined with high blood sugar, leads to fat accumulation in the liver, a condition called steatosis. This fat buildup triggers cellular stress, inflammation, and oxidative stress, marking the transition from simple fatty liver to NASH. Over time, this chronic inflammation can lead to the formation of scar tissue, known as fibrosis, which impairs liver function.
How GLP-1 Agonists Address Liver Health
GLP-1 receptor agonists address liver health through indirect effects that target the root causes of NASH. These medications mimic the natural GLP-1 hormone, which stimulates insulin secretion. By improving glycemic control and enhancing insulin sensitivity, these drugs counter the insulin resistance that drives fat accumulation in the liver.
GLP-1 agonists also aid in weight management. They act on appetite centers in the brain to increase fullness and slow stomach emptying, which reduces calorie intake and leads to weight loss. Since obesity is a risk factor for NASH, the weight loss prompted by these drugs—between 5% and 15% of body weight—alleviates metabolic pressure on the liver. This reduces fat transport to the liver, mitigating steatosis.
Beyond these indirect benefits, emerging evidence suggests GLP-1 agonists may also have direct effects on the liver. While the presence of GLP-1 receptors on human liver cells is still under investigation, some studies indicate these drugs might directly reduce fat production and inflammation within the cells. This suggests a protective mechanism independent of weight loss, though improved metabolic health remains the primary driver of their efficacy.
Clinical Trial Evidence for NASH Treatment
Clinical trials for GLP-1 agonists in NASH have shown promising results. The primary goal of these studies is achieving “NASH resolution without worsening of fibrosis.” This means reducing liver inflammation and cell injury without the progression of existing liver scarring, indicating the disease’s damaging processes have been halted.
One prominently studied drug is semaglutide. In a phase 2 trial, 59% of patients treated with daily semaglutide achieved NASH resolution without worsening fibrosis after 72 weeks, compared to 17% of those on a placebo. While the drug reduced inflammation, it did not produce a statistically significant improvement in the fibrosis stage in that study. Participants also experienced weight loss, reinforcing the link between metabolic and liver health.
Tirzepatide, a dual agonist for GLP-1 and GIP receptors, has also shown positive results. In its phase 2 trial, 61.3% of patients achieved NASH resolution without their fibrosis worsening. These findings position GLP-1 agonists as a promising class of drugs for managing NASH. Ongoing phase 3 trials are expected to provide more data on their long-term impact on fibrosis.
Regulatory Status and Clinical Application
No GLP-1 agonist is currently approved by the U.S. Food and Drug Administration (FDA) specifically for NASH. These medications are approved for type 2 diabetes and obesity, which often coexist with NASH. This leads to “off-label” prescribing, where physicians use a drug for an unapproved condition based on scientific evidence. For patients with NASH who also have diabetes or obesity, a GLP-1 agonist can be prescribed for the approved conditions, with the added benefit of addressing liver health.
The landscape of NASH treatment is evolving. In March 2024, the FDA granted accelerated approval to Rezdiffra (resmetirom), the first medication indicated for adults with noncirrhotic NASH and moderate-to-advanced liver fibrosis. This approval provides a dedicated therapeutic option for patients and marks a new era in NASH management.
The availability of Rezdiffra does not diminish the potential of GLP-1 agonists. Different medications with distinct mechanisms may become part of a broader treatment strategy. As research continues, GLP-1 agonists may eventually gain a formal indication for NASH or be used in combination with other therapies.