Turbocharging the GLP-1 agonist used to treat diabetes and obesity may transform treatment for patients with fatty liver disease, says a world-renowned VCU liver specialist.
Phase 2 clinical trial results of the dual agonist drug survodutide to treat fatty liver disease were published today by the New England Journal of Medicine and presented at the annual European Association for the Study of Liver conference in Milan by principal investigator Dr. Arun Sanyal, the director of the VCU Stravitz-Sanyal Institute for Liver Disease and Metabolic Health and professor at VCU School of Medicine.
The study found that after 48 weeks of treatment with survodutide, up to 83 percent of participants saw measurable improvement of their disease: lower levels of liver fat, inflammation and no worsening of the scarring in the organ, known as fibrosis. In 75 percent of patients treated, the disease resolved, meaning their livers were significantly less inflamed, fatty and scarred. In up to 50 percent of treated patients, fibrosis and liver enzymes improved and their disease did not otherwise worsen.
An agonist is a chemical that mimics a hormone and binds with specific receptors in the brain. Drugs like Wegovy and Ozempic, commonly used to treat obesity, are GLP-1 agonists as they resemble a hormone called glucagon-like peptide 1, which stimulates insulin production, helps to lower blood sugar levels and leads to weight loss. Sanyal and other hepatologists have been researching their potential for treating fatty liver disease while also studying whether enhancing the drug with additional agonists that can act directly on the liver could make them more effective.
The new study’s data suggest that the GLP-1 agonist enhanced with a glucagon agonist, like the drug survodutide, “could be a game-changer” for people living with fatty liver disease and the fibrosis or scarring that occurs as the liver disease progresses, Sanyal said.
“These data demonstrate that direct liver targeting with glucagon agonism in addition to GLP-1 effects helps resolves nonalcoholic fatty liver disease and improve fibrosis while maintaining the benefits of GLP-1 agonism,” Sanyal said.
Nonalcoholic fatty liver disease, now called metabolic dysfunction-associated fatty liver disease or MASH, affects about one in four people globally and is closely linked to obesity. A healthy liver contains a small amount of fat, but when it’s more than 5 percent of a liver’s weight, it can lead to serious health issues like cirrhosis, liver cancer, or even the need for a liver transplant.
Currently, only one drug, resmetirom, has FDA approval to treat fatty liver disease, but it is not for all patients.
Mouse studies have suggested that turbocharging the GLP-1 agonist might heighten the beneficial effects of GLP-1 agonists on the liver by directly targeting the organ to increase energy use and reduce fat levels.
“These findings are remarkable and exciting and open a new chapter in drug development for MASH with fibrosis, where a single agent could potentially target both the liver disease and related medical conditions may provide hope for millions who have both MASH with fibrosis and multiple obesity-related ailments,” Sanyal said.
The trial involved 293 adults from 25 countries with MASH and varying stages of fibrosis over two years. For 24 weeks, patients received weekly injections of either a placebo or started at one of three doses of survodutide (2.4 mg, 4.8 or 6 mg). Over time, participants’ dosage was raised to as high as 6mg, and then continued for another 24 weeks. Of the 295 participants, 282, or 96 percent, finished the trial. As with the GLP-1 agonists, gastrointestinal side effects were common, such as nausea, diarrhea and vomiting.
Phase 2 clinical trials test if a new treatment affects the disease. Several Phase 3 clinical trials of survodutide are underway, including a study to see whether the drug helps overweight or obese patients who have fatty liver disease lose weight and reduce their liver fat.
Obesity is a severe public health problem that leads to other ailments such as type 2 diabetes, liver disease, cardiovascular disease and hypertension. More than 33 million Americans have type 2 diabetes, and Sanyal says between 5 percent and 7 percent of individuals develop clinically significant liver disease.
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Rebecca Barnabi
