GLP-1s Treat and Even Reverse Some Forms of Liver Disease

In the past two decades, the global prevalence of metabolic dysfunction–associated steatohepatitis (MASH) has increased dramatically as a result of the obesity epidemic. Researchers project that by 2040, rates of MASH will increase by 55%. Prior to that most liver diseases were caused by alcohol use and hepatitis C, a viral infection that primarily affects the liver.

MASH, a preventable form of liver disease previously called nonalcoholic fatty liver disease, is caused by a buildup of visceral fat cells that accumulate on top of the internal organs, in this case the liver, and keep it from functioning properly. The liver’s primary role is to filter blood, nutrients, and bile used for digestion, as well as to remove toxins from the body. Excess fat cells blanket the liver and keep it from working at full capacity.

Fat cells are also metabolically active and can cause a chronic state of inflammation in the part of the body where they reside. Over time, these fat cells can cause cirrhosis of the liver, or permanent scarring. Once patients reach this stage, the only option is a liver transplant.

New Research on Glucagon-Like Peptide 1 (GLP-1) Agonists and MASH

Until recently, the lone treatment for early-stage MASH was weight loss to reduce the number of fat cells that surround the internal organs. But new research has shown that GLP-1 agonists can reduce and even reverse the condition. In a study published last month in The New England Journal of Medicine, researchers were able to show that semaglutide resolved fatty liver and inflammation in over 60% of cases and decreased scar tissue in just over a third of patients.

“These findings suggest that semaglutide may prevent fatty liver disease from progressing to cirrhosis and can indeed reverse the course of the disease,” said Arun J. Sanyal, MD, study author and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University in Richmond, Virginia.

Another study published last year in JAMA Internal Medicine had a similar finding, showing that GLP-1 agonists were associated with less progression of the disease and reduced mortality in patients with MASH and diabetes. Another large-scale observational study published in Nature Medicine found that GLP-1s reduced the risk for hepatic failure, which occurs when the liver is unable to perform basic functions, as well as liver cancer, both of which are downstream consequences of MASH.

How GLP-1s Improve Liver Function

“These medications reduce fat burden, which results in fat loss everywhere, including around the liver,” said Ziyad Al-Aly, MD, an assistant professor in the Division of General Medicine & Geriatrics at Washington University School of Medicine in St. Louis and author of the recent study in Nature Medicine. “When fat cells are reduced in size and volume, the normal liver cells have more room to grow and function.”

These medications also seem to work on reducing the inflammation and oxidative stress caused by metabolic disease, which allows for a better environment for the liver to function.

“Fat is not an inert tissue, it’s metabolically active, causing a slow burn to all the cells surrounding it,” said Al-Aly. These medications keep the disease from progressing and reduce scarring, which improves the damage that’s already been done, he said.

Changing How Primary Care Physicians Diagnose Liver Disease

Primary care physicians are most often the first line of defense against liver disease, and as a result, they need to be vigilant in the way that they screen for the condition, said Charu Sawhney, DO, MPH, an internal medicine physician with Harbor Health in Round Rock, Texas.

Physicians need to be aware that even if liver enzymes appear even slightly elevated, there still could be a reason to utilize these medications to prevent later-stage MASH.

“Normal levels for liver enzymes in some patients can be lower than what labs show,” said Sawhney. This is especially true if a patient has other metabolic risk factors such as diabetes, obesity, or high cholesterol.

If liver enzymes continue to go up even after diet and lifestyle changes, patients might require liver imaging, specifically a wave-based ultrasound called elastography, which measures the elasticity or stiffness of tissues on the liver and can judge if certain portions of it have scarred or hardened. When liver cells change texture and become harder, the scan can estimate levels of fibrosis and, therefore, the stage of MASH that a patient is in.

Additionally, the severity of fatty liver disease depends on other factors besides weight and can sometimes be surprising.

“How bad fatty liver disease is in a patient isn’t always related to how much weight someone has gained,” said Carolynn Francavilla, MD, a nationally recognized obesity physician who owns and operates Green Mountain Partners for Health and Colorado Weight Care, both in Denver.

It’s important for physicians to realize that some patients with fatty liver disease might not have obesity as would be expected. For these patients, adipose tissue seems to accumulate on the liver before it does on other parts of the body. This could be related to the quality of our food system, including the use of sugar substitutes like high fructose corn syrup, which research has shown is even harder on the liver. There might also be a genetic propensity toward fat storage around the organs.

A New Way to Treat MASH

If indeed GLP-1s are a potential treatment in those with MASH, this might also change the way that primary care physicians treat these patients and how the medication is prescribed in those with earlier stages of the disease, said Francavilla. Right now, there’s not an official approval from the US Food and Drug Administration (FDA) for prescribing GLP-1s in patients with MASH, but Francavilla hopes that it’s forthcoming.

“It will be really exciting to have these medications as a treatment option because right now there’s only one medication, and it’s for people who have pretty advanced fatty liver disease,” said Francavilla. This medication, called resmetirom, is approved by the FDA to target a protein in the liver to reduce fat and inflammation and scarring. But GLP-1s can be used much earlier to prevent the condition.

“With so many cases of MASH happening so much younger, it’s a disease that physicians really need to take seriously,” said Sawhney. “If we want to catch this disease at the early stages when we can still do something about it, it’s most likely going to be primary care physicians who see it.”