The world is all abuzz about the transformative effects of GLP-1 drugs like semaglutide (Ozempic, Rybelsus, Wegovy) to treat overweight and obesity. But research shows there are often indirect effects: Lower weight from GLP-1s may lead to better health outcomes for heart disease, high blood pressure, diabetes, and – possibly – nonalcoholic fatty liver disease, which doctors now call metabolic dysfunction-associated steatotic liver disease, or MASLD.
Novo Nordisk in November reported promising early results from an ongoing clinical trial on Wegovy for a serious form of MASLD. The company says it will seek FDA approval next year.
If approved, semaglutide would be only the second drug FDA-approved to treat fatty liver disease. The first one, resmetirom (Rezdiffra, approved in spring 2024), works directly in the liver by “reactivating” liver cells that can reduce liver fat. Less liver fat means less inflammation and scarring (fibrosis), along with less of a chance of severe, permanent damage to the liver with that scarring (cirrhosis).
Semaglutide seems to achieve the same thing indirectly through weight loss – something scientists know helps improve fatty liver disease. Wegovy suppresses appetite and body weight and thus reduces the amount of fat that could pile up in the liver.
Improving Access
Lydia Alexander, MD, already prescribes weight loss drugs to help patients with weight-induced conditions, such as sleep apnea, joint pain, high blood pressure, and high cholesterol.
“We’re treating the root cause,” says Alexander, president of the Obesity Medicine Association, or OMA.
Although Wegovy is FDA-approved for weight loss, it is not yet FDA-approved for these related conditions. That means prescriptions for them are “off label” and not typically covered by insurance, making them financially out of reach for many people.
If the FDA approves, prescriptions of Wegovy for liver disease could get into the hands of many people who currently can’t afford it, says Alexander.
That is, of course, as long as insurance agrees to cover it.
Having two competing drugs – Rezdiffra and Wegovy, if approved – for fatty liver would help patients, says Adnan Said, MD, a professor at the University of Wisconsin-Madison School of Medicine and Public Health and chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital.
Having more than one agent available allows insurance companies to look at their contracts and may drive down costs, he says.
What We Don’t Know About GLP-1s for Fatty Liver Disease
As of now, the Novo Nordisk research suggests Wegovy is only acting indirectly on the liver through weight loss. But further research may reveal other, more direct mechanisms, says Ray Kim, MD, president of the American Association for the Study of Liver Diseases.
There are people who have genes that make them more likely to get fatty liver disease who can develop the condition without being overweight. It is unclear whether the people studied in the research who had that condition saw improvements in liver health without losing weight, Kim says. If they did, then weight loss likely wasn’t the cause.
Kim thinks there may be something more than just weight loss at work.
One hypothesis, says Joel Habener, MD, the researcher who discovered GLP-1, is that semaglutide, the main ingredient in Wegovy, changes the way cells make energy in structures called mitochondria.
His research has found that GLP-1 given to fattened mice caused cells to cut back on glucose production, reducing oxidative stress, which can cause inflammation. Inflammation is linked to a host of maladies, from diseases of the heart and blood vessels to dementia. (Habener, a professor at Harvard Medical School, had no role in Novo Nordisk’s latest research.)
“The miracle of GLP-1,” he says, is that it targets the mitochondria, though more study is needed to establish how this works.
Downsides of GLP-1s
On the whole, Habener says, GLP-1s have proven to be quite safe.
They’ve been in use for well over a decade, he says, “and in this time, there is nothing major that's turned up. You just have to be vigilant."
Still, there are some side effects.
A persistent concern, especially for older people, is muscle loss. Muscle mass improves metabolism and insulin sensitivity, not to mention mobility and stability. It’s harder to rebuild muscle after age 60. In addition, Wegovy can cause nausea and vomiting, especially if used incorrectly. And in many cases, it appears that to maintain health benefits from GLP-1s, you may need to take them for life.
It may be that if you learn to eat better and exercise more, you may be able to wean yourself from the drugs, says Alexander from the OMA.
“But if you take it away quickly, you're just going to be right back where you started, and in some people, they may need it for lifelong use. We just don't know the answer yet.”
