Ozempic and Mounjaro have another benefit: treating inflammation
A new study in mice shows that popular weight loss drugs can lower inflammation. What might this mean for the treatment of other diseases and neurodegenerative conditions?
Ozempic, Mounjaro, and similar drugs have dominated headlines in recent years as research has shown how effective they are for treating type 2 diabetes and obesity. But a new study reveals this class of drugs, known as GLP-1 agonists, may also reduce inflammation throughout in the body. That finding suggests they may be useful for treating a wide range of diseases, such as Alzheimer’s or Parkinson’s, or at least inspire research into new ways to treat neurodegenerative or autoimmune diseases.
The new study, published in Cell Metabolism in December, suggests that one major way the drugs work is by causing the brain to send signals to reduce inflammation throughout the body.
This has “broad implications” in part because of how widely used these drugs are, says Mike Schwartz, an endocrinologist at the University of Washington in Seattle who was not involved in the study.
We think about using these drugs to treat obesity and type 2 diabetes, but maybe there are other ways we can use them, says Schwartz.
Inflammation refers to the immune system response to perceived threats in the body. Good inflammation occurs when the immune system gears up to fight a pathogen, such as a bacteria or virus, but metabolic diseases, such as type 2 diabetes and obesity, involve unhealthy inflammation that can injure tissues.
“We need that good inflammation to fight infection,” says senior author Daniel Drucker, an endocrinologist at the Lunenfeld-Tanenbaum Research Institute and University of Toronto in Canada. “But we don’t want inflammation to persist over time, particularly if we have these metabolic conditions, because it will cause heart disease, it will cause diabetes, it will cause obesity complications.”
It has long been known that inflammation decreases when people take GLP-1 agonists, but no one knew why or how.
Beyond weight loss and diabetes
GLP-1 stands for glucagon-like peptide 1, a natural hormone made in the body that has a varied range of effects, including stimulating the release of insulin, slowing the digestion process, reducing appetite, and even blunting the brain’s interest in food.
GLP-1 agonist drugs that mimic this hormone—such as Ozempic and Mounjaro—were initially developed to treat type 2 diabetes, but clinical trials then revealed their potential to treat obesity. Ozempic, whose active ingredient is semaglutide, was later approved as Wegovy to treat obesity; and Mounjaro, whose active ingredient is tirzepatide, was recently approved as Zepbound to treat obesity. Another GLP-1 agonist used in this study, exenatide, is a diabetes medication known by the brand names Bydureon and Byetta. Clinical trials have continued to explore ways these drugs might improve other conditions.
For example, a major trial at the end of 2023 revealed that semaglutide reduced risk of heart attacks, stroke, and cardiovascular deaths. Other trials have shown that semaglutide may improve fatty liver disease and chronic kidney disease. Yet more clinical trials are in progress to investigate GLP-1 agonist effects on depression, alcohol use disorder, and nicotine addiction, as well as Alzheimer’s and Parkinson’s diseases.
But even as researchers try to learn the many ways these drugs may affect different human diseases, they’re also trying to learn how these drugs work.
Inflammation in the body
Drucker wanted to figure out how GLP-1 agonists reduce systemic inflammation in the body, as a decade of research has shown they do.
GLP-1 agonists act by triggering GLP-1 receptors, proteins on the surface of certain cells. When these receptors receive a signal from the GLP-1 hormone, it prompts the cell to complete all GLP-1 functions. Most of the cells with a lot of GLP-1 receptors are in the pancreas—the location of insulin producing cells—and in the brain, which curbs appetite and controls the body’s food reward system. But there are cells throughout the body that also have fewer GLP-1 receptors and respond to the hormone.
Despite recent trials showing that GLP-1 agonists reduce cardiovascular disease, the heart doesn’t have many GLP-1 receptors, Drucker says. Similarly, despite studies showing GLP-1 agonists improve liver and kidney disease, those organs don’t have loads of GLP-1 receptors either, raising questions about how GLP-1 agonist drugs have such significant effects on those organs.
White blood cells—inflammatory cells of the immune system—do have GLP-1 receptors, but “it was clear that GLP-1 agonists damped down inflammation likely more than was occurring just by their effect directly on white blood cells,” says Eva Feldman, a neurologist at the University of Michigan. There just aren’t enough GLP-1 receptors in white blood cells to account for how much these drugs reduced inflammation.
As Drucker’s team conducted various experiments, they eventually deduced that GLP-1 “must be working at least partly indirectly,” possibly through the nervous system, “because what’s the one system we have that can talk to every part of our body?” Drucker says. “It’s our brain and nervous system. It can send signals everywhere.”
Can the brain reduce inflammation everywhere?
To test that hypothesis, the researchers first induced inflammation in mice.
In one experiment they triggered inflammation with synthetic chemicals; in another they used a mixture of bacteria. Then they gave these mice exenatide, semaglutide (Ozempic), or tirzepatide (Mounjaro) and measured the subsequent reductions in inflammation from each drug.
In the next experiment the scientists bred several different strains of mice that were genetically engineered to lack GLP-1 receptors in various parts of the body: in white blood cells, in various organs, and in the brain.
Again, the researchers induced inflammation in each of these mice, gave them exenatide, semaglutide or tirzepatide, and observed whether the drugs suppressed inflammation.
“When we blocked the GLP-1 receptors in the brain,” Drucker says, “we no longer suppressed inflammation” in other parts of the body. The mice missing GLP-1 receptors in the brain had substantially more inflammation than the other mice after all received the drug.
That suggests that the absence of GLP-1 receptors in the brain prevents the GLP-1 drugs from reducing inflammation as effectively as they did in the other mice, which just lacked the receptors in other cells or organs.
The finding is surprising because “the general perception is that that’s not really how inflammation works,” Schwartz says. Conventional ideas about inflammation suggest that the damaged tissue sends out signals telling the immune system what to do, and it’s still likely that occurs as well. But these findings show “that the brain actually is playing a role and can be targeted therapeutically,” Schwartz says.
Next steps
There were already other known ways that GLP-1 agonist drugs may have been reducing inflammation. One was by decreasing glucose and fat tissue since high glucose levels and fat cells both cause inflammation. Another is that the sparse GLP-1 receptors that do exist in various organs may indeed play a role. But neither of those two mechanisms was sufficient to explain the drop in inflammation.
“I think this is the third piece to the puzzle,” Drucker says. “Maybe part of the story is that the brain is instructing these other tissues and organs to dampen down the inflammation.”
Drucker remains cautious about what these findings mean. “I don’t want to pretend this is the entire answer,” he says, but the study has “opened a new way of thinking about how GLP-1 benefits us long term.”
The next steps are to figure out how the brain is lowering inflammation, perhaps through experiments that, for example, direct specific nerves to reduce inflammation. Research published in 2000 from the lab of neurosurgeon Kevin Tracey, for example, has shown that the vagus nerve can turn off inflammation. But the body has a lot of different nerve pathways.
“I think over the next few years, you’re going to see a whole lot of additional experiments digging down to try and identify more precisely those pathways,” Drucker says.
One hope is that a better understanding of how GLP-1 agonists reduce inflammation in the brain could reveal possible therapies for neurodegenerative diseases like Alzheimer’s.
It’s well-established that inflammation in the brain likely contributes to Alzheimer’s, and inflammation has therefore emerged as a therapeutic target for the disease in recent years.
“But how best to alter that inflammation and whether changing it will change the course of the disease, that’s less well understood,” Feldman says. Drucker’s findings “could be really good for neurodegenerative disease, but the jury’s out.”
Drucker is similarly cautious about what these findings mean for conditions like Alzheimer’s that have eluded effective therapies for so many years.
Similarly, although inflammation plays a role in Parkinson’s disease, it’s far too early to know whether GLP-1 agonists could slow the disease’s progression, especially when mouse studies have been far less predictive of success in the areas of neurodegenerative disease than they been in inflammation and metabolism. The broader implication of these findings is that scientists may want to consider investigating whether the brain can be targeted to treat not only metabolic diseases but inflammatory disease states as well. “I’m not saying it will work,” Schwartz says, “but it opens the door pretty wide.”
Like any good scientific discovery, says Tracey, president and CEO of the Feinstein Institutes for Medical Research in New York, the study answers some questions while raising many more. “I think it will accelerate more interest in the important question of what else we have to do to know how this works to treat inflammation and to potentially see the launching of more clinical trials that might help a lot of people.”
Translating findings from mice to humans
A major caveat of Drucker’s study is that it was done in mice.
“There’s always a gap between what is possible to know in humans and what we infer from animal models,” Schwartz says. But the data here are strong enough, he says, “that if someone wants to come along and say, well, that’s just not true in humans, then the onus is on them to show why it isn’t true.”
Tracey agrees that some mice studies translate better to humans than others, and this is one of the more translatable ones.
“I’ve been impressed in the last 30 years with how much is actually translatable between mice and humans in the fields of inflammation and metabolism,” Tracey says. But he and other scientists remain cautious about what this means specifically for the use of GLP-1 agonist drugs. “We’re still learning the benefits and risks to a new class of drugs,” Tracey says. “These things take a long time before we really understand how they work and how to use them.”
