Ozempic and its use to reduce inflammation

The fever broke out a few years ago in the United States, and for several months the entire Spanish media was talking about this phenomenon: insulin-containing drugs such as Ozempic and Mounjaro, intended for diabetics, have demonstrated their effectiveness in treating diabetes. type 2 diabetes mellitus and obesity. Many pharmacies in our country even have a queue.

And if the explosive demand for these drugs leads to limited supply at pharmacies, making it even more difficult for diabetics to access treatment, the situation could even get worse: new research shows that this class of drugs, known as GLP-1 agonists, may also reduce inflammation across the board. body. This discovery suggests they could be useful in treating a wide range of diseases such as Alzheimer’s or Parkinson’s, or at least inspire research into new treatments for neurodegenerative or autoimmune diseases.

New research published in Cellular metabolism in December suggests that one of the main ways the drugs work is by causing the brain to send signals to reduce inflammation throughout the body.

This has “widespread implications,” in part because of the widespread use of these drugs, said Mike Schwartz, an endocrinologist at the University of Washington in the US who was not involved in the study.

However, the European Medicines Agency is currently only considering using these drugs to lower blood glucose levels and reduce the risk of health complications in patients with type 2 diabetes.

“We were thinking about using these drugs to treat obesity and type 2 diabetes, but there may be other ways to use them,” Schwartz says.

Inflammation is the immune system’s response to perceived threats to the body. Good inflammation occurs when the immune system prepares 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 damage tissue.

“We need good inflammation to fight infections,” says Daniel Drucker, an endocrinologist at the Lunenfeld-Tanenbaum Research Institute and the University of Toronto in Canada; “But we don’t want inflammation to persist over time, especially if we have these metabolic disorders, because it will cause heart disease, diabetes and complications of obesity.”

It has long been known that inflammation is reduced when people take GLP-1 agonists, but no one knew why or how.

GLP-1 stands for glucagon-like peptide 1, a naturally occurring hormone produced in the body that has a wide range of effects, such as stimulating the release of insulin, slowing down the digestive process, reducing appetite, and even dulling the brain’s interest in food.

GLP-1 agonist drugs that mimic this hormone (such as the aforementioned Ozempic and Mounjaro) were originally developed to treat type 2 diabetes, but later clinical trials showed their potential for treating obesity. Ozempic, whose active ingredient is semaglutide, was later approved by Vegovi for the treatment of obesity; and Mujaro, whose active ingredient is tirzepatide, was recently approved as Zepbound for the treatment of obesity. Another GLP-1 agonist used in this study, exenatide, is a diabetes drug known under the brand names Bydureon and Byetta. Clinical trials continue to explore ways in which these drugs can improve other conditions.

But at the same time, as researchers try to understand how these drugs can affect various human diseases, they are also trying to learn how these drugs can affect various human diseases. How they act.

Drucker wanted to find out how GLP-1 agonists reduce systemic inflammation in the body, as demonstrated by decades of research.

GLP-1 agonists work by activating GLP-1 receptors, proteins located on the surface of certain cells. When these receptors receive a signal from the hormone GLP-1, they instruct the cell to perform all of the functions of GLP-1. Most of the cells with a large number of GLP-1 receptors are found in the pancreas (where insulin-producing cells are located) and in the brain, which curbs appetite and controls the body’s food reward system. But throughout the body there are cells that also have few GLP-1 receptors and respond to this hormone.

Despite recent studies showing that GLP-1 agonists reduce cardiovascular disease, there are not many GLP-1 receptors in the heart, Drucker says. Similarly, despite studies showing that GLP-1 agonists improve liver and kidney health, there are also few GLP-1 receptors in these organs, raising questions about how GLP-1 agonist drugs have such significant effects on these organs.

White blood cells (inflammatory cells of the immune system) do have GLP-1 receptors, but “it was clear that GLP-1 agonists attenuated inflammation probably more than just their direct effect on white blood cells,” he says. Eva Feldman, neurologist. at the University of Michigan (USA). There are not enough GLP-1 receptors on white blood cells to explain how much these drugs reduce inflammation.

As Drucker’s team conducted various experiments, they eventually concluded that GLP-1 “must act at least partially indirectly,” perhaps through the nervous system, “because what is the only system we have that can talk to us? body?” – says Drucker; “Our brain and our nervous system. She can send signals everywhere.”

To test this hypothesis, the researchers first induced inflammation in mice.

In one experiment, they induced inflammation using synthetic chemicals; in another, they used a mixture of bacteria. They then gave these mice exenatide, semaglutide (Ozempic) or tirzepatide (Munjaro) and measured the reduction in inflammation achieved with each drug.

In the next experiment, the scientists bred several different litters of mice that were genetically modified to lack GLP-1 receptors in different 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 tyrsetide, and observed whether the drugs suppressed inflammation.

“When we block GLP-1 receptors in the brain,” Drucker says; “We are no longer suppressing inflammation” in other parts of the body. Mice that lacked GLP-1 receptors in their brains experienced significantly more inflammation than other mice after taking the drug.

This suggests that the lack of GLP-1 receptors in the brain prevents GLP-1 drugs from reducing inflammation as effectively as in other mice that lacked receptors only in other cells or organs.

This finding is surprising because “the general consensus is that inflammation doesn’t work that way,” Schwartz says. Traditional ideas about inflammation suggest that damaged tissue sends signals to the immune system, telling it what to do, and this is also likely. But these results show that “the brain plays a role and can be treated,” Schwartz says.

There are already other ways in which GLP-1 agonists can reduce inflammation. One was to reduce glucose and fat cells, since both elevated glucose and fat cells cause inflammation. Another reason is that the few GLP-1 receptors that exist in various organs may play a role. But neither of these two mechanisms was sufficient to explain the decrease in inflammation.

“I think this is the third piece of the puzzle,” Drucker says; “Perhaps part of the story is that the brain instructs other tissues and organs to reduce inflammation.”

Drucker remains cautious about what these findings mean. “I don’t want to pretend that this is the complete answer,” he says, but the study “has opened up new insights into how GLP-1 will benefit us in the long term.”

The next steps are to figure out how the brain reduces inflammation, perhaps through experiments that, for example, target specific nerves to reduce inflammation. For example, a study published in 2000 in the laboratory of neurosurgeon Kevin Tracy showed that the vagus nerve can deactivate inflammation. But there are many different nerve pathways in the body.

“I think there will be many more experiments in the coming years to pinpoint these pathways more precisely,” Drucker says.

One hope is that a better understanding of how GLP-1 agonists reduce inflammation in the brain may reveal potential treatments for neurodegenerative diseases such as Alzheimer’s disease.

Brain inflammation has been shown to contribute to the development of Alzheimer’s disease, so it has become a therapeutic target in recent years.

“However, it is not entirely known how best to modify this inflammation and whether changing it will change the course of the disease,” Feldman says. Drucker’s findings “may indeed be useful for treating neurodegenerative diseases, but the jury is still out.”

Drucker is equally cautious about what the findings mean for diseases such as Alzheimer’s, which have eluded effective treatments for years.

Likewise, although inflammation plays a role in Parkinson’s disease, it is too early to tell whether GLP-1 agonists can slow disease progression, especially when mouse studies have been much less predictive of success in the areas of neurodegenerative diseases than in the areas of inflammation and metabolism. The broader implication of these findings is that scientists could consider whether the brain could serve as a target for treating not only metabolic diseases, but also inflammatory diseases. “I’m not saying it will work,” Schwartz says, “but it opens the door wide.”

Like any good scientific discovery, says Tracy, president and CEO of the Feinstein Institutes for Medical Research in New York, the study answers some questions but raises much more. “I think this will increase interest in the important question of what more we need to do to figure out how this works to treat inflammation, and potentially see more clinical trials launched that could help a lot of people.”

An important caveat to Drucker’s study is that it was conducted on mice.

“There is always a gap between what we can know in humans and what we find in animal models,” says Schwartz. But the evidence here is strong enough, he says, “that if someone wants to come along and say, well, that’s not true for people, then the onus is on them to show why that’s not true.”

Tracy agrees that some mouse studies translate better to humans than others, and this is one of the more portable studies.

“Over the last 30 years, I have been impressed by how much translation there is between mice and humans in the areas of inflammation and metabolism,” says Tracy. 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 of this new class of drugs,” says Tracy; “These things take a long time before we really understand how they work and how to use them.”