Ozempic has become a household name but not necessarily for its original use as a diabetes treatment. The drug, generically called semaglutide, is modeled after an unassuming gut hormone called glucagonlike peptide 1 (GLP-1), which stimulates insulin production—as well as the feeling of satiety, or fullness. That latter effect has helped people achieve significant weight loss, a side effect that has prompted pharmaceutical companies to produce obesity medication spin-offs such as Wegovy and Zepbound.
But scientists are now learning that GLP-1 drugs such as semaglutide cause a host of other unexpected effects that could be tapped for treatments. Human clinical trials show the drugs can reduce the risk of kidney and cardiovascular diseases. In March Wegovy (the weight-loss version of Ozempic) gained Food and Drug Administration approval for preventing cardiovascular problems. Recent animal studies further suggest that GLP-1 medications could help treat liver diseases and neurological disorders and that they may tamp down on the inflammation that causes many chronic illnesses.
“What’s interesting and maybe a bit unique about GLP-1 is that there are so many different [avenues of] potential therapeutic utility being explored today,” says Daniel Drucker, a University of Toronto endocrinologist who has been studying GLP-1 drugs since the hormone was first discovered in the 1980s. “It’s not just like one or two additional indications. There seem to be six to 10 really interesting indications where the medicines are being explored.”
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In a new review study published on Thursday in Science, Drucker describes the latest ongoing research on GLP-1 treatments beyond diabetes and obesity. Scientific American spoke with him to discuss how the drugs may be causing such wide-reaching effects.
[An edited transcript of the interview follows.]
When did researchers first realize that GLP-1 drugs might do more than regulate blood sugar and help with weight loss?
A series of really important trials—preceded by animal data—started in 2016, which showed that GLP-1 also protected the heart. There were fewer heart attacks and strokes [among those taking the drug] and fewer people dying of heart disease. Then we wanted to know: How does GLP-1 do that?
The simplistic initial response was that getting good control of your blood sugar and having weight loss both improve the health of your heart. The trouble with that explanation is that we have had many diabetes medicines that lowered blood sugar but didn’t reduce the rates of heart attacks, strokes and death. The same [lack of an effect on the latter areas hasn’t been seen with] medicines approved for weight loss. And even GLP-1 medicines that were pulled from the market because they weren’t very good at lowering blood sugar or inducing weight loss produced a 22 percent reduction in heart attacks, strokes and cardiovascular death in people with type 2 diabetes and cardiovascular disease. So we’re getting a lot of data from the clinic suggesting that glucose control and weight loss are not the whole story for how these medicines work for other conditions.
The benefits for heart disease and kidney disease are strongly supported by clinical studies. What are some other conditions that scientists are still investigating?
We’re seeing all these fascinating reports from people taking these medicines. Some say that their addiction-related need for alcohol is reduced or that they don’t want to smoke as many cigarettes as they used to. Or some people say that their inflammation-related disorders—such as arthritis, inflammatory bowel disease or joint pain—are improved, even well before they realize substantial weight loss. But it’s not by any means proven that GLP-1 medications are going to benefit all of these other conditions. Many trials are underway, and we are still awaiting results. What else might GLP-1 do? We have hints of benefit, but we need larger, bigger trials to prove it. It’s going to be a really exciting five years or so.
How is it that GLP-1 drugs improve cardiovascular health—and have effects in other systems across the body?
For cardiovascular disease, it’s very difficult to identify the mechanisms in humans. I generally separate the potential mechanisms into three or four different categories. First, weight loss and the glucose control [are not the] drivers of the mechanism, but they may help a tiny bit. Second, there are GLP-1 receptors on blood vessels and in our heart and some of our heart cells, so it’s possible that GLP-1 is acting directly on some of those cells to reduce the rate at which heart damage, strokes or atherosclerosis (the buildup of plaque in arteries) occurs. Third, there are the [heart disease] risk factors that GLP-1 modifies. We know that GLP-1 reduces blood pressure and the circulating levels of cholesterol. These indirect risk factors could also be modified favorably by GLP-1 therapy.
Fourth is one that my lab is studying a lot, and it’s inflammation. Having bad inflammation in our body drives many of the complications of chronic metabolic disorders. Parkinson’s disease, Alzheimer’s disease, kidney disease, heart disease, atherosclerosis, metabolic liver disease—they’re all driven to some extent by increased inflammation. GLP-1 seems to reduce harmful inflammation in animal studies, and there’s some evidence that it does so in humans as well.
We’ll never be able to point to one single mechanism in humans that can help us say, “Aha, look, this is what GLP-1 does.” But we can start to tease out a bit more in preclinical studies.
How might GLP-1 be tamping down harmful inflammation?
From preclinical studies [in animals], we know that there are GLP-1 receptors on some immune cells—principally some T cells, [which find and kill infected cells]. So it’s possible that GLP-1 is directly engaging with the immune system by communicating with T cells. We know that weight loss also can reduce inflammation, so that could be a potential indirect effect. And we know that the brain plays a very important role in both sensing inflammation and responding to inflammation by trying to dampen it. And in animal studies, GLP-1 seems to activate some of those pathways in the brain that control inflammation [throughout the body]. But it’s very early days to ask whether that’s true in humans.
What do we know so far about GLP-1 medications’ potential impact on neurodegenerative diseases such as Alzheimer’s and Parkinson’s?
We have a large amount of data that look at GLP-1 in animal models [used to study] Parkinson’s disease and Alzheimer’s. I think the vast majority of those data do support a possible benefit for GLP-1 in animals. What might those mechanisms be? I think a reduction of inflammation is probably central. There are also some GLP-1 receptors in neurons, as well as in astrocytes, which are [brain] cells that control the extent of inflammation. And there’s suggestion that GLP-1 reduces the amount of inflammation from our body that reaches the brain.
We have to be a little bit cautious here. We’ve had four human trials on [the effects of GLP-1 medicines on] Parkinson’s. Three did look positive, but one didn’t show any benefit. There’s a much larger GLP-1 drug trial underway now with people with Parkinson’s, which should publish hopefully in the next few months.
With Alzheimer’s in humans, many of the reports are from clinical trials where [a group of] people with heart disease who were studied had fewer reports of new Alzheimer’s disease diagnoses. There also have been real-world registry studies, where researchers have investigated electronic medical records. There, it looked like there was a reduction in rates of new diagnosis of dementia or cognitive dysfunction in the people who got the GLP-1 medicines. That research doesn’t prove a link, but it’s fascinating.
What does all of this mean for people who are considering taking this medication?
If you’re a person living with type 2 diabetes or obesity, and you’re at high risk for developing heart disease or kidney disease—or if you’re already experiencing heart failure—then the benefits of GLP-1 in those patient populations are proven. It’s very prudent that you and your doctor consider whether those medicines might be good for you. [Editor’s Note: The FDA has approved some GLP-1 medications to prevent cardiovascular conditions in certain high-risk groups. None have yet been approved to treat kidney diseases, however.]
But beyond that, regarding all of the really interesting and exciting additional conditions GLP-1 is being explored for, we just don’t have good enough data yet. I think in the next five years, we will have answers from many of these questions. These trials are well underway.
What are some of the reasons people stop taking the medications?
There are some people who just don’t feel well. If you look at the clinical trial data, I think it’s rare—we have very high rates of people continuing the medicine. But in the real world, the number of people who continue GLP-1 medicines after six or 12 months is disappointing. Many people stop taking the medicines. And of course, that’s from a combination of reasons. They can be expensive. People might not be getting the [health or weight-loss] benefits that they had expected. Many people report really encouraging results; they’re life-changing for some people. I meet people all the time who say GLP-1 medicine has changed their life. But some say they just don’t feel well on these medicines and that they have to stop taking them. Those people exist, too, and we should respect that.
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