Dr. Anne Marie Morse Explains How GLP-1 Drugs Treat Obstructive Sleep Apnea

Glucagon-like peptide-1 (GLP-1) receptor agonists semaglutide and tirzepatide, which have been approved by the US Food and Drug Administration for the treatment of obesity and diabetes, may also reduce symptoms in patients with obstructive sleep apnea (OSA). Notable neurologist and sleep expert Dr. Anne Marie Morse explains how these therapies work, first in combating obesity and weight loss, and then she describes how they can be used to combat OSA. In the words of Dr. Morse, GLP-1s are “definitely not a one-trick pony.”

What is GLP-1, and how do GLP-1 receptor agonists combat obesity and diabetes?

GLP-1 is all the rage right now in terms of what is leading the headlines across media. The reality is that it’s important for us to unpack exactly what GLP-1 is. Is that the only thing we need to pay attention to? The reason you’re seeing these headlines is because of the fact that GLPs are new medications that have been developed. These are agonists, meaning that they act on the receptors, but they are not the exact molecule, which have been utilized now for many years for weight loss and diabetes control. GLP-1 is only one of the peptides that we’re currently talking about. Another that is commonly utilized or that we’re seeing more and more in the news is its partner GIP, which is a glucose-dependent insulin-releasing polypeptide. These 2 peptides actually belong to a class of hormones called incretins. Now, you may have heard of sucretins, which are being released by the pancreas.

Incretins were identified afterward, and these are intestinal hormones released in response to nutrient ingestion, which then are going to potentially help with this glucose-induced insulin response. When you’re talking about its role in regard to diabetes or weight loss, a lot of people are saying this is going to be the wave of the future, and this is what we’re going to see continue taking the world by storm. In fact, we’ve even seen Oprah come out and say, “This is the holy grail.” The reality is that we are now seeing this move beyond just talking about weight loss and diabetes. What’s interesting when we’re learning about the actual utilization of these molecules and where the receptors of these molecules are, yes, they’re present in the GI system; however, they have widespread distribution not only throughout the brain, but also on things like the heart and the kidney.

Why is this relevant? Because even though we’re utilizing these things for weight loss and diabetes, their mean mechanism of action at this point when you’re talking specifically about weight loss actually isn’t working directly on the GI system. It’s working more so on the brain and having that signaling then be able to impact that peripheral system. This is counterintuitive to what one would expect. You would expect that because of the fact that this hormone not only circulates in the central nervous system, but also in the periphery, that the mechanism of action of utilizing an agonist would be it’s working on the stomach, it’s working on the intestines. In fact, that is likely the minority of its effects, because we recognize when physiologically the body is actually producing this and trying to work at normal function. The main amount of that work is actually coming from the central nervous system, and it actually is relatively unclear what the contributions of the peripheral GLP-1s are.

Can a GLP-1 treatment also be used to treat sleep disorders, specifically OSA? If so, how?

GLP-1s, they are definitely not a one-trick pony. They’ve already demonstrated they can do at least 2 things, weight loss and diabetes control. When we look at that, some would say, “Is that all representative of the same thing? I’m causing weight loss and so therefore I’m increasing my insulin sensitivity, and maybe that’s why my type 2 diabetes is getting better.” However, we recognize no GLP-1 has more than 1 function, just even in that it actually is improving your insulin sensitivity, and it is also producing weight loss. It’s doing 2 different things. We’re now seeing the same type of criticisms coming back in regard to, “Hey, we’re using these now in sleep disorders. Is this in fact just another weight loss ploy to get another indication?” The reality is I do think that this is part of the story, but it’s not the complete story.

We recognize that when looking at the physiologic effects of GLP-1, in addition to the metabolic effects that are appreciated through weight loss and diabetes management, some of that effect is likely also mediated through orexinergic effects. There also has been some data looking at GLP-1s specifically at upper airway tone and seeing whether or not that may potentially modify. Now, when we’re seeing GLP-1s, it is really important to say, “Can this actually make a difference?” If I were to objectively utilize this and am able to say, “I have someone who has sleep apnea, I have someone who has insomnia, I have someone who has another sleep disorder,” do we see any meaningful change? Well, what I can say to you is that we can take translational data, and we can tell a really convincing story that GLP-1 actually is definitely more than a one-trick pony.

When you look at animal model data, and look at does it have any influence of the administration and timing of GLP-1 agonists, do we see any change in total sleep time or how cycling occurs? In fact, we do. We see that it increases total sleep time, and depending on the time of day that it’s administered, it can actually augment the amount of slow-wave sleep that these animal models are cycling through. This is really quite interesting because it introduces other opportunities to say, “Well, if I can change the ultradian cycling and the quantity of sleep, are there other roles that this may potentially have?” Now, again, remember I have already mentioned that GLP-1 has this direct and indirect interaction with orexin. Orexin is definitely another molecule that is all the rage right now because we’re seeing the development of orexin agonists and how they may be potentially meaningful in the treatment of narcolepsy.

However, we also know that orexin has significant roles in the quality of sleep, and even potentially sleep disorder breathing and your ability to maintain upper airway tone. We now fast-forward, and we look at the data that are starting to become available. We have data that are coming out on the use of a GLP-1, GIP agonist, and its influence on obstructive sleep apnea. A large-scale phase 3 study is looking at individuals who have OSA with and without CPAP use. Now, when thinking about this many times we’ll just say, “Well, one of the strategies if I have someone who has OSA is weight loss.” We recognize that if you look at some of the data, with every 1% change in weight, we expect to see a 2.6% reduction in AHI or apnea hypopnea index, so that is setting the standard already as to what the expectations are.

Now, of course, you can look at a broad range of different studies that give variability in regard to what this weight reduction and what this AHI change is. And likely, that is a reflection of the fact that there are different endotypes of OSA. And depending on what your weight and fat distribution are, you may see different benefits or potential risks. And again, making sure we also recognize one size fits all is not what we’re talking about here, because obesity is not the only driver for OSA. Now, with this study that was done, this was a very intentionally designed study that recognized that OSA is more commonly being diagnosed in men, unfortunately, likely a biased reflection. When we look at the epidemiologic data, we recognize that between 0 and 18 years of age, it’s probably about 1 to 1 of boys and girls being affected equally. From 18 to 50, we see the scale of maybe it’s anywhere between 2 to 7 times more likely being diagnosed in men versus women, probably a selection bias.

But then you get to the age of 50, and it’s about 1 to 1, and that really is because menopause is being introduced and we’re seeing some significant changes that increase the likelihood for OSA to be present, but also to finally be diagnosed in women. I give all those statistics and epidemiology because this study was designed to ensure that it didn’t over enroll for men, and not and have the purposeful inclusion of women to be well-represented, and so they did cap at 70% enrollment for men. However, all individuals who were enrolled in the study did have to have an elevated BMI greater than 30 and had to have moderate to severe OSA. What did they find? What they found was that there was substantial body weight loss, and so we were seeing up to about 20% body weight loss.

However, what we were also seeing is that the performance of the reduction in AHI exceeded those numbers of seeing that one to 2.6% reduction in AHI. So some of the things that I think are really important from this study is that number one, we saw this in individuals who had no CPAP. Why is that important? Because these are untreated individuals. We weren’t treating them to begin with, and now I’m modifying a very significant risk for all-cause mortality, and I’m helping them to achieve other ways of actually improving overall risk by potentially modifying their glucose control as well as their weight, so that’s a win all around. There’s no way that anyone can argue against that. What about individuals who were on CPAP? Did we see any benefit there? Well, let me tell you something. One of the things that is hotly debated, even when you’re talking about CPAP use, and this is a little bit different even from the pediatric lens, is that when we modify OSA, do we cause weight loss or weight gain?

We recognize the pediatrics, sometimes the failure to thrive phenotype is what we see where there’s an increased metabolic demand because of the obstructive sleep apnea, and so we see a weight gain. We also can see the opposite of the child who might be overweight, and then we get the tonsils and adenoids removed and we see some weight loss, and so it can go in either direction. In the adult world, we see very similar phenomena of that we introduce a CPAP as treatment, we optimize the AHI, and there’s some people, because they have increased energy, they’re able to do better, their leptin and ghrelin might be more stable, so they’re having better food-seeking behavior and more nutritious food choices. We see that it gets better. However, equally we see individuals who have weight gain. Now, with this stated, this enrolled individuals who have obstructive sleep apnea and a BMI greater than 30, and they’re on CPAP, so we’re already dealing with a population who they need weight loss. That’s only going to add to the benefit.

And so what we’re doing here is we’re seeing whether or not do they achieve as much benefit as those who are getting no treatment at all. Well, what did we find? It actually was even better. We saw not only was there weight loss, but we saw even further reduction of the AHI. And so with that stated, what we’re finding is that this is making a difference beyond just the weight loss. We’re seeing that it’s not negatively impacting the CPAP adherence, although that was a part of the protocol, they could not become less adherent. However, it also is raising this thought of, are there other mechanisms that are contributing to the benefit? My personal theory is that there likely is some orexinergic effects. In addition to that, just as we saw in animal models increased total sleep time and improvement in slow wave sleep, I’m putting you in a stage of sleep that is going to be protective to provide more stable breathing.

So overall, I think that this is a win-win-win. Do I think just put CPAPs out of business? Absolutely not. Do I think it broadens the segment of the population who actually will finally be diagnosed and look for treatment? Absolutely. Does it give me more tools in my toolbelt to actually treat every individual with an individualized plan? Yes, and it’s just a reminder that we’re seeing a broadening of different treatments becoming available for all sleep disorders. Recognizing that this is an epidemic in the United States, we need to be mindful of identifying, optimally treating, and remembering sleep is a tool for you to get your best health, wellness, and performance. Live your best life.