Sleep Apnea Squad: New Medications for Sleep Apnea

Project Sleep Podcast
“New Medications for Sleep Apnea”
(Sleep Apnea Squad Episode 6)

Emma Cooksey is the Sleep Apnea Program Manager at Project Sleep and host of the Sleep Apnea Squad podcast series. She was diagnosed with obstructive sleep apnea at the age of 30, after more than a decade of unexplained health problems. Once diagnosed, she felt alone while navigating life with sleep apnea and adjusting to CPAP therapy. In 2020, Emma began hosting a weekly podcast, “Sleep Apnea Stories.” By sharing her journey and encouraging others to tell their stories, Emma has been breaking down stereotypes of sleep apnea while also raising awareness of symptoms and treatment options. She is also on the Board of Directors at Project Sleep. 

Dr. Klar Yaggi is a professor of medicine and the Vice Chief for Research in the Yale Section of Pulmonary, Critical Care, and Sleep Medicine. He also serves as the Director of the Yale Centers for Sleep Medicine. His research employs translational methods applied to sleep science, circadian biology, and respiratory neurobiology to investigate the mechanistic pathways between sleep deficiency (sleep deprivation, noncircadian wakefulness/sleep, and impaired sleep quality/architecture due to insomnia/sleep-disordered breathing) and cardio-metabolic disease, substance use disorders, cognitive impairment, and mental illness. He is committed to mentoring and training the next generation of scientists, which he considers the most rewarding aspect of his professional work, and he has successfully mentored postdoctoral fellows and junior faculty to independence. 

Podcast transcription provided by Mirela Starlight
More information about Sleep Apnea Squad
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Emma in intro: Welcome to the Project Sleep Podcast. For those of you who’ve listened before you might be expecting to hear from Julie Flygare, Project Sleep’s Founder and CEO, but for this special series of podcasts on sleep apnea topics, I’ll be your host. I’m Emma Cooksey, the Sleep Apnea Program Manager here at Project Sleep and I’m so glad you’re here. Project Sleep is a 501(c)(3) non-profit organization dedicated to raising awareness and advocating for sleep health, sleep equity and sleep disorders. 

Emma in intro: We created the Sleep Apnea Squad series to allow listeners to dive deeper into specific topics relevant to living with sleep apnea. For more on today’s topic please check out our corresponding toolkit which is available for free on our website to download, print and share. The link to the toolkit and other Sleep Apnea Squad topics is in the show notes, or you can find the Sleep Apnea Squad page at project-sleep.com. 

Emma in intro: On this podcast all guests express their own opinions. While medical diagnosis and treatment options are discussed for educational purposes, this information should not be taken as medical advice. Each person’s experience is so unique which is why it’s so important to consult your own medical team while making decisions about your own health. 

Emma in intro: If you haven’t done so yet, please hit the subscribe button so you never miss a Project Sleep podcast episode and if you enjoyed the podcast please leave us a rating or review wherever you listen so that we can reach more listeners and raise more awareness. So without further ado, here’s today’s Sleep Apnea Squad episode. 

Emma: So, welcome everybody. Thanks so much for joining us. So, today we’re talking about new medications for sleep apnea. And I think if you’re like a lot of us, you don’t realize that medications are even used for sleep apnea. So, I think for a lot of us, we get our diagnosis and are put onto CPAP and that’s kind of the end of the discussion and we don’t even know that medications can be part of the discussion. So I’m really excited for us to talk about this today. 

Emma: So the reason we’re talking about it is I think our community of people with sleep apnea is so diverse. So I definitely have a group of people who are in the category where they got their diagnosis, they got put on CPAP and they just got on great with that treatment option and they’re quite happy, right? So if you’re in that group, that’s wonderful. 

Emma: But there are a lot of people who fall outside of that group. So whether it’s people who don’t start CPAP to begin with, or have problems and abandon it— those people often end up untreated— with no treatment option. They don’t know anything else to do and they don’t go back. They just are— you know, disappeared. There’s also people who are undiagnosed. 

Emma: So I was at a large sleep conference last month where a lot of people were talking about new data which estimates there are 80 million people in the United States who are affected by OSA, obstructive sleep apnea. And we talk about there being 80% of those people being undiagnosed. So that’s such a huge number of people. So it’s always been my opinion that the more treatment options we have, the more people we can reach, right? So that’s partly why we want to have this discussion today.

Emma: So on to our special guest today. So we’re joined by Dr. Klar Yaggi. So Dr. Yaggi is a Professor of Medicine and the Vice Chief for Research in the Yale section of Pulmonary Critical Care and Sleep Medicine. He also serves as the Director of the Yale Centers for Sleep Medicine. 

Emma: His research employs translational methods applied to sleep science, circadian biology, and respiratory neurobiology to investigate the mechanistic pathways between sleep deficiency and cardiometabolic disease, substance use disorders, cognitive impairment, and mental illness. 

Emma: His lab, the Yale Translational Sleep Circadian and Respiratory Neurobiology Research Center on Yale’s west campus provides infrastructure for supporting multi-disciplinary translational sleep research. And we’re so glad to have you with us Dr. Yaggi, we’re so grateful.

Dr. Yaggi: Thank you so much for the invitation, this is a great topic to talk about. What great resources you’ve put together. 

Emma: Well thanks. Okay, so, I’m just going to do a really quick overview before we kind of hand off to Dr. Yaggi on our first topic. So I think like I was just mentioning, there have been some medications used to date for sleep apnea. I think just the awareness about them isn’t very high. 

Emma: So I’m actually on an American Academy of Sleep Medicine task force right now as one of the patient advocates in that group to— they’re looking at new guidelines for using alerting agents for people with residual daytime sleepiness with sleep apnea. That group is quite interesting to me because I’m sharing with them that my sleep specialist has never mentioned any medications to me in the 18 years that I’ve— you know, been having treatment for sleep apnea. 

Emma: And so I think sometimes the awareness at the local level maybe isn’t as high about what medications might be implemented. So we’re going to talk about that first, but then we’ll come on to talk about some new medications. So a lot of you will have heard— there’s a GLP-1 drug, tirzepatide, which is called Zepbound. So that received FDA approval last December. 

Emma: And we’re going to talk a little bit about it, how it works and what the research showed with that. I know that a lot of people are kind of interested in that as an option. And then we’ll come on to discuss Apnimed’s new drug which is called AD109. It’s not yet FDA approved, but they did just announce some phase three trial results. So we’ll talk a little bit about that. 

Emma: And then I’m hoping we’re going to have time to talk a little bit about picking the right treatment option for the right person. So, and how there’s quite a broad variance between people and how they experience sleep apnea. And the first thing I’d love you to talk about, Dr. Yaggi, is just this idea that there are medications currently being used for obstructive and central sleep apnea and what those are and just a little bit about them. If we could start there, that’d be great. 

Dr. Yaggi: So I think this is a perfect place to start, Emma. And—for— we’ve been using medications like the ones you just alluded to, some of the wake-promoting agents, as well as occasionally some sedative hypnotics among patients with obstructive sleep apnea. And what the sedative hypnotics help us do is reduce arousals. 

Dr. Yaggi: And we know that frequent microarousals— awakenings during the night— can actually destabilize the breathing a little bit. You wake up with a gasp, a deeper breath and that can lead to a central sleep apnea, for example. There’s an emerging literature on the use of sedative hypnotic medications to improve tolerance and adherence with CPAP. We’ll talk a little bit about that. 

Dr. Yaggi: But also how these medications can consolidate sleep. Originally, the sedative hypnotics that were used, either for the treatment of insomnia— which is, I think as many of us know— difficulty initiating or maintaining sleep— were the benzodiazepine class of medications and one of the issues with these medications is they’re really long acting. 

Dr. Yaggi: And in addition, the benzodiazepines like diazepam or valium or clonazepam— another brand name is called Klonopin— in addition to being sedative medications, they’re also muscle relaxant medications. And so there is certainly the potential that these medications can worsen sleep apnea by decreasing the tone in some of the muscles of the upper airway. 

Dr. Yaggi: I think more recently, when sleep doctors prescribe sleep medicines they usually reach for what are called the Z drugs and that’s— are these— are these non-benzodiazepine sedative hypnotics and this is zolpidem, or Ambien, eszopiclone, or Lunesta in this country, zaleplon or Sonata in this country. 

Dr. Yaggi: And they don’t have the same, I think, muscle relaxant properties, the data seem to be bearing out— and they’re much shorter acting, and so much safer to take at night and not have that hangover effect into the morning when people have to get up and drive, etcetera.

Dr. Yaggi: So that’s sort of one class of medications that has been used to treat sleep apnea. The other are what you alluded to, which are the wake-promoting agents and these have really come into favor the last five, maybe to 10 years. 

Dr. Yaggi: The original medications that were FDA approved for this were based on some randomized controlled trials that showed among patients with sleep apnea that still had residual sleepiness, despite perhaps good use of their CPAP— adding a medication like modafinil or Provigil, or armodafinil or Nuvigil really helped to improve daytime function and improve quality of life. 

Dr. Yaggi:  Much more recently, there have been two other recently FDA approved medications with this indication— solriamfetol or Sunosi, which is a dopamine norepinephrine re-uptake inhibitor which is just a fancy medical way of saying this increases the amount of dopamine and norepinephrine in the brain. 

Dr. Yaggi: Another very helpful medication, pitolisant or Wakix is a histamine H3 auto receptor agonist. So this actually increases brain histamine. Both help to improve daytime function and quality of life among patients with sleep apnea. I believe they also have narcolepsy and   idiopathic hypersomnia indications. 

Dr. Yaggi: But the thing, I think, to know about some of these early medicines that have been used to treat sleep apnea— these sedative hypnotics, or the wake-promoting agents, they’re not disease modifying. They’re really used to treat some of the sequelae, or some of the residual symptoms of the disease without really getting at the underlying severity of sleep apnea. 

Dr. Yaggi: What is important to know I think also about these medications is that they’re targets. So sedative hypnotics target an individual patients’ likelihood of waking up to a stimulus, what we call or term the arousal threshold. And the symptoms of excessive daytime sleepiness among patients with sleep apnea— these actually turn out to be of important prognostic significance. 

Dr. Yaggi: And so we know patients who have significant sleepiness with obstructive sleep apnea, this tends to be associated with greater cardiovascular risk, over time, and what we’re learning more recently is that those patients who have a low arousal threshold, in other words, are easily woken up from a respiratory event or a stimulus— it turns out this— it really helps to predict whether patients are able to use or not use CPAP therapy. 

Dr. Yaggi: So it’s not all just behavior and trying hard enough. There’s— there seems to be some underlying physiology that’s— that may impact individual patients’ ability to use CPAP. Some work from our group has shown that there are important sex differences around arousal threshold. Women on average tend to have lower arousal threshold, which may explain the higher prevalence of COMISA, which is Comorbid Insomnia and Sleep Apnea. 

Dr. Yaggi: And we’re also learning— very sort of hot off the press— is that those patients who have a higher arousal threshold, so deeper sleep— these patients tend to respond to CPAP therapy and improve executive function— and this is based on data from the Apple study. So, early forays into pharmacology for sleep apnea and really helpful information, both prognostically and therapeutically for patients. 

Emma: Yeah, that’s really helpful. It’s so interesting. 

Farah: We do have a question. So we have a question about taking zolpidem. Ryan says that, “taking zolpidem, I don’t sleep as long compared to not taking it.” So it looks like, “when taking it, sleeping for about four to 5 hours compared to six.” And Ryan’s wondering if this is common and what the mechanism for that would be. 

Dr. Yaggi: That’s very interesting. Usually it’s to help extend out sleep, as a sedative hypnotic. But I would— you know, none of these medications— you know, all these medications have potential side effects. And so I would say, if his sleep quality is better or—or maybe, you know, he may not need that medication. 

Dr. Yaggi: But it also sounds like maybe he has improved sleep quality perhaps, on the zolpidem, just not getting the same length and perhaps having some improved sleep efficiency on the medication. The interesting thing about zolpidem is it’s one of the few medications that I’m aware of where the dose is different for women compared to men. 

Dr. Yaggi: And so men can take the— get up to the highest dose of the medication, which is about 10 milligrams— 8 to 10 milligrams. There have been reports of parasomnia, so abnormal behaviors— in women, at that higher dose range. So women, the high dose is 5 milligrams, men can go up to 10. But I suspect what’s happening is he’s having improved sleep quality and just may not be requiring the longer sleep. 

Farah: Gotcha. 

Emma: I’m really glad Dr. Yaggi is here to answer some of these questions. (laughs) So the next thing we wanted to touch on is— so last December, the tirzepatide, which the drugs called Zepbound, got FDA approval— for treating people that have both obstructive sleep apnea and obesity. And so I think there’s been a lot of media kind of buzz about GLP-1s and I just wondered if you could just share a bit about how that works with obstructive sleep apnea and what people need to know about. 

Dr. Yaggi: Ah, that’s a great question. I’m going to go back to the slides again, because I think this is a really important topic, and very timely. These drugs are really transforming the way we care for patients with weight gain and obesity and it is the first medication that has been approved ever, as a disease modifying medication for obstructive sleep apnea. 

Dr. Yaggi: But I must say, the story behind these medications is absolutely fascinating. And so what we knew, back in the 1960s, scientists discovered this effect called the incretin effect. And what this effect is, is that scientists observed that when we give patients an oral glucose challenge— so an oral sugar challenge— there was a much greater insulin response than if that same challenge was given, same dose was given, intravenously. 

Dr. Yaggi: And this really suggested that there were some cells, within the gut perhaps, that were really important for enhancing insulin secretion and affecting glucose homeostasis. So fast forward to the 1990s and another group of scientists discovered this in studying this lizard in the desert southwest of the United States known as the Gila monster. 

Dr. Yaggi: They— which is a lizard, honestly, that can survive for months— two to three months without food. Which is obviously an adaptation in a desert environment where food may be scarce. And what the scientists discovered, in the saliva of these lizards is a molecule that was called exendin-4. 

Dr. Yaggi: And this molecule, it turns out to be very similar to GLP-1 which is a molecule that’s secreted in humans and it is— extendin-4, unlike other molecules, is very stable in the bloodstream. Making it really useful, potentially, for drug development. And so this is really what led to this sort of paradigm change in the way we’re treating patients with weight gain and obesity. 

Dr. Yaggi: Both GLP-1’s, which is a hormone— natural hormones, secreted in humans and the gut— exendin-4, stimulate insulin release. It slows the GI tract. So it slows the emptying of the stomach and importantly suppresses appetite or induces satiety. And these medications have really transformed— they were initially, quite honestly, developed for the treatment of type 2 diabetes. 

Dr. Yaggi: But they have— found to have these very impressive weight loss and satiety effects. And other examples of similar molecules being discovered from nature. But the study, Emma, that you were alluding to— led to FDA approval of tirzepatide for the treatment of patients with obesity and moderate to severe sleep apnea. It was called the SURMOUNT-OSA study. This was a Lilly study. Atul Malhotra was the first author on this study and it was published last summer in the New England Journal of Medicine, so in 2024. 

Dr. Yaggi: And it was actually— the study was two separate trials. And tirzepatide, in contrast to semaglutide or Ozempic, which I think people have probably heard of— tirzepatide is a dual agonist. So it’s both a GLP-1 and what’s called a GIP receptor agonist. And so, this dual activity, as we’ll talk about, actually results in a greater amount of weight loss on average compared to Ozempic or semaglutide. 

Dr. Yaggi: But the SURMOUNT-OSA Study was two parallel trials, in a group who were using CPAP therapy and a group who were not using CPAP therapy. So trial one and trial two. And what they observed in this study was— in both trials— was an absolute reduction in— or in the apnea hypopnea index, our main metric of severity for obstructive sleep apnea— of about 20 to 24 events per hour. 

Dr. Yaggi: So a relative reduction in this group of about a little over around 50%. And in fact, 50% of patients also achieved essentially remission with sleep apnea. So either having an apnea hypopnea index of less than five or very mild sleep apnea without real symptoms. In addition to that— in this study, the investigators found that this resulted in improvement of CRP which is a measure of vascular inflammation that has been associated with cardiovascular events. 

Dr. Yaggi: And also significant improvements in hypoxic burden— that is hypoxia that is specifically related to sleep apnea events— and reductions in blood pressure. And we have known, really, for a number of years that a weight reduction, such as what was achieved in the SURMOUNT-OSA study, so 15 to 20% weight reduction, can really half the severity of sleep apnea. 

Dr. Yaggi: And so the magnitude of the impact of this medication on sleep apnea was not a big surprise because we’ve seen from previous medical or surgical weight loss studies that that kind of weight loss will treat sleep apnea. The difference here is that we just really haven’t been able to achieve this, meaningfully, in large groups of patients. 

Dr. Yaggi: And so this has really led to a paradigm shift in how we’re treating obesity. In addition to behavioral interventions of diet and exercise, we’re really now embracing a medical model.  Many patients are able to lose weight with behavioral interventions, diet, increasing physical activity. Many of those patients end up gaining the weight back. And part of the reason for that weight gain back is the issue of a set point that we have in our brain for our weight, or satiety.

Dr. Yaggi: And this— I think these medications are so effective because they get at that issue. And are able to decrease satiety and really result in these meaningful weight losses. So GLP-1, which stands for Glucogon-Like Peptide-1, is produced from intestinal cells in the humans in the small intestine and the colon and is released in response to a meal. 

Dr. Yaggi: And there are receptors throughout the body for GLP-1 in the brain that impact satiety and appetite. In the heart, that may be mediating some of the cardiovascular benefits. In the liver, related to insulin sensitivity. In the stomach, which affects gastric emptying. And in even in the pancreas, which is what I think mediates the insulin secretion. 

Dr. Yaggi: Tirzepatide, as we said, is both a GLP-1 and GIP1 or GIP agonist. GIP stands for glucose insulinotropic polypeptide. It’s produced by a different set of cells in the stomach and the intestine called K cells. Also released in response to meals. And also have receptors throughout the body, that I think really mediate this sort of transformative effect. 

Dr. Yaggi: So, in addition to treating sleep apnea, largely mediated through the weight loss— in addition to resulting in significant weight loss— part of the reason these medications are so transformative is because in addition to that, they are reducing major adverse cardiovascular events. 

Dr. Yaggi: They protect the kidneys from diabetic kidney disease and kidney insufficiency. They prevent the development of diabetes. They protect against metabolic associated liver disease. Even help with the bones. So this just— transformative health benefits associated with this class of medication.

Dr. Yaggi: And just very briefly, there is another sort of blockbuster— sort of what we term metabolic modulator, that again, was developed initially for the treatment of diabetes that are also having significant health benefits outside of diabetes. And these are called the SGLT2 inhibitors. 

Dr. Yaggi: These are widely used currently in diabetes, in cardiovascular disease— and we got curious, in our group, to look at how these medications— this other class of blockbuster medications, may impact sleep apnea. And what we found in two separately derived cardiovascular trials, where these drugs showed cardiovascular benefit— we saw in both trials, they halved the incidence of obstructive sleep apnea. They’re preventing the development of sleep apnea. 

Dr. Yaggi: And so our research group at Yale is now doing a— what’s termed the mechanistic clinical trial, to study this type of metabolic modulator and whether it may be an additional treatment for obstructive sleep apnea and how this might actually treat obstructive sleep apnea, so.

Emma: So what I really want to ask you, ‘cause I’m so curious is, I know you said you’re comfortable sharing with everybody that you’ve been on Zepbound— and I wonder if you might want to share your own experience maybe just a little bit about your own journey with sleep apnea and how you got on with it.

Dr. Yaggi: Yeah, absolutely. I— so like many patients, I think mine was brought— my sleep apnea was brought to clinical attention by my bed partner, my wife. And she— and then one morning said, you snore, you run the sleep program—

Emma: At Yale. (laughs) 

Dr. Yaggi: (laughing) Exactly. She’s Scottish, by the way, so she doesn’t pull punches— as I think you are, as well, Emma. 

(Emma laughing) 

Dr. Yaggi: But— and so I had access to treatment in the sleep cen— I just started using CPAP therapy. Quite honestly, I didn’t even do a sleep study, initially. 

Emma: Don’t tell people that. (laughs) 

Dr. Yaggi: I know— I’m being—

Emma: (laughing) So if you’re tuning in, that’s not what we recommend. 

Dr. Yaggi: Yes. 

Emma: But it might be different for you, just because of your position. (laughs) 

Dr. Yaggi: No, yeah, absolutely. In fact, it’s critically important to do the initial sleep study, for a number of reasons— to make sure there’s nothing else going on, but also for insurance to cover—

Emma: Absolutely. 

Dr. Yaggi: —you need a diagnostic sleep study. But I felt amazing on CPAP therapy. And— but I was I— so I had sleep apnea, I had gained a fair amount of weight over the years, and then tried to implement some lifestyle changes. And was always able to lose weight, but it would sort of creep back up. We’re very busy clinicians, and— academic medicine. 

Dr. Yaggi: And then I went to see a doctor who sort of specializes in weight gain and obesity and we tried tirzepatide, it had just been approved for sleep apnea. I didn’t have some of the other indications for tirzepatide, besides the sleep apnea— and I must say, it—the weight just melted away. I’d never experienced anything like that. 

Dr. Yaggi: And what was different this time around is I honestly did not feel hungry all the time. And that noise of—food— just sort of dropped off. And I was able to combine that with some time restricted eating. There is some circadian science behind that, in fact. 

Dr. Yaggi: And I’ve dropped about 80 pounds on that. And so it has just been transformative for me, personally. I have never felt better and it has been phenomenal to open up this option for patients on our clinic, many of whom are really benefiting from this. 

Emma: What happened with your own obstructive sleep apnea? Did you have another sleep study? Are you still on CPAP, what happened?

Dr. Yaggi: I stopped snoring, so I stopped using the CPAP therapy. I’m not your model patient, most often. But I— my wife didn’t notice any pauses and I don’t think I have sleep apnea anymore. But I—

Emma: So, for a lot of people, I just wanted to share— there’s a couple of things. So I think oftentimes— like the whole overarching theme of today is going to be— each treatment option isn’t necessarily right for every single person, right? So I think that there is some confusion out there— that this is definitely for people that have obstructive sleep apnea and also obesity, right? 

Emma: And I think it’s— there’s a lot of people in my situation where I had really significant obstructive sleep apnea, before I gained weight in middle age. And so I very much like, you know, didn’t have obesity, you know, was definitely in a normal BMI or whatever they would say. And needed my CPAP because I had moderate obstructive sleep apnea. 

Emma: So even though— people like me, you know, could be helped with maybe a lessening in severity of their OSA— I think we have to be like, realistic about if people had OSA at, you know, a lower body weight, the chances are this might not be the thing that, you know, means that they don’t ever have to use CPAP again, or what have you. 

Dr. Yaggi: You’re 100% right. 

Emma: I think the other thing just to mention is obviously like the weight loss takes time, right? So I think one of the things you mentioned in going over the SURMOUNT-OSA Study was they did have a group of people on CPAP and a group of people who were only doing the medication. 

Emma: And so for some people, like if it’s going to take a long time for that medication to work, then the chances are you might be, you know, using another treatment option at the same time. Just to kind of make people aware of that. 

Dr. Yaggi: I think those are both excellent points. And you know, we know that weight gain and obesity is not the only risk factor for the development of sleep apnea. We obviously have very thin patients who can have very severe sleep apnea and I think we’ll have some opportunity to talk a little bit about that.  

Dr. Yaggi: But the other point is critically important, right, is that the SURMOUNT-OSA Study was done over a year. And so they assessed outcomes at one year. And this is not going to act immediately— the same night you start taking it. It’s largely mediated, we believe, through the weight reduction. And that’s going to take some time. 

Dr. Yaggi: And so until that occurs, you should stay on therapy. As I did. I only recently stopped the CPAP— either CPAP, or other therapy, to treat—

Emma: And ordinary people would probably do a follow-up sleep study. (laughs) 

Dr. Yaggi: Yes they would. Yes they would. And that’s what I would tell them to do.

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Emma: Okay, so we’re going to kind of switch gears now. So we’ve been talking about Zepbound, which is currently available. But now I wanted to talk about— there’s a company called Apnimed, developing a brand new drug, and this is not a GLP-1. It’s not for people with OSA and obesity, it’s for anyone with OSA. And it’s not FDA approved yet, but I think they did just announce some phase three trial results that are really promising. 

Emma: So I just—just really briefly, I remember meeting somebody from Apnimed, maybe a couple of years ago at one of the sleep meetings—conferences— and I can remember him just describing, it’s like this pill that you would take, you know, every night— and you know, it works to you know keep your airway open— and I remember thinking to myself, this just seems too good to be true, and this is going take us 10 or 15 years, but here we are. (laughs) 

Dr. Yaggi: Yeah, it’s amazing. 

Emma: Yeah. So, I thought maybe you could talk us through a little bit about that drug, AD109, and the, you know, like what their trials have shown and just a bit about that. That’d be great. 

Dr. Yaggi: Absolutely. We’ll go back to the slides because this is a really exciting development. And it is still— as you rightly indicated, it is not FDA approved, but the studies look really promising. And the fascinating thing is that this works through a totally different mechanism. 

Dr. Yaggi: This class of medications is being referred to as the anti-apneic neuromuscular modulators. And in part based on the known impact or cause of the decreased muscle tone that occurs in the genioglossus muscle and the muscles of the upper airway during non-REM sleep and the withdrawal of tone that occurs in REM sleep. 

Dr. Yaggi: The scientists who brought this to trial put together two already separately approved treatments for other conditions. And so, AD109 is a combination of aroxybutynin— and oxybutynin is a medicine that’s used, believe it or not, in the— for the treatment of bladder spasms, and it is an anti-cholinergic medication— and atomoxetine, which is a medication that’s currently being used in ADHD. And it is a selective norepinephrine reuptake inhibitor.

Dr. Yaggi: So it promotes adrenergic tone, leading to muscle activation. And the scientists who brought this drug initially to a phase one trial, Andrew Wellman’s group and Luigi Taranto-Montemurro, found in a small group of patients—so this was only about 16 patients initially— there were really impressive effects with the combination of atomoxetine and oxybutynin. 

Dr. Yaggi: Either one alone didn’t really have an impact, it was when you put them both together that we saw this dramatic decrease in the severity of sleep apnea, as measured by the apnea hypopnea index, still our main metric of severity and diagnostic criterion for sleep apnea.

Dr. Yaggi: And it appeared to be largely related to its impact on muscle— on muscle function. And so there— a couple of years ago, they went and did a slightly larger, phase three trial— and showed very similar outcomes. About a 40 to 50% reduction in the apnea hypopnea index, and a significant decrease—again— in the hypoxic burden. At least the hypoxia was greater with a slightly larger dose of the oxybutynin. 

Dr. Yaggi: There have been some safety data on these medications, and in the phase 2 trial, all the adverse events were sort of mild to moderate in severity. No serious adverse events, or unexpected. The one that we’re sort of keeping an eye on is there was a time limited increase in some insomnia symptoms in some patients, and that’s likely mediated through the atomoxetine which is this noradrenergic medicine used in the treatment of ADHD. But that apparently lasted only a few days, then resolved. 

Dr. Yaggi: The company just released— back in May—their, as you indicated, Emma, the topline phase three trial. So this is a trial, believe of about 300 patients, followed over six months, with very similar results. There is a second phase three trial that has just been completed and is now being analyzed. And it is expected that these trials will likely lead to FDA approval. 

Dr. Yaggi: And so, in terms of disease modifying treatments, we have the tirzepatide medication, which is targeting patients with moderate to severe sleep apnea who have a BMI greater than 30. It’s a once weekly injection. In contrast, if this medication is approved, Apnimed has a wider range of indications. 

Dr. Yaggi: It’s indicated for mild, moderate, and severe patients with sleep apnea with BMIs up to 40 and 42 in women and lower BMIs as well. It’s a once daily tablet with a rapid onset of actions. We’re not waiting a year, perhaps, for the effects of weight loss to see benefit. So very exciting development. It is, I think a really interesting time to be in the field of sleep medicine and have these emerging tools at our fingertips. 

Emma: Yeah. I think one of the things I think is so exciting about the Apnimed pill— is just the number of people we might be able to reach, right? I think that sometimes— I talk to people who can’t get their significant other to go— and even have a sleep study because they don’t want to use CPAP, right? They’ve already prejudged—

Dr. Yaggi: Right. 

Emma: —that that’s not for them. And so for those people, I think that having more options like that, that are obviously like taking a pill— most people are, you know, more comfortable with. So yeah, I think it’s a good thing in terms of how many people we can reach. 

Emma: So, do we want to go back— so, the other thing I wanted you to explain just really quick for everybody watching— so I think that for the ordinary person on the street, we don’t really know what a phase three trial is versus anything else. Can you explain the significance of that and just that there are certain hoops to jump through in order to get the FDA approval so that doctors can start prescribing? 

Dr. Yaggi: Yes, that’s a great question. Thank you for answering that. So phase three trial is— are typically much larger trials that are powered to look at effects in various subgroups of patients—sex differences, race, ethnicity differences, etcetera. 

Dr. Yaggi: So it allows for looking at effects and potentially adverse effects in a wider group of people. So phase one is usually safety, maybe some efficacy. Phase two is really efficacy. Phase three, larger groups of patients and looking at differential effects or side effects. 

Emma: Okay, that’s super helpful, thank you. So, I had a really— I’m in all sorts of Facebook groups and I had a really interest— there was a really interesting question where somebody asked this morning, she’d been prescribed acetazolamide for central sleep apnea and she was just kind of asking generally like, you know— she hadn’t heard of it before and she just wondered. 

Emma: So I wondered if you might want to take us on to talking about other medications that might be either available or being researched. I think you’d mentioned— did you touch on acetazolamide before or no?

Dr. Yaggi: No, not yet. I have some information on that, so I’m glad you asked. 

Emma: That would be great. 

Dr. Yaggi: Alright, so acetazolamide. So acetazolamide is actually a medication that’s been around for a while. I work— I was telling Emma, in the ICU, we use this drug quite frequently in the intensive care unit. It is a diuretic medication. And so it’s a diuretic that makes— gets rid of fluid in the body. It’s a sort of unique diuretic medication in that it also has— allows the kidneys to get rid of bicarbonate. 

Dr. Yaggi: And that induces— not to get too technical— what’s called a metabolic acidosis, which triggers a respiratory alkalosis. So these drugs get rid of bicarbonate in the body, get rid of fluid in the body, and increase respiratory drive. They impact what we call ventilatory control in the brain as well. And in so doing, these drugs, in meta-analyses, have been demonstrated to significantly reduce the apnea hypopnea index. 

Dr. Yaggi: And importantly, have very similar effects among patients with both obstructive and central sleep apnea, and they also have some modest hypertension effects. We use these quite frequently in patients who have difficult to control central sleep apnea, but the data suggests that these are beneficial for both obstructive and central sleep apnea, likely related to ventilatory control stability. 

Dr. Yaggi: And these effects really seem to increase at a dose of about 500 milligrams. So, yet another option. I think— these drugs are available. I would say that most of the studies have been shorter term studies, with these drugs, among sleep apnea— and I think the field in general would like to see the safety of these medications over the long term, but we’re certainly using these clinically in selective patients right now.

Emma: So we’re almost out of time. I, like— we really want to dig into some of the sort of phenotype, like how to— I mean I think you call it precision medicine, like trying to decide what is the best treatment option for an individual person— so do you want, like maybe you have time just to talk about— a little bit, like explain— I think you’ve explained arousal threshold, a little bit earlier. But did you want to talk a little bit about loop gain and some different things like that. 

Dr. Yaggi: Yeah! 

Emma: Maybe 15 minutes. (laughs)   

Dr. Yaggi: That sounds good. I can do this very quickly, actually. I think this is a really important—

Emma: We were just saying before we went live that we could probably talk about this topic for a whole hour. 

Dr. Yaggi: And it’s such a great field. It’s a young field, and what’s really exciting is all these different treatment options—CPAP, and devices. And now medications for our patients. I think there’s really a need in our field for new approaches, and I think at the very top of the hour, Emma, you alluded to this. 

Dr. Yaggi: I think for way too long, we have been using a CPAP for everyone approach, this sort of one-size-fits-all approach, and you know, about half of our patients do really well with that— the other half don’t do well. And I think that approach is failing way too many patients. 

Dr. Yaggi: And I think what has really changed over the last five to seven years, is our understanding of the pathogenesis. That sleep apnea— and we sort of touched on this— is not just anatomy. It’s not just weight gain, it is not just how the upper airway is designed. What we term in individual patients, anatomical predisposition, and that relates to how collapsible the airway is, how much negative pressure it turns out, to draw that airway closed. 

Dr. Yaggi: But what we’ve really learned, now, is that in addition to an individual patients’ anatomic predisposition— so weight gain, small jaw, what we call retrognathia, there are these non-anatomical traits. Loop gain, or ventilatory control stability, how responsive the muscles are, how— muscle responsiveness, and how likely an individual is to wake up from a respiratory event or a stimulus, their arousal threshold.

Dr. Yaggi: It turns out that more patients have sleep apnea related to these non-anatomic physiologic traits rather than anatomy. So not all patients—

Emma: Which is fascinating, right?

Dr. Yaggi: Exactly. And so this is really where we are right now, in the field, is that instead of CPAP for all, maybe we’re able to now better phenotype these patients off their original sleep studies, and use things like CPAP or oral appliance or surgery, position— some of the metabolic therapies to treat the anatomic predisposition. 

Dr. Yaggi: But we now have medications like the acetazolamide for overly sensitive ventilatory control in a device called phrenic nerve pacing or Remede. Perhaps it’s the patients with the muscle responsiveness issue that would do best with Inspire, or some of these neuromuscular modulators. There’s even a literature on muscle training or myofunctional therapy.  

Dr. Yaggi: And for those patients who have low arousal threshold, using sedative hypnotics to at least make CPAP more comfortable. So we are really, I think, at the verge of entering this more precision medicine approach, which is exciting, and hopefully as you indicated, treat more patients and not discourage patients from just—

Emma: It is so great. Like look at you, getting that in. Okay, so let’s just round up. Thank you so much, Dr. Yaggi. I’m so grateful. So the first thing, I just listed a few resources here. So, the sleep apnea treatment options toolkit, like obviously this session will then have its own toolkit, but for now, we do have a page on that where we talked about some different medications and it’s got some links so that might be helpful to some people watching. 

Emma: The other thing is, we oftentimes— I know that there are people in rural areas or, you know, not necessarily close to a big sleep center, but oftentimes we encourage people to find a board-certified sleep specialist. Just because their level of knowledge tends to be a lot higher than people who are in primary care. So I just put that link there just in case people want to find an accredited sleep center.  

Emma: Another thing is, I’ve heard from a number of people who maybe have been prescribed Zepbound, and were kind of going back and forward with insurance companies. So just to let you know that there is this website where people can go, with— to get help with prescription costs. So whether it’s paying out of pocket or coupons or different things. 

Emma: And the other thing to mention is, we talked about Apnimed’s AD109 medication and so they have a really good website, apnomed.com, where you can find so much information. They have patient stories, they have links to their phase three trial that we talked about. So you might want to go and check that out there. 

Emma: I always like to shout out the different patient advocacy organizations working in the space. So there’s the Alliance of Sleep Apnea Partners, ASAP. The American Sleep Apnea Association has changed its name and its mission to Wellness, Sleep and Circadian Network. So, they can— they’re still on sleephealth.org is their website. So you can still find them there. But just to let you know that that name changed. 

Emma: Then there’s us and then there’s the Reggie White Foundation. So for anybody who particularly needs help with— they can’t afford CPAP, or they’re having problems, those two organizations, the Wellness, Sleep and Circadian Network and Reggie White Foundation both have programs to help people with access to CPAPs. So just to let you know that. 

Emma: And just to mention, we have a free Sleep Helpline. So we have a staff member who— there’s no medical advice from the helpline, but it’s navigational support. So, if you’re struggling to find the right doctor to go to, or you just have questions about your sleep, please give our Sleep Helpline a call. We’d love to hear from you. 

Emma: The Rising Voices program is currently underway for this year, but this is our training program where we take people living with sleep disorders and turn them into patient advocates. So myself and Farah have both been through the Rising Voices Program and yeah, are sharing our stories all over the place. (laughs) 

Emma: So I encourage people just to either join our email list or you can always email [email protected] if you want more information. Additionally, we have an army of speakers that can speak at companies, any sort of groups that have speakers, we’d love to have a speaker share their story just to raise awareness. 

Emma: And then thank you so much to everybody tuning in who is a personal donator to Project Sleep, but also thank you to our corporate sponsors Apnimed, Lilly and Resmed for your support. We couldn’t do this program if we didn’t have that support. And a big thank you to everybody for tuning in.