I just want to take the minute before the talk actually starts to introduce our speakers and the session so that everybody gets their full share of time. Our session is Treatment Alternatives to CPAP for Treatment of OSA, and we have four talks in this session. The first talk will be by Dr. David Kent from Vanderbilt, who will be talking on hypoglossal nerve stimulation for sleep apnea. Our second speaker is Dr. Andrea Anton from Medical College of Wisconsin in Milwaukee, and she will be discussing pharmacotherapy for sleep apnea. And then I'm happy to introduce our local dental sleep medicine specialist, Dr. Eugene Azuma, who will be giving a dentist's perspective on the management of sleep apnea. And then when none of the above work for you, that will be something that I can talk about at the end. I am at Loyola University Medical Center in Maywood, Illinois. So with that, I'm going to hand it over to Dr. Kent. Thanks. It's a pleasure to be here, and I'm grateful that any of you are here with us instead of out on the beach right now. So thank you. My name is David Kent. I'm actually an otolaryngologist at Vanderbilt University Medical Center, but I do exclusively both medical and surgical treatment for obstructive sleep apnea. I have a line of research and some research colleagues that I work with that are looking at new neurostimulation treatments for sleep apnea, and so I'm going to talk quick today. I'm going to take you on sort of a whirlwind tour of the upper airway, and if we can get to some of that new stuff, I'll talk to you a bit about it. I do receive funding from various hypoglossal nerve stimulation companies for some of this work, and we've got some federal funding as well. I'm not going to take a lot of time to lean into why it's important to talk about non-CPAP alternatives other than to say there's a dose-dependent effect of CPAP on the human body, and if people aren't wearing CPAP all night, then we see that there is a significant amount of residual disease. This was actually a great paper that was published by some Vanderbilt colleagues in 2016 right about as I was joining the institution, and I ended up really miffed that I wasn't on it, but they had patients who were partially compliant with CPAP, set a small timer while they were wearing a watch pad overnight, and take it off overnight. What they found was that basically two-thirds of those patients who did not wear their CPAP for more than six hours of the night still had moderate to residual sleep apnea when you take that last third of the night and you average it over the course of their total sleep time, and this may be why some of these large CPAP trials with poor compliance rates maybe don't show those great improvements in cardiovascular disease risks that we feel like are lurking out there. These patients struggle with these therapies. I do a lot of prescribing CPAP and managing it and trying to fix people's compliance issues, nasal surgeries, ways to improve pressure modality tolerance, et cetera, but there are some patients I think that it just doesn't work for them, and this was actually a really interesting study that was published out of an Australian group and some German colleagues as well who looked at essentially this concept of mean disease alleviation, and when they took patients who were using hypoglossal nerve stimulation therapy for most of the night and they compared that to patients who were wearing their CPAP machines for most of the night and they actually matched them using a propensity scoring algorithm, they found that in general both therapies were resulting in equivalent amounts of mean disease alleviation for patients overnight, and so I do think that there's a really important component of this practice where alternative non-positive airway pressure therapies can be of use, and so we're going to review some of that data, but I'm also going to take you on a bit of an anatomy journey here, so when we talk about hypoglossal nerve stimulation, there are many elements of the upper airway that surgeons and otolaryngologists take in consideration into how those structures interact with one another, and for us today the important components are going to be the soft palate, the soft palate especially, and the two muscles that are the two extrinsic muscles that are really responsible for moving the palate forward and opening that airway are the palatal glossus, which connects the tongue to the back of the palate, and then the palatopharyngeus muscle, which pulls that trailing edge of the palate down into the pharyngeal airway and opens it like a trap door, there are the lateral pharyngeal walls that are made up by the constrictor muscles, and then there's the tongue, which is the sort of major component of our conversation today, that genioglossus muscle, that big fan-shaped muscle you see on this agile image there is responsible for protruding the tongue, and then we've got retractor muscles that work in concert with the protruder muscle to shape and move the tongue. There are other intrinsic musculature that we won't get into, and then there's obviously the epiglottis, which actually can cause some isolated independent sleep disorder breathing issues, and when we look at that anatomy from a conceptual standpoint, when we're looking at the airway in the OR and trying to figure out, well, how is this patient's airway collapsing, you may have heard of this concept of complete circumferential collapse of the upper airway. It's circumferential collapse of the soft palate is what we're looking for. The data behind circumferential palatal collapse, or CCC, is actually pretty weak, because there was a feasibility study published in 2012 with hypoglossal nerve stimulation, where about eight patients in a secondary part of that feasibility study were screened with DICE prior to a drug-induced sleep endoscopy, prior to being implanted with a hypoglossal nerve stimulator. Three of those patients were responders, five were not. The ones who did not have CCC were the ones who were the responders, and so based on that sort of scant evidence, the tens of thousands of patients that have been implanted with this therapy since then are screened out if they are seen to have this finding on drug-induced sleep endoscopy. But what I hope to convince you of a little bit today is, what does that collapse pattern actually mean physiologically, and how else might we be able to deal with it? So getting into the hypoglossal nerve stimulation data, what matters for us is this anterior movement of the tongue. And there are probably three classes of supporting mechanisms for the upper airway. There's that tongue tone, keeping the tongue out of the airway, like keeping a ball valve out of the pipe. But then it turns out that tracheal traction, pulling down towards the feet, or caudally, actually really matters for extrinsically stabilizing the airway. And then there's the intrinsic pharyngeal muscle tone, and these opposing forces may actually have synergistic effects. So when we look at this endoscopically, it's a 180-degree view from the standard bronchoscopy view that's heading into the airway. So anterior is at the bottom of the screen when otolaryngologists do these exams. And on the left side, you see what would be termed an anterior posterior palatal collapse. In fact, this degree of palatal collapse may not be limiting airflow, whereas you see the entire airway squishing down in this sort of sphincter kind of pattern, where the lateral walls have an increased collapsibility in that circumferential palatal collapse. And I'll share a little data with you coming up about why that matters. Lateral wall collapse, moving a little more caudally in the airway, beyond the level of the soft palate. You could argue with some of my colleagues here that this palate may not actually be collapsing at all, and everything that you're seeing in that endoscopy image is just the left and right sidewalls of the airway collapsing. Turns out this also affects responder rates for hypoglossal nerve stimulation. We move a little lower yet, and you see the tongue base collapsing posteriorly in this particular endoscopy image. What's also important here is that you don't see the lateral walls of the upper airway collapsing. And finally, in isolated epiglottic collapse, you can actually see with inspiration that tongue base is actually trying to move forward. You probably see a little bit of geniohyoid muscle contraction, but that epiglottis is still prolapsing posteriorly and actually limiting airflow. So when we dig into this physiologic supporting mechanism, almost every surgery that we have available for sleep apnea today is either ablative, or it moves things from posterior to anterior, whether it's a maxillomandibular advancement, a palatal surgery, or hypoglossal nerve stimulation. So when hypoglossal nerve stimulation is operating on the airway, this is what it looks like. On the bottom, you can see that that tongue base snaps forward every time the stimulator activates. And what's really key here is that you also see that the soft palate is snapping forward with the tongue base. So this therapy is actually having a multilevel effect, and that multilevel component is what's key to this therapy being a little bit different than some of the other ablative surgical options or static surgical options that we have available. When we look at the evidence, almost all of the evidence that is available in this field today is coming from one particular implantable system. That is Inspire therapy that you've heard of. It was FDA approved for obstructive sleep apnea in April 2014. There are three components to this system. There's a respiratory sensing lead, there's a cuff electrode that goes on the distal portion of the hypoglossal nerve, and there's an implantable pulse generator that's actually what is generating the electrical signals. There are other companies that are working on coming to market and getting FDA approval, and we may see some of that as early as the next 12 to 18 months, but right now, these guys are the only game in town here in the U.S. That system is now implanted through two incisions, and it's a closed loop therapy, meaning it has a respiratory stimulation sensor that ideally is activating at end expiration to move that tongue forward to crack the airway open prior or immediately preceding the inspiratory effort. And so, when we implant it surgically, we're trying to get it just on the nerve branches that are responsible for that genioglossus muscle and a couple other secondary tongue muscles but that don't pull the tongue into the mouth, they protrude it instead. The battery on that therapy as it exists is rated for about an 8 to 11-year life. It's not currently rechargeable, and so it does have to be replaced once that battery reaches end of life. So when you look at the FDA indications for this therapy, it's essentially patients with moderate to severe sleep apnea who have demonstrated an inability to benefit or tolerate CPAP therapy who have appropriate airway anatomy. And that appropriate airway anatomy, again, comes back to this concept of circumferential palatal collapse and actually probably also lateral wall collapse, although that isn't currently an indication criteria for whether or not a patient meets candidacy for it. So where did this data come from? Well, the pivotal trial of this therapy that was published in 2014 was called the STAR trial, or Stimulation Therapy for Apnea Reduction trial, 22 centers, and they implanted 126 different patients, and they did have some exclusion criteria with a body mass index greater than 32, as well as this CCC criteria, and this data came from that earlier feasibility study that I mentioned to you, where they found that responders were, frankly, people that were less overweight, that had the less collapsible airways, which is measured by both this concept of circumferential palatal collapse, as well as an overall lower body weight. Now, I'll show you a couple slides that are essentially demonstrating outcome data, but the story behind all of these outcome data and what this therapy essentially does is that in general, we see that it moves the majority of people from severe sleep apnea typically down into a mild range of residual disease, but what's also really important here is that we see significant improvements in the oxygen desaturation indices, and we also see substantial improvements in quality of life and daytime sleepiness scales. So these are patients who have not been able to benefit from positive airway pressure therapy, and the improvements that they get in their subjective symptomatology can be on par with some of your best CPAP users. These are people that are desperate to feel better, and this therapy can be really effective in doing that. These results have been durable, so these patients were followed out over a period of five years. There was some loss to follow-up in terms of people being willing to come back and sleep in the sleep laboratory again, but overall, we see again that median shift of patients from severe OSA down into a mild or moderate range of residual disease, significant improvements in oxygen desaturation indices, and quality of life as well. The company has had an FDA post-approval registry that they've continued to run patients through, and they've actually closed enrollment for that now. They've accrued up to 5,000 patients that they're tracking out in terms of how they do with this therapy, and we see again that trend sort of holds. We take patients from severe sleep apnea, not too severe, but severe sleep apnea, down into this range of mild residual disease, significant improvements on quality of life. Now, if we look at some of the emerging evidence for non-inspired hypoglossal nerve stimulation therapies, you may hear about working on coming to market a product from another company called Levonova. This therapy is a little bit different from the Inspire device in that it doesn't go on the distal portion of the hypoglossal nerve. It's not trying to activate just the tongue protrusor muscles. It's actually also trying to activate the retractor muscles of the tongue, the styloglossus and the hyoglossus muscle, but to do it in a pattern where the tongue is stiffened, but it isn't pulled back into the airway, and so it has this helical cuff electrode array that works around the hypoglossal nerve and activates these muscles in different combinations. The data that was just published actually a little bit earlier this year is from a much older trial that was accruing patients in the early 2000s. The overall apnea-hypopnea indice outcomes that you see here are maybe not quite as robust as you saw with the STAR trial data that's been published, although the overall share responder rate numbers decreasing sleep apnea into the moderate residual range and decreasing by at least 50% are reasonably within the same infield as the STAR trial data. The company that bought the original neurostimulation company back in the mid-2000s has sort of rebooted this trial, the OSPRI trial. This is an FDA pivotal trial for them, and those data are currently being accrued, and that study is ongoing, and so I think a lot of people in this field are interested to see those outcomes. There's also an organization that is working on a bilateral hypoglossal nerve stimulator, and so the low-level concept here is that if one hypoglossal nerve is good, two is ostensibly better. What we see in the initial feasibility study data that was published overseas is while the outcomes look reasonable, this isn't currently blowing currently available hypoglossal nerve stimulation therapy out of the water. We'll see if in this pivotal U.S. trial that's currently ongoing that has closed to accrual whether or not those results are non-inferior or even possibly better, and so I think also surgeons in the field are interested to see these outcomes. So I'm going to take a couple minutes to jump into what might be on the horizon, and the question is, well, why does hypoglossal nerve stimulation fail? It turns out that when it fails, it's not because it didn't move the tongue enough. The retroglossal airway opens up with hypoglossal nerve stimulation therapy. Where we see therapy fail is when patients have residual palatal collapse and lateral wall collapse, and it turns out that what's happening with this anterior tongue displacement is it's just trying to pull those other airway structures anteriorly through its elastic connections through the lateral pharyngeal sidewall. There's no neurostimulation of the lateral walls or the soft palate going on here. It's like we've got a tow rope on a rubber band that's just trying to drag the palate forwards with it. Now, you may have heard that these organizations are working on increasing access to therapy and trying to increase both the BMI ceiling for therapy as well as the apnea hypopnea index indications. It's maybe going to be a bit controversial in our field because the issue that I see here is that as body weight goes up, we see that both complete circumferential collapse and lateral wall collapse of the upper airway increase in their prevalence, and the problem that we have in our country here is that we're getting bigger. There's an obesity epidemic. We'll see if these GLP-1 agonists change the whole story on that, but greater portions of larger BMI individuals have moderate to severe sleep apnea. So if you look at the U.S. population in that body mass index that's less than 32, two-thirds of the U.S. population have a lower BMI. But only a third of patients with moderate to severe sleep apnea have a BMI less than 32. Those aren't currently surgically accessible to me with hypoglossal nerve stimulation therapy, and we want to look for other potential treatment options. So I wasn't the guy who named this talk, and I think that I can't necessarily say hypoglossal nerve stimulation is the future of sleep apnea therapy. I think it's a component of it, and in isolation, it's probably not for the majority of sleep apnea patients. Combination therapy may be something, and I'll talk quickly through these next couple slides. I mentioned to you that the pharynx is extrinsically modifiable by tracheal traction. It turns out lung volume is what physiologically modifies caudal traction on the upper airway, and lung volume has major effects on airway collapsibility. I don't have time to share all this data with you today, but it's actually really interesting, and people have been looking at this for 20, 30 years. One of the main reasons that CPAP is effective for opening the airway is not because it's a pneumatic splint that's blowing things open, it's because it modifies an expiratory lung volume, and when you fill the lungs, they descend within the mediastinum, and that passively stretches the upper airway like stretching a spring that stabilizes it without the muscles having to do any extra work. In human beings, it turns out that the human hyalurongeal complex is actually highly mobile, the voice box and the bone above it, the hyoid bone, and there are other ways that we can pull down on the upper airway. Those strap muscles that connect those structures to the chest wall actually enable a wide degree of control of the upper airway, and they're innervated by a network of nerves coming out of the C-spine called the antiservicalis. There's one spot where we can stimulate those nerve branches, and this is what it looks like. I stuck a couple electrodes in my own neck here, and what you're seeing is hypoglossal nerve stimulation on the left, protruding the tongue, and on the right side, you're seeing my thyroid notch drop every time we stimulate because I'm activating the antiservicalis and the strap muscles that are connecting the voice box to the chest wall. So if we want to model the effects of this therapy and quantify it, which is what we're currently doing in our research, we have to look for an effect size. And when the upper airway is controlling airflow, if we change the collapsibility of the upper airway, we can actually plot that change in airflow across a couple different ranges of pressure and then see how we're altering collapsibility of the upper airway. So I won't beat you up with data. I'll show you a cool video. So what you're seeing here is that when we activate hypoglossal nerve stimulation therapy in the operating room with a percutaneous electrode, it opens the airway here, right? The tongue is moved out of the way. But you can see that every time this patient breathes in, the airway is still collapsing and there's still flow limitation. But when we add in another vector of therapy treatment and we activate the antiservicalis and we pull the airway caudally, you see the whole pipe stiffens right there. And this patient goes on to breathe in a non-flow limited manner because we're operating on two of these airway stabilizing mechanisms now. And what we're seeing in the data that we're generating is that this has substantial effects on stabilizing the upper airway and decreasing airflow. So in the interest of time, I'm going to hop just to the summary here and show that when we are generating this data, we are decreasing airway collapsibility by two to three centimeters of water pressure with antiservicalis stimulation. That's on par with what hypoglossal nerve stimulation therapy does. But what is critical in the data that we're seeing is that the biggest effects on airway stabilization are on those collapsing lateral walls and the soft palate, which has to pull caudally into the airway to stabilize. That's what antiservicalis stimulation does to the soft palate. So in summary, we think that ACS is tensioning the palate. It's pulling the tongue down off of the soft palate. It's stabilizing those lateral pharyngeal walls. And we're seeing an anterior tilt of the epiglottic cartilage with it. So in summary, hypoglossal nerve stimulation is very effective, but it's not for every patient with sleep apnea. And we think that these combination therapies may hold some promise for the future. Our ongoing human research data support this. We think that these therapies in combination may complement hypoglossal nerve stimulation to yield greater effects than either in isolation. And this may allow us to deescalate single-channel therapy and expand the patient population that we currently have access to with these therapies. So thank you for your time. Thank you. Good afternoon, everyone. Welcome. Thank you, Sunita, for inviting me today to talk about pharmacotherapy for sleep apnea. Is it coming soon to a pharmacy near you? I hope you're gonna figure it out, the answer by the end of my talk. Let's see, it's, the presentation is loading here. Okay, well, I'm, I can see, okay, here, because it's not showing on my screen. Perfect, sorry. Okay, so my name is Andrea Anton. I am at the Medical College of Wisconsin and the VA in Milwaukee, and I have no conflicts of interest to disclose. So I only have two objectives. I want to remind everyone what we know and how our understanding evolved on the obstructive sleep apnea pathogenesis, and really talk about OSA treatment in the context of pharmacotherapy. So, tremendous amount of work has been completed over the last decade or so, and our understanding has evolved. The pathogenesis of sleep apnea is rather complex, and it's a combination between anatomical traits, we heard about the collapsibility of the upper airway, but the non-anatomical traits or endotype are as important. In patients with collapsible airway, 70% have one or more of non-anatomical traits or endotypes present. What is an endotype? It's a subtype of disease that share a common pathophysiological mechanism. So what are the endotypes in obstructive sleep apnea? This include low arousal threshold, high loop gain, and poor muscle responsiveness. My panelists, we're gonna talk to you about therapies that target the anatomical trait. There is no doubt that CPAP, it's further line therapy, is the most effective. However, patients struggle with tolerability and compliance and failure rate is as high as 50%. You're gonna hear about other interventions, you heard about hypoglossal nerve stimulators, my colleagues were gonna talk about other therapies that target the anatomical trait. The eccentric circle really talks about pharmacotherapies that try to address the other non-anatomical endotypes, and that's what I'm gonna talk about. So these are the drugs. So I'm gonna talk about norepinephrine reuptake inhibitors and anticholinergic agents, along with the new kid on the block, a topical potassium channel blocker in trying to improve the upper airway dilator muscle response the role of carbonic antidress inhibitors in lowering the loop gain, and the Z-drug and their impact on the arousal threshold. So let's start with intervention that try to modulate the upper airway dilator muscles. You heard how the pharyngeal muscles are quintessential in maintaining upper airway patency during sleep. But unfortunately, about a third of the patients with obstructive sleep apnea, they have minimal activation of their pharyngeal muscles in response to negative airway pressure. Why is this happening? Well, thought that maybe is mediated by withdrawal of the serotoninergic tone during sleep. So serotoninergic medications have been tried. This was a nice review published in 2019, and you could see that the results actually on different serotoninergic agents were not impressive. The working theory is actually that the tone is because you have decreased noradrenergic tone during non-REM sleep, and increased muscarinic inhibition during REM sleep. So let's try to address that. So you have two old drugs, atomoxetine, which is a selective norepinephrine reuptake inhibitor used in ADHD, oxybutynin, an anticholinergic used for hyperactive bladder. And this was a proof of concept trial published in 2019. This was a randomized control trial of 20 patients with sleep apnea one night, 80 milligram of atomoxetine, five milligram of oxy versus placebo. And what you could see on the right is that the individuals on atomoxetine and oxybutynin had a 63% decrease in AHI that was statistically significant. There was improvement in oxygenation indices. And the mechanism of actions was through improvement of the genioglossus muscle activity. Side effects, no change in blood pressure, but with some increase in heart rate. Since then, 2019, 2022, we have total of five studies. This was a meta-analysis that pretty much confirmed the original study, but five studies, 70 patients, one night, the main difference only decreasing 11 events per hour. Additional outcome, there was some improvement in oxygen desaturation in the six arousal index, side effects pretty well known with the actual medications, urinary hesitancy, and dry mouth. Okay, one night, what about one month? Well, the study was published earlier this year, a randomized controlled trial of 39 patients who underwent three polysomnograms, three different doses of auto-oxy versus placebo, and the authors tried to see the efficacy, safety, and tolerability. The graph on the right is pretty busy, but what I want you to just take away from it is really the only, the highest dose work, the 80 over five, that compared to baseline, nine to one, there was significant decrease in apnea, hypopnea index, and improvement in oxygen, improvement in the hypoxic burden, not really change at 30 days, and in between the three drugs and placebo, there was no significant change, so not too exciting. Side effects, again, pretty similar to, are described with the actual medications, higher the dose, more side effects, and again, there is a signal there, the heart rate goes up, so are these medications really good for our patients with cardiovascular comorbidities? 2023 was a busy year for this combination of medications. We have two other studies that I would like to share with you. The one on the left, Mariposa trial, is not published yet. The results were discussed at ATS. It's a multicenter trial of atomoxetine and aroxibutinine, aroxibutinine and enantiomere of oxy versus placebo, 30 days, 200 patients, and AHI improved by 47%. Side effects similar, and based on those results, now two phase two, I'm sorry, two phase three trials are underway, one of six months, one of one year. The study on the right was also published this year, and it's one night trial, but it's a different patient population. 17 Japanese OSA patients, it's a randomized control, crossover trial, 80 over five, and this did not work. So this is a stark reminder of ethnic differences in OSA pathogenesis, and we know that Japanese individuals, East Asian individuals have higher degree of airway collapsibility. They also have more distinct craniofacial bone restrictions that may account for this result. So really, this was not a positive study. So we talk about combination of medication, what about one drug? Can we find a single norepinephrine reuptake inhibitor? Riboxetine is an anti-seizure medication, and results were rather modest. This was a randomized control trial, crossover, 16 patients, and you could see they try riboxetine by itself, riboxetine in combination versus placebo, and on the right, you could see that riboxetine compared to placebo resulted in modest, you know, it was statistical significant, but you see that the change in HI was only by five, so patients still had residual sleep apnea, and the mechanism of actions were through decreasing collapsibility of the upper airway and increased loop gain. Similar, some improvement in oxygenation indices, and addition of oxybutynin didn't add much to the improvement in outcome. Side effects, what I shared with you before, heart rate goes up, and also was reported decrease in sleep quality. This is neat, I think. What if we can treat sleep apnea with a nasal spray? How would that work? It really is by increasing excitability of the mechanoreceptor through a topical potassium channel blocker, and through the negative reflex, pressure reflex that you would have increase in the genioglossus muscle activity, and you would improve upper airway collapsibility. So this was an amazing study, had two parts, an animal study and a human study, and they tried different ways of applying the spray, the brine, the medication, the spray, the drops or the endoscope, or two different doses, a spray or half a spray, and interesting enough, when they measured the upper airway collapsibility by changing critical closing pressure, the change was statistically significant no matter the way they did it, and was about two centimeter water. Is two enough? Yes, two is enough. This is similar to what surgery does, what oral appliance do, or supine therapy. So the magnitude of the change is similar to other interventions that we are using in treatment of sleep apnea. So this is one night study, more to come on it. What about loop gain? High loop gain is present in a lot of patients that count through 30 to 40% of OSA pathogenesis. How would carbonic anhydrase inhibitors work? Would cause a metabolic acidosis, increases your ventilation, you drop the CO2 and you decrease the loop gain. So there are two meta-analyses, I'm going to discuss only one, the one published in 2020, 28 studies, 500 patients, they combine obstructive and central sleep apnea patients all together. The overall effect size was minus 0.7, which is equivalent of 38% decrease in apnea hypapnea index, or 13.8 events per hour. Higher the dose, more impactful, there was no change between obstructive sleep apnea and central sleep apnea. But what I want to see is actually a post hoc analysis on the right, you could see that the bars all over the place. So the columns to the left, you know, you could see that about 50% of the patients had anywhere between, had more than 50% reduction. Okay, oh, here, I'm pointing to the ceiling. Okay, 50 to 75, so more than 50% reduction in HI, but look at it, about 10% of patients had worsening of the apnea hypapnea index. And unfortunately, the variability of response is also associated with inability to predict who's going to respond. What about sulfium? This is also a carbonic anhydrase inhibitor. It's actually an anti-epileptic. This study was done in Sweden. This is a phase two randomized control trial of 68 patients, and look at it, all the lines are going down. So 400, 200 versus placebo, four weeks, that resulted in significant decrease in apnea hypapnea index, regardless of the level of severity of your sleep apnea. So side effects, paresthesia, and headache, and based on those, the results on the carbonic hydrase inhibitors, we have more studies underway. We have the ACE of heart study, panacea study, looking at acetozolomide in sleep apnea, and we have now a phase three study on efficacy, safety, and tolerability of sulfium in obstructive sleep apnea. What about a low arousal threshold? And I'm gonna briefly talk about the Z drugs. Limited benefit on the left, you have azopiclone. This was an older study, physiological study, 19 patients, three milligram of azopiclone versus placebo. You could see there was 23% decrease in apnea hypapnea index. It was statistically significant, but you could see, oh, oops, you could see that the AHI patients still had residual sleep apnea. Other outcomes increased total sleep time and did increase arousal threshold. Zopiclone, there were two studies, actually by same group. One was 30-day trial. That was a negative study. It was a signal that in the zopiclone group, you could see that was within the group, there was significant decrease in AHI. So the author thought, well, maybe we need a higher dose. So instead of 7.5, let's give 15, and really was no change. So we heard the magic word combination therapy before. So with combination of drugs work or interventions work. So the last two studies are actually a proof of concept studies. 20 patients, randomized controlled crossover trial of a zopiclone on oxygen versus placebo and sham air, and it did work. There was significant decrease in apnea hypapnea index, and those responders seem to have milder disease, less collapsible airways. This is busy, but what I really want to point out is that maybe if we know what the underlying endotype is, maybe we can approach these patients in a personalized, you know, not one-size-fits-all approach. So this study was published earlier this year. So those are patients who were offered, if they had an incomplete response to oral appliances, they were offered EPAP and supine preclusion therapy. So that was phase one. And then based on their endotype, they were either offered zolpidem, oxygen, or atomoxetine, oxybutyne. And if it still had unresolved sleep apnea, they were offered CPAP. And you don't need to look at, to see all the categories, but bottom line, amongst 20 patients, you only have one circle that's above the line. So if you're trying through a sequential approach, but this is very labor-intensive, and, you know, I'm not sure how we're gonna figure it out in the real world. And are new drugs in the horizon? Well, this is a study that look at intranasal administration of oxytocin. So yes, there are new drugs coming our way. So what have we learned so far? Current pharmacotherapy trials have limited benefit. Long-term data on efficacy, safety, and adherence is needed. Combination may be better, and new drugs are underway. So we need to make sure that we can identify these physiological endotypes, and then emerging data on drug therapy. And sleep apnea is quite excited, but probably not early for prime time, and find them at the pharmacy nearby. Thank you, everyone. Thank you, everyone, for taking the time to come to Hawaii. And it's a tough call. You're working, and you had to come to our little island from East Coast, West Coast. Suffer with the time zone differences, unfortunately. It's one of the things we have to, as a local resident, we have to deal with, unfortunately. Thank you, Dr. Kumar and the CHESS organization for having me. I am Dr. Eugene Azuma. I'm a practicing dentist in Honolulu. Basically, I'm a general dentist who has been to a number of different sessions and seminars regarding sleep apnea, and it terrified me. And it, basically, I looked at that, and I said, you know, general dentistry does certain things. In the real world, when you have to deal with someone who's dying from sleep apnea, and it's a very common thing, I just had an epiphany, and I said, you know, no one's doing this. We need to get more into this. Because in Hawaii, it's few and far between. So, that's one of the reasons why I joined the American Sleep and Breathing Academy, and I kept going and kept going. And, you know, they, for some reason, decided to put me on the board, so. Anyway. I'm gonna go over different things. I'm not from the world of academia. I am a wet-finger dentist. I saw a patient just not a couple hours ago, so. Anyway, so, I'm gonna go over different alternatives to sleep apnea, for sleep apnea. Because, you know, as we all know, there's so many constraints that we have to practice within. If a patient is 65 and older, you have to deal with Medicare and different devices. Medicare has such a stringent stronghold as to dictate as to what type of appliance you can use, what lab it's fabricated in, who can do it. You have to be certified. And I was certified as a Medicare provider in the state of Hawaii, and there was nobody else. And after a year of not getting referred patients, because as a dentist, we cannot diagnose, we cannot treat, we cannot refer a patient to ourselves, to actually treat people with an oral appliance. We had to be referred the patient. And as being referred the patient, now we had different protocols. They had to be CPAP non-compliant, they had to try this, they had to do that. We had all these hoops and hurdles. And I'm sure all the general dentists in your areas have to go through the same trials and tribulations. So, this is where I'm at, and this is where I had to do, so this is my experience. I have no disclaimers to, no representations or anything to claim. So, anyway, I'm gonna go over first, oral appliance therapy. Now, I had a problem with this. I said, you know, okay, what's gonna, there's like 120, 30 different appliances to choose. Every single lab has their own appliance, and they put their own name on it. So, what appliance do we use? What are we gonna do? What is our objective? So, first of all, we have to go to anatomy. Then, there's different types of mandibular advances, adjustment things. So, of course, you have the teeth, you have different landmarks you have to deal with. So, one of the first things I do after doing the effort sleepiness scale and doing the, basically, the protocols, follow the book. I take a cone beam on all my sleep patients. Why is that? Cone beam doesn't work. You're taking an X-ray of someone who's in an upright position awake. What information does it give me? It gives me, in my case, a lot of information because what I do is, in my office, I look at everything from the flaccidity of the nares to the nasal airway to the paranasal sinuses, going down the posterior pharyngeal wall. And I look at the epiglottis. I look at all of these things. And so, this tells me a lot of information. So, in this slide here, you can see the tongue position is not all the way up. This is the hard palate. This is the soft palate. And you can see the elongation of the soft palate. What's happening in this patient? That soft palate, over the years of breathing in and out, has elongated because it's starting to dry. This patient couldn't put their tongue up in the upper, into the palate. Why is that? Because probably during their formative years, from back when they were babies, it goes back to nature versus nurture. We have this blueprint where, nature gave us this blueprint where, if environmental stressors, such as whether or not mom had to go to work, whether they were breastfed or bottle fed, all of these things, when the child is developing, the bony structures are still soft. So, how they got their nourishment, whether it be through the bottle or the breast. If it's for the breast, the mouth is open. So, the orbicularis, aureus muscles don't constrict on the soft bony palate. So, you get a wide open type of bony structure on the roof of the mouth. So the roof of the mouth is also the floor of the nasal sinus. So this same bone, if you have to work, and back in our day, we had the platex bottle with the little tiny nipple. So when mom had to go to work, we got this little bottle. So when we were hungry, we basically did this to get our nourishment. So that constricted the bone, which is soft. So it basically caused an evagination into the nasal sinus. So you got a high palatal arch. If you have a high palatal arch, if you're trying to sleep, your tongue doesn't have a place to reside. Naturally, in a normal person, you have a normal palatal arch. You have inadequate tongue space. When you're sleeping in a supine position, the saliva is sticky enough to help hold the tongue away naturally from the posterior pharynx. So these things are constricted or affected by whether or not they were best for the body. It goes way back. And then after a while, you saw a rise in the need for orthodontics. Orthodontistry is a method of straightening teeth. But the orthodontists didn't think about the airway. They didn't consider the airway. All they thought about was teeth alignment. So what did they do? Bring everything in. You bring everything in, you crowd the tongue. The tongue has nowhere to go. So it goes back of the throat, blocking the airway, causing apnea. So all of these things are causing effect, which then lead us to where we are today. In this particular cone beam CT, and by the way, I encourage you all to go back home and check with your dentist in your area and try and coordinate care with them. Because there is a trend for a lot of dental offices to have 3D cone beams like this. So if you, as a pulmonologist, had this information, you could see the airway. You could tell whether or not this person would be able to tolerate CPAP or not because of the constrictions. In this particular slide here, you can see foreign body in the airway in the sinus. This one, unilateral blockage. Patient can breathe better to the left side than the right side because look at the airway patency there. Did I skip a slide? I did. So same thing. You can see basically the airway inside of this shows you what area we're located. So right in this area, the paranasal sinuses, you can see the constriction. So based upon this, you can tell and have a relationship with the dentist. And they can give you a copy of that. So you can tell whether or not CPAP is going to work for your patients. Because if you have a spaghetti noodle, angel hair pasta airway, they have to see an ENT, at least address that nasal lavages, something, afrin sprays, whatever it may be. And the CPAP won't work because you're going to have to tow the flow rate all the way up. And they're going to not be able to breathe or exhale. You can inflate the balloon, but you can't exhale. So they're going to be drying out their tissue and breathing through their mouth, exhaling to their mouth. Now, this is going to be a further complication. It will lead to periodontal disease, teeth loss, all these other factors. So you also got to look at, we as dentists, look at certain things. Some of the key things is the tongue. If we see scalloping at the borders of the tongue, that's one of the telltale signs. Because at night, what's happening is the brain is monitoring your sleep, is pushing the tongue against the inside of your teeth. And that's why you're getting the scalloping borders. That also leads to also bruxing, because your tongue is attached anteriorly to the base of your jaw. So where your jaw goes, your tongue goes. So sleep position is important, because if you're a back sleeper with a pillow in back of you, your jaw will be, you relax your jaw during sleep. It actually allows gravity to take over, and the tongue blocks the airway. So then you have to go with a hypoglycemic nerve stimulator or something else to help these things. But during sleep, we go to different stages. And when we relax the muscles that control the jaw position, this is what we get. If you have somebody who had orthodontic work in the past, they have teeth extraction. They have this crowding. They brought all this together, and there's no room for the tongue to reside. So they're mouth breathers, drying out the airway. So depending on the type of condition, if they're bruxes, bruxers, you cannot use something like this. This is called a dorsal appliance. It goes over the top teeth and the bottom teeth. This appliance is not Medicare approved because it's not connected. It has to be connected. So something like this, where it has a connected bar here, that's called a heater bar. This appliance here is Medicare approved if done by a Medicare lab. So there are all these different qualifications or quantifications that need to be done. This is an EMA appliance. This is a 3D printed appliance. And so these are side views of those appliances. So of course, we have studies. But we all know CPAP works. We all know oral appliance works if they're being used. And talk about compliance. So there's different things like tongue retention devices, like a binky thing that basically sucks the tongue and helps keep the tongue out of the posterior mandible. So this is what I was alluding to earlier. There's now a trend to reform the palate, reform the mandible to broaden the scope instead of collapsing and broadening everything back. Because it's taking advantage of the stem cells in the middle palate or suture. So this increases the tongue space, increases the airway. This is some example of appliances. They have right here expansion areas where actually a key gets put in, the patient turns the key every couple of weeks to expand the palate. This moves and grows bone in that palate or suture and actually broadens the palate, creating more room for the tongue. So these are different devices in there. So you have the next thing is remodeling of the posterior pharynx. This is a typical UPPP. This is the result that you get. If the ENT cuts too much, then the patient has problems sleeping at night because they can't sleep supine. Because the palatal arch helps to direct the saliva flow down to your esophagus. If you cut too much, it'll go up and they'll aspirate it. So this is an example of a non-surgical UPPP. Basically, this is a person saying ah. And this is a person, we use an erbium laser and we're basically firing it into the soft palate. This is actually stimulating neocollagenesis. And you get tightening of the collagen so you get more response from the stimulation from the brain saying open up. And so this is the patient afterwards. This was after three treatments. Okay, sorry. So this is examples. This is like a comb beam of this area. Now you can see what it actually did. It actually smoothened the soft palate, the posterior pharynx. This is actually me. So you can actually see that my airway opened up 230.7 as opposed to 200.3. Anyway, so I'm getting that ejection sign but, you know, we're going to nasal breather versus oral breathing. And we, as a dentist, I go and I work on everything. And so it's a cumulative effort of all of these different treatment modalities that I used to practice in my practice. So thank you. Thank you, Dr. Zuma. Thank you. That was all very interesting. Being the last speaker of the session, the advantages, some of the material has been covered by other speakers. So I can rush through my presentation in the last seven minutes. So if your patient doesn't want any of the above options that have just been discussed, some not being available and others, what can they do? So these are the things that I will discuss. Weight loss is something that we see our patients, most of them are obese and yet it's not something that we actively practice beyond just telling them to lose weight. But this is kind of your weight loss math. So a 10% weight gain can increase the severity of sleep apnea by 30% and likewise weight loss can reduce the severity by 26%. Results of the sleep ahead study, this was the action for a prospective cohort study in diabetics looking at intensive lifestyle intervention versus just diabetic support and education. So looking at sleep apnea was one of the outcomes that were studied and the 10-year results were published two years ago. And so the ILI group had monthly visits with weigh-in and activity record review and lifestyle modification sessions whereas the other group had usual care which was a visit every three months. So the results of the study showed that there was a significant reduction in the apnea-hypopnea index at 10-year follow-up between the two groups from their baseline. However, the difference between the ILI and the usual care was not statistically significant at the 10-year follow-up. But you can see that there was greater number of remission of sleep apnea in the active intervention group compared to usual care. But what is interesting is that for every kilogram of weight that was lost in the ILI group, the AHI decreased more compared to the weight, the decrease in AHI in the usual care group. So the study also showed that irrespective of weight loss, there was a reduction in the AHI that depended on which group the patients were assigned to. So there are factors beyond weight loss related to the lifestyle that changes that were implemented that are probably responsible for the reduction in the AHI. So this slide actually shows the change over the 10 years in terms of AHI, and you can see that even those who were severe at baseline about 10% actually had no OSA at the follow-up visits. A similar study of active intervention. This is a study from Spain looking at mainly men, middle-aged with a BMI greater than 25. This was an eight-week program looking at weekly sessions addressing all of those items there. And again, such a session would be great as a research setting, but it's kind of difficult to follow and do in your own clinical practices. And again, the study investigation showed that in the intervention group, there was a significant change in the apnea-hypopnea index. Sorry, I'm not sure how that red box came, but however, and along with weight loss, that there was a significant change that occurred. And so this is the changes in the AHI between the control group and the intervention group, all of which was significant at both time intervals. Weight loss through active intervention or weight loss through medication. So this is one of the first GLP-1 agonists that was introduced before the ozempic and the dual receptor blockers. And so in this study, they looked at, again, change in weight and change in AHI. And as you can see, the first, the top graph shows you the change in AHI being row in parallel with weight loss, but then there is a plateau effect and the change in AHI kind of plateaus, though the weight loss continues. So this shows that it's not just weight that is responsible for the severity of sleep apnea and that there are other factors such as the endotypes that Dr. Anton referred to that also contributes to sleep apnea. And again, the study showed that at the end, there were resolution of OSA and change in the severity of OSA with weight loss. What are some data related to bariatric surgery? This is a study from France, and they showed significant reduction in weight following bariatric surgery and showed that about 22% of these patients at follow-up had no sleep apnea. And among the factors that they looked at that predicted success in terms of reduction in AHI was a younger age as well as a less severe oxygen desaturation index. So severity that is less in terms of oxygen desaturation where predictors for improvement in AHI. The ATS came with guidelines on the role of weight management in treatment of sleep apnea, and these were published in 2018 with comprehensive lifestyle intervention compared to no intervention receiving a strong strength of recommendation. So this is something that we should be actively doing in our, among our clinic patients. And the recommendation is to, as noted here, to reduce caloric intake, increase aerobic activity to more than 150 minutes per week. But what patients often need is more feedback, and so I think some of the programs are shown in some of the previous under research settings. If they could be replicated in our clinical practice would benefit our patients. Coming to positional therapy, so the prevalence of positional sleep apnea ranges from 53 to about 77% depending on the definition used. The most commonly used definition is a supine AHI that's twice that of the non-supine AHI. And there are many devices that are now available starting with, you know, we used to prescribe or tell patients about the tennis ball method, and that is actually available on Amazon if you search for it, the tennis ball t-shirt. But there are several other devices that are currently available in the market. This study is from 2010 comparing the change in AHI with the use of a device that's called Zoma. And it showed both a statistically significant decrease in the AHI with both, but the decrease was better with CPAP compared to positional therapy. However, what the study also showed was that the use of a positional barrier like that was able to keep patients off the supine sleeping posture. This is another positional therapy device looking at a vibrotactile neck-based device, so the device vibrates when the patient sleeps on their back. I don't think they gave us data on how much sleep disruption that causes, but in the end, it did show a reduction in the apnea-hypopnea index. Comparing that device to CPAP, this is a study from Taiwan, and it showed that patients when it was a crossover randomized trial and patients actually preferred their CPAP to position therapy. Again, looking at sleep position training versus oral appliance, there was, you know, a decrease in the AHI at three months and 12 months, but this study was plagued by a high dropout rate in both groups. And patients also reported a persistent snoring and tiredness both in the position therapy and the oral appliance groups. Elevation of the head of the bed. So this was an interesting study that was published last year, and it showed the use of dyes and evaluating how the airway collapses in supine and lateral position. They showed that there was a significant reduction in the AHI, though the mean AHI still was in the moderate range for many of these patients. Neuromuscular electrical stimulation. Some of you may be familiar with this device, which goes by the name of Excite OSA. So this was a study published in 2021, and that had 70 patients complaining of snoring and had mild sleep apnea. So an AHI of less than 15 using a home sleep study. So the protocol is 20-minute stimulation daily for six weeks, and they had 38 of these 70 patients had mild sleep apnea, and they showed a statistically significant reduction in the AHI in this group. They also reported improvement in snoring, especially, and this is both objective and subjective from the bed partners. There are some adverse effects reported in terms of salivation, a metallic sensation, and I have this at the VA where I work, and so the metallic taste is something that patients often complain about. Use of oxygen, I think Dr. Anton described one of these studies looking at high and low loop gain. This is from Andrew Wellman's group, and they showed that the reduction in the AHI was statistically significant in those with high loop gain and not so in the low loop gain. So it's important to determine the endotype before prescribing oxygen. This is the combination therapy that was, again, discussed by Dr. Anton, and so I won't go into this in detail, but again, the therapy did show that the way it helped ameliorate the AHI was through these endotypes by increasing the arousal threshold and decreasing the loop gain. However, the problem with that is that not all labs are capable of doing complex physiology assessments to determine endotype as was used by the Harvard group. Another way of looking at the use of supplemental oxygen was the study from Oxford. So the investigators wanted to answer the question whether using oxygen could attenuate the increase in blood pressure that was seen in the morning after CPAP withdrawal. So this was, again, a randomized crossover trial with a period of washout in between, and they were able to show that oxygen was able to attenuate the increases in blood pressure after CPAP discontinuation, though it was difficult to explain what the mechanism behind that attenuation was as there was no change in the morning heart rate or overall change in the secretion of sympathomimetics between the two groups. Lastly, on high-flow nasal cannula, this was first published several years ago by Brian McKinley, the University of Utah, and what he showed was that at high-flow rates, there was decrease in snoring as well as improvement in airway patency. They showed a statistically significant decrease in the AHI, specifically, more so with the hypopneas as compared to the apneas. It has been used in a pediatric study and it was shown to be successful. For any pediatric sleep specialists here would know, it's difficult to have the patients use CPAP and this might seem like a feasible alternative. And so, sorry for the whirlwind talk, but I think we went over. Anybody has any questions, I would suggest they can come up front and we can try and answer them. Thank you again for being here. Thank you.

obstructive sleep apnea

hypoglossal nerve stimulation

pharmacotherapy options

oral appliances

non-CPAP alternatives

clinical trials

symptom improvement

reducing OSA severity

weight loss

combination therapy