What is Sleep Apnea?

Sleep apnea is an increasingly common but underdiagnosed disorder characterized by repeated interruptions in normal breathing during sleep. It is associated with increased risk for several serious health problems, including:

• hypertension
• cardiovascular disease
• type 2 diabetes
• cancer
• gout
• cognitive dysfunction
• autoimmune disorders
• pregnancy complications

Fortunately, effective treatment options are available for sleep apnea, and dietary and lifestyle changes can reduce the severity of disease. Emerging research also suggests that integrative interventions, such as antioxidants, can improve sleep quality and respiratory function in patients with sleep apnea.

What are Risk Factors for Developing Sleep Apnea?

• Overweight and obesity
• Male sex
• Asian or Hispanic ethnicity
• Allergies
• Older age
• Anatomical abnormalities in the airway

What Signs and Symptoms are Associated with Sleep Apnea?

• Snoring/gasping/choking sounds while sleeping
• Pauses in breathing while sleeping
• Intermittent waking and insomnia
• Nocturia (frequent waking to use the restroom)
• Daytime sleepiness or fatigue
• Dry mouth, sore threat, or headache upon waking
• Difficulty concentrating or remembering things
• Irritability or depression
• Sexual dysfunction
• Refer to the STOP-BANG questionnaire in the Screening section of this protocol

What are Conventional Medical Treatments for Sleep Apnea?

• CPAP (continuous positive airway pressure) and positive airway pressure variations
• Oral appliances to help keep the upper airway open
• Surgery for when the obstruction is due to an anatomical problem, such as enlarged tonsils or adenoids
• Pharmacotherapy
• Hypoglossal nerve stimulation

What are Novel and Emerging Therapies for Sleep Apnea?

• Acetazolamide
• Renal denervation
• Nasal expiratory positive airway pressure therapy
• Oral negative pressure therapy
• Hormone replacement therapy (for women)

What Dietary and Lifestyle Changes Can Be Beneficial for Sleep Apnea?

• Weight loss
• Diet (Mediterranean diet, low-sodium diet)
• Exercise
• Alcohol avoidance
• Side sleeping or at least turning the head to the side while sleeping on your back
• Acupuncture
• Smoking cessation

What Integrative Interventions May Be Beneficial for Sleep Apnea?

• N-acetylcysteine (NAC): Supplementation with the antioxidant NAC has been shown to ameliorate signs and symptoms of sleep apnea, including apnea-related arousals, daytime sleepiness, and snoring, among others.
• Coenzyme Q10 (CoQ10): CoQ10, an antioxidant with beneficial effects on the cardiovascular system and metabolism, may benefit sleep apnea patients at increased risk for cardiovascular disease, hypertension, and impaired glucose tolerance.
• Vitamin D: Studies have found low vitamin D levels are associated with increased risk for insulin resistance, diabetes, and metabolic syndrome among patients with obstructive sleep apnea.
• Omega-3 fatty acids: Sufficient levels of omega-3 fatty acids are associated with a host of cardiovascular and anti-inflammatory benefits, which may be important for individuals with sleep apnea.
• B vitamins: Supplementation with B vitamins has been shown to reduce levels of serum homocysteine, an amino acid associated with increased risk of cardiovascular and neurogenerative diseases and shown to be elevated in patients with obstructive sleep apnea.
• Probiotics: Studies involving animal models of sleep apnea and intermittent hypoxia have found that probiotics can improve some side effects of systemic inflammation in the heart and brain, as well as hypertension.

Sleep apnea is characterized by repeated disruptions in normal breathing during sleep.¹ These frequent respiratory interruptions result in periods of low blood oxygen levels, nervous system dysfunction, and sleep fragmentation. People with sleep apnea often stop breathing periodically then suddenly gasp for air during sleep; loud snoring is also common in people with sleep apnea and is often reported by bed partners of those affected.

There are two main types of sleep apnea: obstructive and central. Obstructive sleep apnea is much more common and is associated with increased risk of several major health problems and greater mortality risk.²

Epidemiological studies have historically estimated the prevalence of obstructive sleep apnea to be around 3% to 7% in men and 2% to 5% in women, but it is believed to be vastly underdiagnosed.³ The National Healthy Sleep Awareness Project estimates that at least 25 million adults in the United States are living with obstructive sleep apnea.⁴

Obstructive sleep apnea can lead to several health concerns as a result of chronic sleep deprivation: daytime sleepiness, cognitive difficulties, depression, and increased risk of accidents and injuries.^1,5 In addition, a significant and growing list of serious chronic diseases have been associated with sleep apnea, including cardiovascular and neurological diseases, obesity, polycystic ovary syndrome, and insulin resistance and type 2 diabetes.^1,5,6

The first-line treatment approach for obstructive sleep apnea is a device that provides continuous positive airway pressure, known as CPAP.^5-7 The device is worn during sleep and introduces mildly pressurized air into the airways to keep them open. CPAP therapy can be cumbersome and uncomfortable, so recommendations for CPAP are generally reserved for patients who experience excessive daytime sleepiness, those with comorbid hypertension, and those for whom their sleep disruption affects their quality of life.⁷ Research suggests CPAP use might improve blood pressure and cognitive function for those with sleep apnea.^8-11

Some patients are unable to tolerate CPAP, in which case other therapies may be considered. Dental devices and surgical procedures to open the airway may be beneficial in some people with sleep apnea. Other methods sometimes recommended include variations of positive airway pressure and negative pressure devices.⁷

Dietary and lifestyle interventions can have a significant impact on the severity and consequences of sleep apnea as well. Weight loss is the most common and well-supported adjunct to CPAP, and can provide additional benefits by reducing inflammation.¹² Exercise, a lateral sleep position, avoidance of alcohol and sedatives, and a generally healthy diet may also help manage symptoms and severity of sleep apnea. Integrative interventions may both reduce the severity of sleep apnea and help minimize the consequences of some of the serious conditions associated with sleep apnea.

In this protocol, you will learn about the causes of sleep apnea and factors that increase sleep apnea risk. Conventional treatment approaches will be reviewed, as will several novel and emerging treatment strategies. A number of lifestyle considerations and natural, integrative interventions that may lessen the impact of sleep apnea will be discussed as well.

Anatomy of the Airway¹³

Obstructive sleep apnea is innately an anatomical disorder driven by abnormalities in the upper airway that increase collapsibility and reduce airway function. Enlargement of soft tissues within and around the airway, including the tongue, soft palate, tonsils, and fat deposits, can cause narrowing of the airway.¹⁴ The epiglottis, which prevents food from entering the airway, normally remains open during breathing, but may collapse during sleep and is also a frequent source of obstruction and snoring.¹⁵ Many groups have attempted to correlate the anatomical sources of obstruction with obstructive sleep apnea severity with limited success.¹⁶ However, the nature of the obstruction may have significant implications for treatment strategies, and a comprehensive assessment of the underlying pathophysiology of obstructive sleep apnea may facilitate an individualized approach to treatment.¹⁷

Types of Sleep Apnea

There are two main types of sleep apnea: obstructive and central, with obstructive being much more common.¹⁸ In obstructive sleep apnea, the upper airway intermittently becomes fully or partially blocked during sleep. In central sleep apnea, the respiratory control centers in the brain do not provide sufficient stimulation to maintain regular breathing during sleep. In some cases, referred to as complex sleep apnea, elements of both obstructive and central sleep apnea occur simultaneously.^19,20

Obstructive sleep apnea. In obstructive sleep apnea, anatomical abnormalities and sleep-associated neuromuscular dysfunction coalesce to result in repeated airway blockages.²¹ The temporary pause in airflow results in frequent arousal as the brain reacts to reinitiate breathing. Obstructive sleep apnea is a state-dependent condition that occurs only during periods of sleep, primarily due to the positioning; when in the supine position (on the back), gravity promotes collapsibility of the airway and blocks airflow.²² Obstructive sleep apnea is very common among adults. A community-based study of over 5,800 adults 40 years or older found that over 46% of subjects had some degree of obstructive sleep apnea, suggesting that the condition is vastly underdiagnosed.¹⁸

Central sleep apnea. The natural breathing reflex is regulated by the autonomic nervous system and responds automatically to changes in blood carbon dioxide levels.²³ In central sleep apnea, however, the brain does not adequately respond to the excitatory signals that trigger respiration, including carbon dioxide levels, and regulation of breathing is disrupted.²⁴ Disordered breathing is thought to occur only during sleep because sleep diminishes the brain’s response to excitatory signals.²⁵ Central sleep apnea occurs primarily in infants (both preterm and term) in the first weeks of life, adults abruptly transitioning to high altitudes, and patients with heart failure, but it may also be idiopathic in nature (no clear cause).²⁴ Compared with obstructive sleep apnea, central sleep apnea is much less common, occurring in less than 1% of adults.¹⁸

Mixed or complex sleep apnea. Mixed sleep apnea, also referred to as complex sleep apnea, involves both obstructive and central components. Approximately 5.5% of people with sleep-disordered breathing—the broad category that includes apneas as well as less severe hypopneas (shallow and/or slow breathing)—have complex sleep apnea.^18,24 In many cases, central apnea is revealed during treatment of the obstructive aspect of sleep apnea.²⁰

Sleep apnea is associated with several serious health conditions, and at least some of these associations appear to be causal to some degree. This means sleep apnea may directly contribute to the development of the associated health condition, although this may not always be clearly delineated in each individual patient.

Conditions Associated with Sleep Apnea

High blood pressure (hypertension). Historically, there has been conflicting evidence regarding an association between sleep apnea and blood pressure. For example, in a cross-sectional analysis of over 6,000 participants in the Sleep Heart Health Study, participants with severe sleep apnea were 37% more likely to experience hypertension than those without evidence of sleep apnea.²⁶ However, in a 5-year follow-up of a subset of these patients without hypertension at the start of the study, there was no association between the development of hypertension and sleep apnea after accounting for body mass index (BMI), suggesting this association may instead be caused by obesity.²⁷

A direct association between obstructive sleep apnea and hypertension is most strongly supported by studies that demonstrate that treatment of obstructive sleep apnea also lowers blood pressure. Meta-analyses of clinical trials have found that, on average, treatment of obstructive sleep apnea using CPAP results in a 2.5‒7.2 mm Hg reduction in systolic blood pressure and a 2.0‒4.99 mm Hg reduction in diastolic blood pressure.^8-10 These effects are small, but may have significant implications for heart health, as 1‒2 mm Hg reductions in blood pressure have previously been shown to decrease the risk for cardiovascular diseases, including stroke and heart failure.²⁸ The association between sleep apnea and blood pressure is likely bidirectional and driven by a number of factors, including overactivation of the sympathetic nervous system, oxidative stress resulting from intermittent hypoxia (periods of low oxygen levels), and disruption of hormone levels.²⁹

Cardiovascular disease. Sleep apnea, and particularly obstructive sleep apnea, is highly prevalent in patients with cardiovascular disease (CVD), including heart failure, stroke, atrial fibrillation, and end-stage renal disease.³⁰ Intermittent hypoxia is thought to cause endothelial damage, inflammation, and metabolic dysfunction, which contribute to an increased risk for CVD.³¹ There has been some conflicting evidence, however, on whether treatment of sleep apnea improves cardiovascular outcomes. In a clinical trial of 2,717 adults with moderate-to-severe obstructive sleep apnea and CVD, management with CPAP did not reduce the frequency of CVD events.³² Similar results were seen in a smaller clinical trial of 244 patients with obstructive sleep apnea and coronary artery disease; however, when results were adjusted for adherence to treatment (ie, comparing those who used CPAP for <4 hours per night with those who used it for ≥4 hours per night), CPAP reduced CVD risk by 71%.³³ A meta-analysis of eight studies on obstructive sleep apnea found CPAP reduced the risk for atrial fibrillation by 42%, providing further support that CPAP, when used properly, reduces CVD risk in patients with obstructive sleep apnea.³⁴ The cardiovascular benefits of CPAP and other sleep apnea treatments in patients with central sleep apnea and heart failure, however, are less clear.³⁵

Obesity and type 2 diabetes. Obesity is a well-established risk factor for obstructive sleep apnea, and the relationship between obesity and sleep apnea is likely bidirectional. Disordered sleep has been found to increase the risk for weight gain through physiological and hormonal changes, as well as behavioral changes.³⁶ Obstructive sleep apnea is also closely associated with type 2 diabetes. Approximately 54% to 75% of patients with type 2 diabetes have obstructive sleep apnea, and type 2 diabetes patients are 48% more likely to have obstructive sleep apnea than individuals without diabetes.^37-39 Additionally, type 2 diabetes patients with obstructive sleep apnea are over three times more likely to develop diabetes-related complications than those without.³⁸ This relationship likely reflects the complicated interplay among metabolic changes, weight gain, and hypertension.^38,39 Intermittent hypoxia may also cause insulin resistance.⁴⁰ There have been conflicting results regarding the ability of CPAP treatment to improve glycemic control in patients with type 2 diabetes.^41-44 However, preliminary results suggest treatment of type 2 diabetes with dapagliflozin (Farxiga) (a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, a class of medicine that lowers high blood glucose levels in people with type 2 diabetes) can improve sleep and decrease oxygen desaturation events in patients with type 2 diabetes and sleep-disordered breathing, suggesting that treatment of comorbid type 2 diabetes may improve sleep apnea symptoms as well.^45,46

Obesity hypoventilation syndrome is a condition characterized by BMI ≥30 kg/m², elevated daytime carbon dioxide levels, and sleep-disordered breathing.⁴⁷ While this disorder is often closely associated with the presence of sleep apnea, and particularly obstructive sleep apnea, it is a separate clinical entity.

Cognitive deficits and mood disorders. Studies suggest obstructive sleep apnea may be associated with the development of cognitive deficits in areas including attention, executive function, visuospatial reasoning, and both short- and long-term memory.⁴⁸ This may be driven by a number of factors, including chronic sleep deprivation and hypertension.⁴⁹ An estimated 27% of individuals with mild cognitive impairment (MCI) have obstructive sleep apnea, which may accelerate the progression from MCI to Alzheimer disease in some affected individuals.⁵⁰ Results from a small clinical trial involving 54 individuals with MCI and obstructive sleep apnea suggest proper adherence to CPAP treatment is associated with small but significant improvements in memory, attention, and everyday function.¹¹

Obstructive sleep apnea has also been linked to several affective disorders, including anxiety and depression.^51-53

Evolving Concepts of Disease Association with Sleep Apnea

Cancer. The incidences of certain cancers, including kidney, melanoma, and breast cancers, are higher in patients with obstructive sleep apnea than in the general population.^66,67 In a study that followed 390 adults over 20 years, moderate-to-severe obstructive sleep apnea was associated with a 2.5-fold increased risk for cancer diagnosis and a 3.4-fold increased risk for cancer death.⁶⁸ In another study, which followed over 1,500 individuals for up to 22 years, those with moderate sleep-disordered breathing had a 2-fold higher risk of dying from cancer, and those with severe sleep-disordered breathing had a 4.8-fold higher risk, compared with healthy subjects.⁶⁹ Intermittent hypoxia has been proposed as a driver for cancer development in obstructive sleep apnea patients, but the exact cause of this association remains unclear.⁷⁰

Gout and hyperuricemia. Gout is a painful arthritic condition caused by an excess of uric acid in the blood (hyperuricemia), which accumulates as crystals in the joints and causes inflammation.⁷¹ People with gout appear to be at increased risk of sleep apnea; an analysis of US Medicare beneficiaries found that among adults 65 years or older, individuals with gout were over twice as likely to develop new obstructive sleep apnea.⁷² This association is likely bidirectional, as several studies have found that patients with obstructive sleep apnea experience incident cases of gout up to 64% more frequently than adults without sleep apnea.^73,74 Furthermore, individuals with high uric acid levels have been shown to be more likely to snore more than five nights per week and to experience daytime sleepiness.⁷⁵ Serum uric acid levels have been found to be elevated in individuals with obstructive sleep apnea, and increasing uric acid levels are strongly associated with the presence of obstructive sleep apnea and sleep apnea risk factors.^76,77 In addition to gout, hyperuricemia in obstructive sleep apnea is also associated with an increased risk for CVD.⁷⁸ Further research is needed on the implications of this relationship, though, as studies suggest CPAP therapy does not reduce uric acid levels.⁷⁹

Pregnancy complications. Sleep-disordered breathing, including obstructive sleep apnea, is common in pregnancy, often characterized by snoring, fatigue, and daytime sleepiness as pregnancy progresses.⁸⁰ A growing body of evidence suggests that in pregnant women, sleep-disordered breathing may have effects on the health of both the mother and fetus, but this remains controversial.^80-82 However, in a study of 3,705 pregnant women, sleep-disordered breathing was associated with increased risk of gestational hypertension, gestational diabetes, and preeclampsia.⁸³

Low testosterone levels and erectile dysfunction. Several studies have confirmed that serum testosterone levels are often lower in men with obstructive sleep apnea.⁸⁴ One study found that men with obstructive sleep apnea had 17% lower serum testosterone levels than controls.⁸⁵ Another study, which compared 36 men with obstructive sleep apnea with healthy controls, found that lower serum testosterone levels were associated with greater sleep apnea severity and increased BMI.⁸⁶ Decreased testosterone levels may also explain the observation that men with obstructive sleep apnea have a 55% increased risk for erectile dysfunction than men without obstructive sleep apnea.⁸⁷ This effect is likely driven by other factors as well, such as endothelial dysfunction, as CPAP has been shown to improve some measures of erectile dysfunction but is not associated with elevations in testosterone levels.^88,89

Other conditions. Obstructive sleep apnea has also been associated with glaucoma,⁹⁰ Parkinson’s disease,⁹¹ polycystic ovary syndrome (PCOS),⁹² hypothyroidism,⁹³ kidney stones,⁹⁴ and chronic kidney disease.⁹⁵

Obesity

Obesity is the number one risk factor for obstructive sleep apnea. Obesity is so strongly associated with obstructive sleep apnea that, compared with CPAP management, weight loss alone improved measures of inflammation and insulin resistance in patients with obstructive sleep apnea.¹² Obesity is thought to contribute to increased risk for obstructive sleep apnea by compromising the airway and decreasing lung volume. Excess fat deposits in the upper airway, including the pharynx, tongue, soft palate, and uvula, can lead to narrowing of the airway and may promote collapsibility.¹⁴ Studies of individuals with a family history of obstructive sleep apnea suggest that, while genetics may play a role in the heritability of the disease, familial aggregation of obstructive sleep apnea is primarily driven by patterns of obesity within families.⁹⁹

Sex and Hormone Levels

Male sex is a significant risk factor for obstructive sleep apnea, with males being twice as likely to develop obstructive sleep apnea as females.¹ The increased prevalence of disease in males, coupled with the observations that postmenopausal women and women with PCOS are at increased risk for obstructive sleep apnea relative to their healthy premenopausal counterparts, has led some to suggest that estrogen may play a protective role against the development of obstructive sleep apnea.^100,101 However, experimental evidence to support this theory is lacking, and more information is needed on estrogen’s role in the development of sleep apnea.¹⁰²

Ethnicity

Results of a multiethnic study involving 2,230 adults aged 54 years or older found that individuals of Chinese and Hispanic ethnicities were at increased risk for sleep-disordered breathing compared with White and Black individuals. Additionally, Chinese individuals were 37% more likely to develop severe sleep-disordered breathing. Some of this disparity may be due to differences in access to care, though, as individuals of Chinese ethnicity were 49% less likely to receive a diagnosis of sleep apnea from their doctor compared with their White counterparts.¹⁰³

Age

The risk for sleep apnea increases with age. Individuals over 50 years of age are considered to be at increased risk for obstructive sleep apnea.¹ This may be due to factors such as diminished efficiency of muscles and soft tissues in the upper airway or reduced sleep quality.¹⁰⁴

Anatomy

Individuals with anatomical abnormalities of the bony and soft tissues in the head or neck are at high risk for obstructive sleep apnea. Additionally, a neck circumference greater than 40 cm is considered a risk factor for obstructive sleep apnea.¹

Nasal Allergies (Allergic Rhinitis)

In a study in over 1,900 individuals with asthma, allergic rhinitis was associated with 1.44-fold higher odds of obstructive sleep apnea compared with those with asthma alone. When allergic rhinitis duration and severity were taken into account, the odds rose to almost 2-fold.¹⁰⁵ Allergic (and non-allergic) rhinitis is thought to increase the risk for obstructive sleep apnea by a combination of increased airway resistance due to inflammation and a reduction in pharyngeal diameter resulting from increased mouth breathing.¹⁰⁶

Dietary Habits

Among individuals with sleep apnea, certain dietary habits have been linked to poorer quality of sleep. An analysis of a multiethnic cohort of over 1,800 individuals found obstructive sleep apnea was associated with lower intake of whole grains, increased consumption of processed red meats, and lower overall quality of diet. This association was at least partially driven by a decrease in slow-wave sleep with red meat consumption.¹⁰⁷ Additionally, studies have linked later evening meals with the presence and severity of obstructive sleep apnea.^108,109

Sleep apnea often goes undiagnosed largely because the direct symptoms are witnessed only by bedmates, and the indirect symptoms, such as those related to sleep deprivation, can be vague or attributable to many possible causes.¹ The most common sleep apnea symptoms include^1,6,110:

• Snoring. Loud or irregular snoring often indicates the presence of sleep apnea, and it is more pronounced in obstructive sleep apnea. Apneas may also interrupt snoring and cause the patient to snort.
• Pauses in breathing. Sleep apnea often causes pauses in breathing during sleep that are noticed by another person. Someone with sleep apnea may pause breathing for a period during sleep then gasp for air.
• Frequent nighttime waking and insomnia. It may be difficult to remain asleep. Patients may also awaken suddenly with shortness of breath. Poor sleep and insomnia are often the primary symptoms of central sleep apnea. Nocturia, or frequently waking to go to the bathroom, is also common.
• Dry mouth, sore throat, and headache upon waking.
• Fatigue and excessive daytime drowsiness. Patients with sleep apnea are susceptible to falling asleep at work and while driving.
• “Brain fog.” This can include difficulty concentrating, reasoning, and paying attention.
• Feeling moody, depressed, or irritable.
• Lack of libido or sexual dysfunction.

Screening

Despite the high prevalence of sleep apnea and its association with serious health conditions, obstructive sleep apnea is underdiagnosed and many patients remain untreated.¹¹¹ Women are disproportionately underdiagnosed; despite a 2:1 ratio in the prevalence of sleep apnea in men versus women, women are 70% less likely to receive treatment than men, even with evidence of sleep-disordered breathing.¹¹² Therefore, simple clinical screening for obstructive sleep apnea, particularly in high-risk groups, is important.

Several screening tools have been developed and validated to identify patients at high risk for obstructive sleep apnea, as well as the likelihood of clinical complications of obstructive sleep apnea in pre-surgical and hospital settings. One of the most widely used screening tools is STOP-BANG, which stands for “Snoring, Tiredness during daytime, Observed apnea, high blood Pressure, BMI >35 kg/m², Age >50 years, Neck circumference >40 cm, and male Gender.”¹ The STOP-BANG test is graded on a yes/no basis, with each “yes” being equal to 1 point. A score of 3 or greater indicates high risk for obstructive sleep apnea, and a score of 5 or more indicates high risk for moderate-to-severe obstructive sleep apnea.^1,113

Table 1: The STOP-BANG Obstructive Sleep Apnea Questionnaire*

Although screening tools are often highly sensitive for prediction of obstructive sleep apnea, they are not a replacement for formal testing. Additionally, before diagnosing sleep apnea, physicians should rule out a number of other conditions that can cause similar symptoms, including restless leg syndrome, gastroesophageal reflux disease, narcolepsy, swallowing disorders, mood disorders, or obesity hypoventilation.

Testing

The definitive test for sleep apnea is an overnight polysomnography, often called a sleep study. This test has traditionally been done in a clinical laboratory setting and monitors the occurrence of apneas (paused breathing) and hypopneas (shallow and/or slow breathing) by measuring respiratory effort, breathing patterns, and blood oxygen saturation.⁶ Polysomnography also includes neurological testing to monitor limb movements, body position, and the sleep-wake state.¹¹⁶

As an alternative to laboratory-based polysomnography, home sleep apnea testing is now available for patients suspected of uncomplicated obstructive sleep apnea. At-home testing utilizes portable devices to measure physiologic variables, including respiratory effort, airflow, heart rate, and oxygen saturation. These devices are classified as Type III or Type IV based on the number of sensors used and the variables measured.¹¹⁷ Several clinical trials have compared the efficacy of at-home sleep apnea testing devices with in-laboratory polysomnography and have found that these tests result in similar patient diagnoses, time-to-treatment, adherence, and outcomes.^118-121 In addition to making testing easier and less cumbersome, at-home testing is associated with significantly lower patient costs compared with in-laboratory polysomnography.¹²¹

Classification

The criteria for diagnosis of sleep apnea are based on the frequency of apneas and hypopneas per hour that last ≥10 seconds, known as the apnea-hypopnea index (AHI).⁶ An AHI of 5 or greater is considered clinically definitive for a diagnosis of sleep apnea.¹²² Classification of mild, moderate, or severe sleep apnea is based on a combination of clinical presentation and sleep study results.

Table 2: American Academy of Sleep Medicine Obstructive Sleep Apnea Classifications¹²²

Obstructive sleep apnea may also be classified based on a combination of phenotype and endotype.^17,123 The phenotype of the disease represents the observable characteristics of the disease or patient (such as obstructive sleep apnea in the elderly, men, or Black patients), whereas the endotype refers to the underlying biological mechanisms which drive disease (such as fat distribution, hyporesponsive muscles of the airway, or abnormal craniofacial structures). These classifications are not based on the severity of disease, although certain phenotypes may correlate with increased risk for more severe disease.

CPAP: Continuous Positive Airway Pressure

CPAP is first-line treatment for obstructive sleep apnea.⁷ Numerous studies show that this method of applying constant mild air pressure to the airway during sleep reduces apneic and hypopneic episodes and helps relieve the signs and symptoms of sleep loss, such as fatigue, drowsiness, and cognitive and mood changes.¹²⁴ Studies suggest these benefits are associated with significant improvements in quality of life, particularly for those with moderate-to-severe obstructive sleep apnea.^124,125 The more hours per night a CPAP device is used, the greater the benefit.¹²⁶

One barrier to consistent CPAP use is comfort, which may affect adherence. It is estimated that only about 66% of people who are prescribed CPAP are properly adherent, which has remained largely unchanged over the past two decades.¹²⁷ In addition to the cumbersome nature of the masks, CPAP treatment is associated with dry mouth, nasal discharge, congestion, bloody nose, headache, sore throat, hoarse voice, and reduced sense of smell.⁷ People who tolerate the CPAP mask and straps but find the constant air pressure uncomfortable may prefer one of two other options for positive airway pressure. The first is called bilevel positive airway pressure, or BiPAP. With BiPAP therapy, a lower level of air pressure is used during expiration, and a higher level during inspiration. This may improve comfort, especially for people who use higher pressure settings with CPAP and have trouble exhaling against the pressure, and is considered an effective strategy for treatment of obstructive sleep apnea. The second is called auto-adjusting positive airway pressure, or APAP. With APAP therapy, the device automatically adjusts its pressure output to the pressures it senses during the breathing cycle and reduces the pressure applied when no events are detected over a period of time. APAP may be more comfortable for people whose apnea occurs mainly in certain sleep positions or in response to variable triggers, such as alcohol consumption, allergies, and upper respiratory infections.¹²⁴ Clinical guidelines recommend the use of CPAP or APAP over BiPAP when possible, as lower pressure during expiration may not prevent the occurrence of airway collapse. BiPAP therapy is also more expensive than CPAP or APAP which may represent a barrier for many patients.⁷

The cardiovascular benefits of CPAP have been somewhat controversial. Meta-analyses of clinical trials have collectively found that CPAP therapy is associated with small but significant reductions in both systolic and diastolic blood pressure, particularly in those with moderate-to-severe obstructive sleep apnea.^8-10,124 However, the effects on the frequency of cardiovascular events such as stroke or heart attack remain less clear. Some retrospective studies suggest CPAP treatment may reduce the risk for cardiovascular events, but other observational studies and, most importantly, randomized clinical trials have not found a significant reduction in the frequency of cardiovascular events and CVD in obstructive sleep apnea with CPAP use.^32,128-131 However, cardiovascular benefits may be greater in patients with more severe obstructive sleep apnea, who are often excluded from clinical trials.¹²⁴ Additionally, in a small study of 244 patients with coronary artery disease and obstructive sleep apnea, a significant reduction in cardiovascular events was found when adjusting for adherence, suggesting increased use of CPAP may confer better cardiovascular benefits.³³

Clinical trials have demonstrated that CPAP improves insulin sensitivity in patients with severe obstructive sleep apnea,^132,133 but the effects of CPAP on blood glucose control are less convincing.¹²⁴ A 6-month clinical trial examining the use of CPAP in individuals with obstructive sleep apnea and type 2 diabetes found that patients treated with CPAP experienced greater reductions in glycated hemoglobin levels compared with control patients.⁴¹ However, many other trials and studies suggest CPAP use has no effect on glycemic control, and the American Academy of Sleep Medicine has concluded that there is insufficient evidence to support the use of CPAP for glycemic control in adults with obstructive sleep apnea.^{42-44,124,133}

Oral Appliances

Oral appliances, the most common of which is the mandibular advancement device (MAD), are used during sleep to physically keep the upper airway open by either holding the lower jaw forward or moving the tongue forward.¹³⁴ These devices are usually custom-fitted by a dentist and are more likely to help people who have mild-to-moderate sleep apnea and are female, younger, and carry less excess weight.^134,135 They are particularly effective for patients who complain of snoring, regardless of apnea status.¹³⁵ Although not considered a first-line treatment for obstructive sleep apnea, oral appliances are sometimes used in those who are unable to tolerate CPAP.¹²⁴

Upper Airway Surgery

Surgery can be an important part of the treatment approach for sleep apnea when the obstruction is due to an obvious anatomical problem, such as enlarged tonsils or adenoids, or a deviated septum. The goal of surgical intervention is to open the airway and decrease collapsibility. There is considerable variability in the success rate of sleep apnea surgery, with estimates of benefit ranging from as low as 35% to as high as 98.8%.^136-138 There are no major studies that successfully identify which patients will most likely benefit from surgery, but it is generally considered an appropriate option for patients with a severe, correctable anatomic abnormality.

Pharmacotherapy

Given the heterogeneity of obstructive sleep apnea, effective pharmacologic treatment has been challenging, despite significant clinical trial efforts.¹³⁹ Central sleep apnea, however, may respond to medications that stimulate breathing or promote sedation. Modafinil (Provigil) has been approved for daytime sleepiness in patients with sleep apnea. Other medications that are sometimes prescribed, but are not FDA-approved for sleep apnea, include acetazolamide (Diamox) and theophylline, to stimulate breathing, as well as the sedatives triazolam (Halcion) and zolpidem (Ambien).¹⁴⁰

For people with obstructive sleep apnea who continue to suffer from excessive daytime sleepiness despite CPAP therapy, modafinil (or armodafinil) can reduce daytime sleepiness and improve wakefulness. Common side effects of modafinil include anxiety, headache, nausea, and nervousness, which lead to high rates of discontinuation.¹⁴¹ In 2019, the FDA approved solriamfetol (Sunosi) for the treatment of excessive daytime sleepiness in adults with obstructive sleep apnea, which represents an effective option with a more tolerable safety profile.¹⁴²

Hypoglossal Nerve Stimulation

The hypoglossal nerve is one of 12 cranial nerves and is involved in control of the tongue.¹⁴³ When stimulated, the hypoglossal nerve causes the base of the tongue to protrude forward, which results in opening of the airway.¹⁴⁴ The hypoglossal nerve is stimulated by a device, which is surgically implanted under the skin on the chest. A pressure sensor in the device detects breathing patterns and delivers electrical stimulation to the hypoglossal nerve intermittently to trigger dilation of the airway during inspiration.¹⁴³ In a meta-analysis of outcomes for 200 patients with obstructive sleep apnea, hypoglossal nerve stimulation reduced AHI by up to 57% and was associated with reduced daytime sleepiness.¹⁴⁵ An analysis of 5-year outcomes for patients who received hypoglossal nerve stimulation found that 63% experienced a greater than 50% reduction in AHI, with sustained improvements in daytime sleepiness and overall quality of life.¹⁴⁶ Hypoglossal nerve stimulation may be helpful for individuals with obstructive sleep apnea who fail to respond to CPAP, and greater improvements in AHI can be expected for those with more severe disease, older age, and lower BMI.¹⁴⁷

Acetazolamide

Acetazolamide is a carbonic anhydrase inhibitor that is thought to promote respiratory stimulation by improving the body’s natural response to fluctuations in carbon dioxide levels.¹⁴⁸ A meta-analysis of 24 studies of acetazolamide use in sleep apnea found that the drug reduced AHI by about 38% and was effective in both central and obstructive sleep apnea.¹⁴⁹ In addition to improving sleep-disordered breathing, studies suggest acetazolamide reduces blood pressure in hypertensive adults with obstructive sleep apnea.^150,151 Acetazolamide may be a particularly useful option for patients with sleep apnea resulting from sudden transition to high altitudes.¹⁵²

Nasal Expiratory Positive Airway Pressure and Oral Negative Pressure Therapy

Because many people find CPAP difficult to use, other devices based on the same principle—using air pressure to keep airways open—have been developed.

Nasal expiratory positive airway pressure (EPAP). This treatment creates positive pressure only in the expiratory phase of the breath cycle, rather than continuously. The pressure is generated by adhesive nasal patches that function as one-way valves that close during exhalation, providing air resistance pressure. These nasal patches may be more tolerable to some people than a CPAP facemask. A meta-analysis of 18 studies, which included a total of 920 patients with obstructive sleep apnea, found that nasal EPAP reduced AHI by an average 53.2% and was associated with improved oxygen levels and reduced daytime sleepiness. In studies that compared nasal EPAP with CPAP, EPAP was associated with smaller reductions in AHI, suggesting it may not be as efficacious as CPAP.¹⁶¹ There is limited evidence available demonstrating who is likely to respond well to EPAP, but it is generally not recommended for patients with severe obstructive sleep apnea, reduced airway size or lung volume, high risk for airway collapse, nasal obstruction, blood gas abnormalities, or for use after stroke.^162,163

Oral negative pressure therapy. In this therapy, negative pressure is provided through an oral suction device that draws the tongue and soft palate forward, maintaining airway openness.¹⁶⁴ In a pilot study, oral negative pressure therapy significantly reduced obstructive sleep apnea severity and improved wakefulness.¹⁶⁵ Study results published in 2019 described significant reductions in AHI and oxygen desaturation associated with oral negative pressure therapy, with 64% of patients achieving a ≥50% reduction in AHI.¹⁶⁴

Diet and Weight Loss

Obesity has been described as the most important risk factor for obstructive sleep apnea, and weight loss is recommended for most patients with obstructive sleep apnea and excess weight.¹⁷² A study in 690 adults found that a 10% weight loss was predictive of a 26% reduction in AHI, whereas a 10% weight gain predicted a 32% increase in AHI.¹⁷³ Weight loss intervention has also been shown to improve measures of inflammation and insulin resistance in obstructive sleep apnea, an effect which was not observed with CPAP alone.¹² For some patients with severe obstructive sleep apnea and obesity who struggle with conventional weight-loss strategies, bariatric surgery has been found to improve apnea severity, but up to 20% of patients may experience persistent moderate-to-severe obstructive sleep apnea after surgery.¹⁷⁴

A 6-month randomized study in 40 subjects with a BMI ≥30 kg/m² and moderate-to-severe obstructive sleep apnea found that a Mediterranean diet combined with increased physical activity was more effective for both weight loss and reduction in severity of sleep apnea than a prudent diet coupled with physical activity.¹⁷⁵ Both the Mediterranean diet and prudent diet emphasize whole grains, legumes, fruits, vegetables, nuts, fish, and poultry, but the Mediterranean diet features more olive oil, suggesting an important role for heart-healthy fats in weight loss for sleep apnea management.¹⁷⁶ Additionally, a low-sodium diet has been proposed to improve symptoms of obstructive sleep apnea by reducing fluid retention, but showed greater reductions in AHI than diuretics, suggesting other potential benefits of a low-sodium diet for adults with severe obstructive sleep apnea.¹⁷⁷

A thorough discussion of weight loss strategies is included in the Weight Management protocol.

Exercise

Exercise, even without weight loss, appears to reduce both the severity and symptoms of obstructive sleep apnea.¹⁷⁸ A meta-analysis of 80 randomized controlled trials found that exercise training reduced AHI to a greater degree than MADs, and was comparable with CPAP for reducing daytime sleepiness.¹⁷⁹ A study in 43 obese/overweight adults with obstructive sleep apnea found that a supervised exercise program involving 150 minutes per week of moderate-intensity aerobic exercise plus strength training led to reductions in sleep apnea severity, depressive symptoms, and fatigue, and also improved daytime functioning.¹⁸⁰ In a randomized controlled trial, a 6-month graduated walking program, which increased in duration and intensity over the course of the program, improved not only obstructive sleep apnea severity and oxygen desaturation, but was associated with significant reductions in cholesterol levels.¹⁸¹ The well-established cardiovascular benefits of physical activity may thus have important implications for heart health in sleep apnea patients at risk for CVD.

Alcohol Avoidance

Studies suggest alcohol use is associated with a 25% to 33% increased risk for obstructive sleep apnea.^182,183 Alcohol is a central nervous system depressant that can contribute to obstructive sleep apnea. Like other sedatives, it can decrease respiratory center activity and weaken the signals triggering inhalation. It may also cause weakness in the muscular structures of the pharynx, increasing the tendency for airway collapse, causing snoring and obstructive apnea. People with obstructive sleep apnea have also been found to be more susceptible to the effects of alcohol and may have a higher risk of alcohol-related automobile accidents compared with people without sleep apnea.¹⁸⁴

Sleep Position

For some people, sleep position has a marked impact on severity of apneic and hypopneic breathing during sleep. Lying on one’s back (supine position) is associated with the occurrence of obstructive sleep apnea, as gravitational pull increases risk for airway collapse.¹ For some individuals with obstructive sleep apnea, changing sleep position can improve the severity of disease. A study of 85 adults found that in patients with moderate obstructive sleep apnea, switching from sleeping on their backs to on their sides reduced the frequency of airway collapse by nearly 50%.²² Simply turning the head, so that the body remains supine but the head is rotated to a lateral position, also reduces AHI, although not as drastically as full-body side sleeping.¹⁸⁵ Strategies for maintaining a non-supine position during sleep include using barriers such as firm pillows. Additionally, sleep-position trainers in the form of a vibrational device or smartphone app have been shown to effectively reduce supine sleeping, AHI, and daytime sleepiness in clinical trials, and are associated with >75% adherence.^186,187

Acupuncture

Acupuncture has been explored as a treatment option for patients with obstructive sleep apnea with mixed results. Two small clinical trials found that acupuncture was associated with reduced AHI and respiratory events using both manual acupuncture and electroacupuncture.^188,189 However, a more recent randomized controlled trial found that, after 10 acupuncture sessions, there was no significant change in AHI, blood pressure, or quality of life in hypertensive adults with obstructive sleep apnea.¹⁹⁰ A meta-analysis of nine clinical trials published in 2020 found that acupuncture significantly improved AHI, daytime sleepiness, and oxygen saturation, particularly in patients with moderate obstructive sleep apnea.¹⁹¹ Importantly, all of these trials have been small and the quality of evidence supporting acupuncture as a treatment for obstructive sleep apnea is low to very low—larger, more rigorous controlled trials are needed.¹⁹¹

Smoking Cessation

The effects of smoking on risk for and severity of obstructive sleep apnea remain controversial.^192-194 However, the combined effect of smoking and sleep apnea has been linked to worse cognitive impairment and metabolic parameters.^195,196 Although further clinical trials are needed to demonstrate the benefits of smoking cessation for obstructive sleep apnea severity, current evidence suggests it may improve important comorbidities related to sleep apnea.

In addition to the interventions described in this protocol, readers should also review the Life Extension protocols on Weight Management, Cardiovascular Disease, Chronic Inflammation, and Diabetes, given the strong associations between sleep apnea and metabolic health. In addition, a number of strategies for improving sleep quality and sleep hygiene in general are described in the Insomnia protocol and may be of use for those with sleep apnea.

N-acetylcysteine

Oxidative stress is thought to cause many of the clinical signs and symptoms of sleep apnea, including cardiovascular, neurological, and immune dysfunction. N-acetylcysteine (NAC) is an antioxidant that reduces intermittent hypoxia resulting from excitation of the sympathetic nervous system.¹⁹⁷ In an animal model of sleep apnea, supplementation with NAC mitigated oxidative stress and inflammation that occurred as a result of intermittent hypoxia.¹⁹⁸ In rats, NAC in combination with an arginase inhibitor reduced systemic oxidative stress resulting from chronic intermittent hypoxia, including normalization of elevated blood pressure.¹⁹⁹ In a randomized placebo-controlled trial in 20 adults with obstructive sleep apnea, 600 mg NAC given three times daily for 30 days resulted in significant reductions in AHI, apnea-related arousals, oxygen desaturation, daytime sleepiness, and snoring. These effects were also associated with significant reductions in measures of oxidative stress, including decreased lipid peroxidation and increased total reduced glutathione level.²⁰⁰ Although larger clinical trials are needed, these results suggest a promising role for NAC and antioxidants in the treatment of systemic symptoms associated with sleep apnea.

Vitamins C and E

Vitamins C and E are antioxidants that may have potential roles in the treatment of sleep apnea. In an animal model of obstructive sleep apnea, treatment with vitamins C and E was associated with reduction in markers of both oxidative and carbonyl stress resulting from intermittent hypoxia.²⁰¹ In a preliminary study, 10 people with obstructive sleep apnea were found to have dysfunction of the delicate lining of blood vessels (the endothelium) compared with healthy controls, which improved to a level comparable with that of controls after a single 500-mg dose of intravenous vitamin C.²⁰² In another study, a combination of vitamin C (100 mg) and vitamin E (400 IU), taken by mouth twice daily for 45 days, led to reductions in the frequency of apneic episodes and daytime sleepiness and improved sleep quality in 20 men with obstructive sleep apnea being treated with CPAP. Those who received the vitamin combination were also able to reduce pressure settings on their CPAP machines.²⁰³ In a clinical trial involving 26 men, treatment with an antioxidant cocktail containing both vitamins C and E, as well as coenzyme Q10, was associated with significant improvements in measures of respiratory function in patients with obstructive sleep apnea.²⁰⁴ These results support the increased emphasis on clinical trials examining the use of antioxidants in the treatment of sleep apnea.

Coenzyme Q10

Coenzyme Q10 (CoQ10) is involved in mitochondrial energy production and is best known for its beneficial effects on the cardiovascular system and metabolism.²⁰⁵ As demonstrated in the study mentioned previously, CoQ10 in combination with other antioxidants improved respiratory function in men with obstructive sleep apnea.²⁰⁴ Although specific trials examining the use of CoQ10 in patients with sleep apnea are still needed, patients with sleep apnea are at increased risk for CVD, hypertension, and impaired glucose tolerance, and supplementation with CoQ10 may confer a benefit in all of these conditions.²⁰⁵

Selenium

Selenium is a micronutrient involved in regulation of many enzymes involved in the cellular response to oxidative stress and inflammation, including glutathione peroxidase.²⁰⁶ The role of selenium in obstructive sleep apnea remains unclear. In a 2013 study of the concentrations of trace minerals in 44 individuals newly diagnosed with mild-to-moderate obstructive sleep apnea compared with healthy controls, those with sleep apnea had lower levels of red blood cell selenium and glutathione peroxidase activity than people without apnea, and selenium was negatively associated with AHI values.²⁰⁷ However, in a more recent study in 146 subjects, serum selenium levels were significantly elevated in individuals with obstructive sleep apnea compared with healthy controls, and selenium levels were positively correlated with AHI. The authors of the study postulated that elevated selenium may represent a defense mechanism in patients with obstructive sleep apnea and that antioxidant supplementation may improve the response.²⁰⁸ Although the exact role of selenium remains unclear, it is likely important for progression of obstructive sleep apnea, and further investigation is warranted.²⁰⁶

Vitamin D

Low vitamin D levels are associated with a wide variety of systemic effects, including modulation of the immune system, myopathy, and inflammation.²⁰⁹ In recent years, there has been an increased appreciation for the role of vitamin D deficiency in the occurrence and progression of sleep apnea. In a meta-analysis of 14 studies including almost 5,000 subjects, serum vitamin D levels were lower among patients with obstructive sleep apnea, which was incrementally exacerbated with increasing disease severity.²¹⁰ Studies have also found that low vitamin D levels are associated with increased risk for insulin resistance, diabetes, and metabolic syndrome in patients with obstructive sleep apnea.^211-214 There is often an inverse relationship between levels of vitamin D and parathyroid hormone, and higher parathyroid levels have also been found to be associated with increased risk for hypertension in adults with obstructive sleep apnea.²¹¹ In a small randomized controlled trial in 19 white adults with obstructive sleep apnea, daily vitamin D supplementation (4,000 IU) was associated with significant reductions in metabolic markers; however, neuropsychological and quality of life measures remained unchanged.²¹⁵ Larger and, importantly, more diverse clinical trials are needed to examine the effects of vitamin D supplementation on obstructive sleep apnea and associated comorbidities. Mutations in the vitamin D receptor have been found to at least partially account for some of the variability in vitamin D levels observed in patients with obstructive sleep apnea; thus, genetically diverse populations should be included in clinical trials.²¹⁶

Omega-3 Fatty Acids

Sufficient levels of omega-3 fatty acids are associated with a host of cardiovascular and anti-inflammatory benefits, which may have important implications for individuals with sleep apnea.²¹⁷ A study that examined the red blood cell membrane fatty acid profiles of individuals with obstructive sleep apnea found that lower membrane levels of the omega-3 fatty acid docosahexaenoic acid (DHA) were associated with increased likelihood of severe sleep apnea.²¹⁸ Although there has been speculation that omega-3 fatty acids may represent a therapeutic option for treatment of immune or metabolic comorbidities of sleep apnea, formal studies in humans are still needed.²¹⁹

B Vitamins

A number of studies have found that people with obstructive sleep apnea, particularly those with severe disease, have higher levels of homocysteine, an amino acid linked to increased risk of cardiovascular and neurodegenerative diseases.²²⁰ A 6-year analysis of 1,825 patients with obstructive sleep apnea found that elevated homocysteine levels were associated with an 86% increased risk for developing concurrent hypertension.²²¹ The effects of CPAP therapy on homocysteine levels is unclear, with some studies suggesting a modest improvement after three months of use and others observing no effect after six months of use.^222,223

Supplementation with B vitamins can reduce serum homocysteine levels.^224,225 A randomized controlled trial demonstrated that a high-dose B-complex vitamin reduced measures of oxidative stress and inflammation, and studies have shown that B vitamin supplementation is associated with reduced risk for stroke.^224,226 Although trials are needed which demonstrate a clinical benefit of B vitamin supplementation in obstructive sleep apnea, evidence suggests it represents a promising option for exploration.

More information about the importance of keeping homocysteine levels low and strategies to do so are available in the Homocysteine Reduction protocol.

Probiotics

Changes in the gut microbiome have been linked to a variety of systemic diseases. The prevailing theory is that gut dysbiosis causes damage to the intestinal wall, resulting in a “leaky gut,” which causes chronic low-grade inflammation. There has been increasing interest in the role of the microbiome and gut dysbiosis on the development of obstructive sleep apnea and associated comorbidities, but studies have so far been limited primarily to animal models.²²⁷ However, an analysis of fecal samples from 93 patients with obstructive sleep apnea reported varying degrees of microbial dysbiosis in patients, dominated primarily by decreased levels of bacteria that produce short-chain fatty acids and increased prevalence of disease-causing bacteria.²²⁸ Studies involving animal models of sleep apnea and intermittent hypoxia have found that probiotics can improve some of the side effects of systemic inflammation in the heart and brain, as well as hypertension.^229,230 Studies in humans are needed to explore the effects of probiotics on obstructive sleep apnea occurrence, severity, and comorbidities.