July/August 2022

New Research on Sleep Apnea
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 15 No. 4 P. 18

Recent studies increase awareness about risks for this widely undiagnosed and undertreated condition.

Obstructive sleep apnea (OSA) is a common disorder that causes people to stop breathing repeatedly through the night. Apnea episodes can last 10 seconds or more and occur hundreds of times each night, resulting in reduced blood oxygen concentration. Warning signs include loud snoring, gasping, or choking during sleep, and it’s common for those with sleep apnea to wake up feeling fatigued or irritable and to experience headaches and mood swings. Left untreated, OSA can lead to serious health problems, including depression and anxiety, high blood pressure, pulmonary diseases, cardiovascular disease, and increased mortality.

Furthermore, sleep disorders such as sleep apnea and insomnia have been found to contribute to incremental increases in health care utilization and expenditures. Recent research also provides insight into apnea’s association with an increased COVID-19 infection risk; its damaging effects on the brain, including a possible link to dementia; opportunities to improve adherence to sleep apnea treatments; benefits and challenges of current treatment options; and the possibility of future oral pharmacological treatment options.

Health Care Utilization and Expenditures
Sleep disorders such as sleep apnea and insomnia significantly increase the utilization of health care resources and cost to the health care system. In a 2021 analysis published in the Journal of Clinical Sleep Medicine, researchers found the number of medical visits and prescriptions filled were nearly doubled in people with sleep disorders such as sleep apnea and insomnia compared with persons without sleep disorders. Affected patients were also more likely to visit the emergency department and have more comorbid medical conditions. By using the conservative prevalence estimate found in this study, the overall incremental health care costs of sleep disorders in the United States is approximately $94.9 billion.1

Sleep Apnea Treatment
Positive airway pressure (PAP) machines such as continuous PAP (CPAP) are the most widely used treatment for moderate and severe sleep apnea. PAP devices deliver a continuous stream of positive pressurized air into the person’s airway via a mask and tube that keep the airway unobstructed throughout the night. Studies of the effect of PAP therapy show that people with sleep apnea who consistently use their machines feel better and experience reduced apnea and hypopnea episodes during sleep; fewer complications of the disease, including reduced daytime sleepiness, depression, blood pressure; and other benefits.

Despite the proven benefits of CPAP treatment, roughly 50% of people don’t fill their prescriptions or stop using the devices within the first year, primarily due to discomfort. Other treatment options such as oral appliances may be used by those who can’t tolerate PAP therapy; these enlarge the airways by moving the tongue or mandible forward. However, these options take time to get used to and are frequently perceived as intrusive or bulky, resulting in insufficient use. Surgical treatments are available; however, they’re invasive and pose additional concerns for older adults.2

CPAP Therapy for Older Adults
A new study found that CPAP therapy may have limited effectiveness in adults aged 80 years and older. Investigators followed health outcomes in 369 sleep apnea patients older than 70 for three months. Approximately one-half were assigned to CPAP therapy. The researchers measured sleepiness levels, sleep-related quality of life, anxiety, depression, and blood pressure levels. Results were then compared between participants older and younger than age 80. In the 80-years-and-older group, those who used CPAP experienced no improvements in sleep apnea–related symptoms, quality-of-life metrics, mood-related symptoms, or blood pressure when compared with the members of the group who didn’t receive the treatment. 3 Additional research is needed to understand the implications.

Potential Drug Treatment
Medications may be used to help manage symptoms of sleep apnea such as daytime sleepiness or difficulty falling asleep; however, none is recommended as primary treatment. Only a few drugs, such as antidepressants and respiratory stimulants, have been tested for treatment and were found to be ineffective or to cause tolerance or serious adverse effects and complications.

Research demonstrates that carbonic anhydrase (CA), an enzyme responsible for conversion between carbonic acid and carbon dioxide in the body, is elevated in people with sleep apnea.4 A new Swedish study indicates that CA inhibitors may have a future role in the treatment of OSA. The researchers conducted a four-week randomized controlled trial, with 59 patients with moderate or severe sleep apnea completing the study. Patients were randomly assigned to two groups receiving either 400 or 200 mg of the CA inhibitor and a third group (the control group) received placebo. Overall, treatment with the CA inhibitor reduced the number of breathing pauses and promoted oxygenation during the night. Among patients receiving the higher dosage, the number of breathing pauses decreased by approximately 20 per hour. For about one-third of patients, breathing pauses decreased by about 50%, and for 1 in 5, the number of pauses fell by at least 60%.5 The study results, together with the drug’s established safety data, provide support for continued research on CA inhibition as a potential new treatment for OSA.

COVID Risk
Researchers from Kaiser Permanente Southern California reported in a 2021 study that people suffering from severe OSA are at greater risk of COVID-19 infection. Data collected from nearly 82,000 US patients were evaluated to determine the presence of sleep disorders between 2015 and 2020. Of these, about 1,500 people tested positive for COVID-19, with 224 hospitalized and 61 who were placed in intensive care and/or died. Untreated sleep apnea was associated with higher COVID-19 infection rates, while those with greater CPAP adherence—who used therapy at least four hours a night during the pandemic period—showing a reduced infection rate.6

Women at Risk
A new Tel Aviv University study of hundreds of Israeli women found that those aged 50 and older who snore are at increased risk for sleep apnea. The findings are important because many women who suffer from sleep-disordered breathing are unaware that they’re at increased risk for sleep apnea. The researchers examined two groups: relatively young women, aged 20 to 40 (ie, premenopause), and those 50 and older, postmenopause. They found that roughly 15% of the older women were at intermediate or high risk for sleep apnea, compared with only about 3.5% of the younger women. They also determined that 11% of the women who snore were at increased risk for sleep apnea, compared with only 1% among the women who didn’t snore.7

The study authors noted that there’s a lack of awareness and underreporting of sleep apnea in women, which places them at risk of serious systemic diseases such as hypertension, cardiovascular disease, and stroke. The authors also observed that these women were likely to report fatigue, headaches, masticatory muscle soreness upon awaking, and sleep problems such as insomnia to their doctors.7 It’s important that attending physicians make the connection, ask the right questions, and seek further diagnosis in cases of suspected sleep apnea.

Cognitive Behavior Therapy
Comorbid insomnia and sleep apnea (COMISA) is highly common, with a global prevalence between 18% and 42%.8 Patients with COMISA experience nocturnal sleep disturbances; impairments to daytime functioning, mood, and quality of life; and high health care utilization.9

A recent Australian study of 145 patients with COMISA found that when comorbid insomnia symptoms are treated with cognitive and behavioral therapy for insomnia (CBTi), there’s increased acceptance and use of CPAP therapy to treat sleep apnea. Providing CBTi to patients decreased rejection of CPAP devices by 87% and increased long-term CPAP use by one hour each night over the first six months. At six months, combined CBTi and CPAP therapy led to significant improvements, including the following9:

• 52% in global insomnia severity, compared with 35% in the control group;

• 48% in nighttime insomnia complaints, compared with 34% in the control group; and

• 30% in dysfunctional sleep-related cognitions, compared with 10% in the control group.

The study suggests that patients should be screened for insomnia symptoms and, if present, be treated with CBTi to improve subsequent acceptance and use of CPAP therapy for those with COMISA.

Sedentary Lifestyle
Researchers at Brigham and Women’s Hospital and Harvard Medical School in Boston, Johns Hopkins Bloomberg School of Public Health in Baltimore, and other institutions collaborating on a new study found that less physical activity and increased sedentary behavior may independently contribute to the development of OSA through increased adiposity, inflammation, insulin resistance, and body fluid retention.10

The research team analyzed data from 137,917 participants enrolled in the Nurses’ Health Study, Nurses’ Health Study II, and the Health Professionals Follow-up Study. People with OSA spending less than four hours per week sitting watching TV were compared with those spending more than 28 hours per week doing so. The researchers found that less active participants had a greater chance of developing OSA. Those with very sedentary jobs were at a 49% higher risk of developing the sleep breathing disorder than were those in active occupations. Study participants who watched more than four hours of TV each day had a 78% higher risk of developing OSA than did the least sedentary among study participants. Higher levels of physical activity and fewer sedentary hours were associated with lower OSA incidence.10 The study’s results suggest that promoting an active lifestyle may help reduce excess weight, cardiovascular disease, and OSA incidence.

Age Acceleration
In 2019, preliminary results from the Multi-Ethnic Study of Atherosclerosis found that increasing severity of sleep-disordered breathing and sleep disruption are associated with epigenetic age acceleration, by which an individual’s biological age is higher than their chronological age. The study included 622 adults with a mean age of 69 years, with 53.2% being female. Study participants were measured for blood DNA methylation—a marker for fast biological aging—and their sleep was evaluated by polysomnography. Results showed that each standard deviation increase in the apnea-hypopnea index (average number of apneas and hypopneas experienced each hour during sleep) was associated with the equivalent of 215 days of biological age acceleration. Similarly, each standard deviation increase in the arousal index, a measure of sleep disruption, was associated with the equivalent of 321 days of age acceleration. Additionally, the associations were stronger in women than in men, suggesting that women may be particularly vulnerable to the adverse effects of sleep-disordered breathing.11

Sleep Apnea and the Brain
Sleep apnea’s damaging effects on the heart are well known, but it’s increasingly evident that it also takes a significant toll on the brain. Sleep apnea episodes reduce oxygen levels and damage neurons, which can lead to changes in brain matter and subsequent memory loss and other complications such as trouble concentrating or recalling information, reduced cognition, fluctuating moods, increased stress, irritability, depression, and anxiety.

Physical and Chemical Changes
Disparities in areas of the brain essential for memory storage, which can explain problems such as executive dysfunction, memory and cognitive impairments, and mood fluctuations, are more prevalent in people with OSA than in those without the disorder.12 Sleep apnea has also been shown to cause injury to the insular cortex of the brain along with decreased levels of the neurotransmitter GABA (gamma-aminobutyric acid) and increased levels of excitatory glutamate, which at high concentrations has been shown to damage neurons.13

Link Between Sleep Apnea and Dementia
A recent study provided evidence of a link between sleep apnea and dementia, finding that people with OSA showed brain changes that were similar to those of people suffering from the early stages of dementia. Severe OSA was linked to an increase in beta-amyloid protein, which in Alzheimer’s builds up on the walls of the arteries and/or in between neurons in the brain, increasing the risk of dementia. The study involved 34 individuals with recently diagnosed, untreated OSA and 12 individuals who were asymptomatic for sleep disorders. It explored associations between brain amyloid burden using a positron emission tomography brain scan and measures of sleep, demographics, and mood. The OSA group recorded a higher amyloid burden, which was associated with higher apnea-hypopnea index, poorer sleep efficiency, and less time spent in stage N3 sleep (a period of deep sleep important for the body’s regenerative processes such as wound healing and memory formation).14

Another study investigated the extent of Alzheimer’s-like indicators in autopsy tissue from the hippocampi of 34 people and the brainstems of 24 people with OSA.12 The researchers looked for both amyloid plaques and neurofibrillary tangles, another known indicator of Alzheimer’s disease. In the disease, plaques and tangles first appear in the hippocampus and a nearby cortical area—both structures associated with memory—before spreading to the rest of the cortex. While the study found both plaques and tangles in the brains of people with sleep apnea, the plaques were more strongly associated with severe sleep apnea.

Final Thoughts
Sleep apnea is believed to be widely underdiagnosed and undertreated. The consequences are serious and place many people at risk of poor quality of life, serious long-term complications and comorbidities, and increased health care utilization. Health care professionals should monitor patients for risk factors and routinely question them about their quality of sleep. Referral of high-risk patients to sleep specialists for accurate diagnoses while promoting the routine use of PAP devices or oral appliances as well as weight loss and moderate exercise is essential to reducing patient risk.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
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2. Kim J, Tran K, Seal K, et al. Interventions for the treatment of obstructive sleep apnea in adults: a health technology assessment. NCBI Bookshelf website. https://www.ncbi.nlm.nih.gov/books/NBK535532/. Published March 2017.

3. Martinez-Garcia MA, Oscullo G, Ponce S, et al. Effect of continuous positive airway pressure in very elderly with moderate-to-severe obstructive sleep apnea pooled results from two multicenter randomized controlled trials. Sleep Med. 2022;89:71-77.

4. Hoff E, Zou D, Schiza S, et al. Carbonic anhydrase, obstructive sleep apnea and hypertension: effects of intervention. J Sleep Res. 2020;29(2):e12956.

5. Hedner J, Stenlöf K, Zou D, et al. A randomized controlled trial exploring safety and tolerability of sulthiame in sleep apnea [published online February 24, 2022]. Am J Respir Crit Care Med. doi: 10.1164/rccm.202109-2043OC.

6. Hwang D, Chen A, Arguelles J, et al. 680 Impact of obstructive sleep apnea and positive airway pressure therapy on COVID-19 outcomes. Sleep. 2021;44(Suppl 2):A266.

7. Emodi-Perlman A, Soliman J, Frideman-Rubin P, Eli I. Symptoms of nocturnal masticatory muscle activity among women of different age groups and their association to obstructive sleep apnea—a cross sectional study. J Clin Med. 2022;11(5):1199.

8. Zhang Y, Ren R, Lei F, et al. Worldwide and regional prevalence rates of co-occurrence of insomnia and insomnia symptoms with obstructive sleep apnea: a systematic review and meta-analysis. Sleep Med Rev. 2019;45:1-17.

9. Sweetman A, Lack L, Catcheside PG. Cognitive and behavioral therapy for insomnia increases the use of continuous positive airway pressure therapy in obstructive sleep apnea participants with comorbid insomnia: a randomized clinical trial. Sleep. 2019;42(12):zsz178.

10. Liu Y, Yang L, Stampfer MJ, Redline S, Tworoger SS, Huang T. Physical activity, sedentary behaviour and incidence of obstructive sleep apneoa in three prospective US cohorts. Eur Respir J. 2022;59(2):2100606.

11. Li X, Liu Y, Rich SS, Rotter JI, Redline S, Sofer T. 0291 Sleep disordered breathing associated with epigenetic age acceleration: evidence from the multi-ethnic study of atherosclerosis. Sleep. 2019;42(Suppl 1):A118-A119.

12. Owen JE, Benediktsdottir B, Cook E, Olafsson I, Gislason T, Robinson SR. Alzheimer’s disease neuropathology in the hippocampus and brainstem of people with obstructive sleep apnea. Sleep. 2021;44(3):zsaa195.

13. Macey PM, Sarma MK, Nagarajan R, et al. Obstructive sleep apnea is associated with low GABA and high glutamate in the insular cortex. J Sleep Res. 2016;25(4):390-394.

14. Jackson ML, Cavuoto M, Schembri R, et al. Severe obstructive sleep apnea is associated with higher brain amyloid burden: a preliminary PET imaging study. J Alzheimers Dis. 2020;78(2):611-617.