Obstructive Sleep Apnea and Effects on Metabolic Derangements
ABSTRACT: Obstructive sleep apnea (OSA) is a chronic disorder characterized by repeated episodes of complete or partial obstruction of the upper airway during sleep. The resulting daytime fatigue and sleepiness are widely acknowledged. Prevalence of the condition ranges from 3% to 7%, with some estimates up to 20% of the US population. Despite our understanding of the disease, the majority of patients go undiagnosed. Of note, OSA is increasingly recognized as an independent risk factor for several clinical derangements. Identifying and treating patients with OSA is a significant way to rapidly reverse these metabolic abnormalities. This article will review the risk factors associated with OSA, introduce a good diagnostic tool for the disease, and the possible ensuing benefits of treating OSA in patients with concurrent metabolic derangements.
Patients with chronic snoring and untreated sleep apnea have a higher risk of both stroke and cardiovascular disease.1,2 Most of these patients have a higher BMI as well as low activity levels and hypertension.1,2 It is also possible for patients with normal BMI and without hypertension to present with snoring and sleep apnea.1,2 Sleep apnea can be associated with recent weight gain, which in turn contributes to tiredness. As a result, people may eat for stimulation and skip exercise. Over time, these habits result in obesity—which can worsen sleep apnea—leading to a progression in severity of both conditions.
There are multiple metabolic derangements associated with obstructive sleep apnea (OSA). Sleep deprivation from any cause increases blood glucose, blood pressure, and triglycerides. In addition, it causes higher evening cortisol levels, reduces serum leptin secretion, and increases inflammatory cytokines.3 Treating sleep deprivation rapidly reverses these metabolic abnormalities for several reasons, including increased sympathetic nervous system activity, adrenal cortisol, and catecholamine output.4,5
Assessing the Patient
A useful tool used to assess patients’ risk for OSA is the Berlin Questionnaire. It is a simple validated 10-item questionnaire certified by the American College of Physicians.6 The questions focus on BMI, snoring, sleepiness, and blood pressure, and consist of 3 categories related to the risk of having sleep apnea.6
Patients can be classified into high risk or low risk based on their responses to the individual items and their overall scores in the symptom categories.6 The classification of high risk is allotted to patients if there are 2 or more categories where the score is positive; low risk is only 1 or no positive category.
Making the Diagnosis
Polysomnography (PSG) is the gold standard for diagnosis of OSA.7 The study typically involves a minimum of 12 channels of recordings that include electroencephalogram, electrooculogram, electromyogram, oronasal airflow, chest wall effort, body position, snore microphone, ECG, and oxyhemoglobin saturation level.
For diagnosis, the study should last at least 6 hours to observe the different stages of sleep. One-night PSG testing has an estimated sensitivity of 75% to 88% in detecting mild OSA (apnea-hypopnea index [AHI] of 5 or greater).8
The American Association of Sleep Medicine (AASM) practice parameters recommend a full-night PSG for the diagnosis of all sleep-related breathing disorders. Cost and availability are major barriers to PSG use. In patients where there is a high pretest probability of OSA, an overnight pulse oximetry at home is becoming more popular and can be done with far less expense than at a sleep center.
If the pulse oximetry is positive, patients then undergo a formal sleep study as the titration of continuous positive airway pressure (CPAP), particularly in more complicated patients, can only be done in a sleep center with a formal PSG. Based on an extensive evidence-based review, AASM has concluded that oximetry lacks the sensitivity and specificity to be a reliable diagnostic tool.8
Recent guidelines by AASM recognize that portable/home-based monitoring might be indicated for the diagnosis of OSA in patients for whom in-laboratory PSG is not possible due to immobility, safety, or critical illness. According to the guidelines, portable monitoring can be used as an alternative to PSG for the diagnosis of OSA in patients with a high pretest probability of moderate to severe OSA or to monitor the response to CPAP treatments. Nevertheless, the guidelines stress that portable testing is not acceptable for other patient groups, including those with comorbidities, or to screen asymptomatic patients.9
An apnea is defined as no airflow for ≥10 seconds and a hypopnea as a ≥30% reduction in airflow for ≥10 seconds with a correlating 4% oxygen desaturation.6 The severity of OSA is defined by the number of hypopneic or apneic episodes per hour of sleep—otherwise known as the apnea-plus-hypopnea index.
Guidelines for treatment require an AHI. Mild OSA includes AHI values of 5 to 15; moderate is 15 to 30, and severe is >30 events/hour of sleep.6 Although some patients are able to reduce their AHI to normal levels with weight loss, few patients are able to maintain this type of weight loss.
In some patients, a split-night protocol may be used. This means that the first portion of the sleep study (diagnostic) was so severe that the patient was placed on CPAP therapy for the second portion of the night (titration).6
CPAP therapy is the gold standard sleep apnea treatment and can range from 4 cm to 20 cm water pressure.10
As referenced earlier, OSA is a recognized independent risk factor for several clinical derangements. Studies have shown that CPAP therapy benefits patients with OSA and various comorbidities. These include:
•Diabetes. The Sleep Heart Health Study (SHHS), which included a group of community dwellers (n=2656), found sleep-disordered breathing to be independently associated with insulin resistance and glucose intolerance.11,12 Research has shown that CPAP treatment can improve insulin responsiveness without a significant change in obesity, as was the case with our patient (see A Case Study).11,12
• Hypertension. Several reports have demonstrated a clinically significant reduction in blood pressure with CPAP therapy in obstructive sleep apnea syndrome (OSAS) patients. Faccenda et al reported a significant fall in blood pressure levels among normotensive OSA patients when therapeutic CPAP was compared with a tablet placebo. The reduction in blood pressure was most pronounced in patients with severe OSAS.13 Pepperell et al also found a greater decline in blood pressure levels among severe OSAS patients in a study where therapeutic CPAP was compared with sham CPAP.14 Another study focused particularly on severe OSAS patients and found a reduction in mean arterial pressure in the region of 10 mm Hg with therapeutic CPAP, whereas there was no change with sham CPAP.15
Several studies have utilized a placebo-controlled design that has compared ineffective CPAP therapy with therapeutic CPAP. Dimsdale et al demonstrated a significant fall in blood pressure levels during sleep in a group of OSAS patients compared with sham CPAP. However, blood pressure levels also fell with sham therapy, which demonstrates the importance of a placebo-controlled design in studies of CPAP efficacy.16 Robinson et al found no significant reduction in blood pressure levels with CPAP therapy in a group of patients with moderately severe OSAS who were not sleepy.17
• Coronary artery disease. The association of OSAS with ischemic heart disease has been suggested for many years, initially from a case series of patients with OSAS who demonstrated nocturnal myocardial ischemia.18-20 Franklin et al demonstrated the simultaneous association of nocturnal ST-segment changes with obstructive apnea among OSAS patients with coexisting ischemic heart disease.18 In addition, Peled et al demonstrated a reduction in sleep-related myocardial ischemia with CPAP therapy in a group of OSAS patients who had coexisting ischemic heart disease.21
Long-term outcome studies provide the most convincing evidence of beneficial effects of CPAP therapy on the progression and outcomes of coronary artery disease in OSAS. Treatment with CPAP relieved ischemia throughout the night. This is thought to be due to multiple factors including the decrease in heart rate under CPAP, the increase in oxygen saturation, and the decrease in AHI—followed by a decrease of myocardial wall stress. Treatment of patients with OSAS with CPAP can prevent further ischemic events.21
•Arrhythmias. The recent report from the SHHS provides convincing evidence of an independent association between OSAS and nocturnal cardiac arrhythmias, including atrial fibrillation and complex ventricular arrhythmias.22,23 CPAP therapy has been reported to result in resolution of pathological cardiac dysrhythmias.22 Furthermore, researchers found a higher rate of recurrence of atrial fibrillation in OSAS patients who did not accept CPAP therapy compared with OSAS patients who were effectively treated.22,23
• Cerebrovascular disease. Although there is considerable evidence of a higher than expected incidence of OSAS in patients suffering a cerebrovascular event, the evidence for an independent causative effect of OSAS in the pathogenesis of stroke is less persuasive.
Recent reports, however, add support to OSAS as an independent risk factor for the future development of stroke.24-26 OSAS patients have been reported to be twice as likely to suffer a stroke compared with non-OSAS subjects over a 3.5-year follow-up after adjustment for confounders.24-26 Further supportive evidence is provided by large population-based studies such as the SHHS and most recently, the Wisconsin Cohort Study (WCS).27,28
• Endothelial dysfunction. A role for endothelial dysfunction in the pathogenesis of cardiovascular complications in OSAS has been supported by studies demonstrating impairment in endothelium-dependent vasodilatation. Treatment with nasal CPAP has been reported to reverse endothelial dysfunction.29 It is known that a major vasodilator substance released by the endothelium is nitric oxide (NO), and decreased production or activity of NO may be an early sign of atherosclerosis.30 Decreased levels of NO have been found in OSAS patients, and levels increase with CPAP therapy.30
• Metabolic deregulation. Many studies that have reported an independent association of OSAS with several components of the metabolic syndrome, particularly insulin resistance and abnormal lipid metabolism. The SHHS and the WCS have recently identified OSAS as an independent risk factor for insulin resistance, after adjustment for potential confounding variables, such as age, sex, and BMI.27,28
There is evidence of an independent association between OSAS and abnormalities in lipid metabolism. Leptin, an adipocyte-derived hormone that regulates body weight through control of appetite and energy expenditure, has been implicated as an independent cardiovascular risk factor.31,32 Effective CPAP therapy has been associated with improved insulin sensitivity in OSAS.11,12 OSAS has been associated with hyperleptinemia, and effective treatment with CPAP has been reported to be associated with a decrease in leptin levels.31,32
Long-Term Cardiovascular Morbidity and Mortality
Peker et al reported an increased incidence of cardiovascular disease among incompletely treated OSAS patients compared with those efficiently treated over a 7-year follow-up period in a group of patients that were free of cardiovascular disease at baseline.33 Marin et al showed that long-term cardiovascular morbidity and mortality increased only in patients with untreated severe OSAS, whereas simple snorers, OSAS patients with mild disease, or patients with severe OSAS who accepted CPAP treatment showed morbidity and mortality figures very similar to those obtained in the general population.34 The incidence of hypertension, ischemic heart disease, and other cardiovascular disorders during follow-up was not significantly different between treated and untreated patients irrespective of acceptance or refusal of CPAP treatment. Only untreated patients showed excess cardiovascular mortality during follow-up.
Apnea is an increasing population-health concern and a large number of treatable OSA is not diagnosed. Several studies have shown improvement in metabolic derangements, insulin insensitivity, cardiovascular disease, and cerebrovascular disease after OSA diagnoses and subsequent effective CPAP therapy. The gains in sleep quality and likely ensuing quality of life are also major reasons to identify patients at risk.
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Olwaseun Oladiran, MD, is a 3rd year family medicine resident at Southern Colorado Family Medicine in Pueblo, CO. Her interests include preventative medicine, procedural medicine, and women’s health.
Steven Milligan, MD, is a family practitioner at the Centura Family Care and faculty member at the Southern Colorado Family Medicine Residency in Pueblo, CO. He is a diplomat of the American Board of Family Practice since 1987 and a fellow for the American Academy of Family Practitioners since 1990.