Obstructive sleep apnea and type 2 diabetes: interacting epidemics

Type 2 diabetes is a major public health concern with high morbidity, mortality, and health-care costs. Recent reports have indicated that the majority of patients with type 2 diabetes also have obstructive sleep apnea (OSA). There is compelling evidence that OSA is a significant risk factor for cardiovascular disease and mortality. Rapidly accumulating data from both epidemiologic and clinical studies suggest that OSA is also independently associated with alterations in glucose metabolism and places patients at an increased risk of the development of type 2 diabetes. Experimental studies in humans and animals have demonstrated that intermittent hypoxia and reduced sleep duration due to sleep fragmentation, as occur in OSA, exert adverse effects on glucose metabolism. Based on the current evidence, clinicians need to address the risk of OSA in patients with type 2 diabetes and, conversely, evaluate the presence of type 2 diabetes in patients with OSA. Clearly, there is a need for further research, using well-designed studies and long-term follow-up, to fully demonstrate a causal role for OSA in the development and severity of type 2 diabetes. In particular, future studies must carefully consider the confounding effects of central obesity in examining the link between OSA and alterations in glucose metabolism. The interactions among the rising epidemics of obesity, OSA, and type 2 diabetes are likely to be complex and involve multiple pathways. A better understanding of the relationship between OSA and type 2 diabetes may have important public health implications.     

Relationship between serum substance P levels and daytime sleepiness in obstructive sleep apnea syndrome

OBJECTIVE: We hypothesized that intermittent hypoxia might influence serum substance P levels, and that this effect might in turn contribute in excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: Fifty-five patients with newly diagnosed OSAS and 15 age-matched nonapneic control subjects were enrolled in this study. Full polysomnography was performed in all patients. Single blood samples were drawn between 8:00 am and 9:00 am after the sleep study. Substance P levels were analyzed with a competitive enzyme immunoassay (substance P EIA kit; Cayman Chemical; Ann Arbor, MI). RESULTS: There were no significant differences in age, gender, body mass index, smoking habit, and snoring between the two groups. Serum substance P levels in the OSAS group were significantly lower than that in the control group (p < 0.0001). Serum substance P levels were positively correlated with rapid eye movement sleep (r = 0.330, p = 0.049) and slow-wave sleep (r = 0.324, p = 0.049) phases. Serum substance P levels were negatively correlated with Epworth sleepiness scale score (r = - 0.253, p = 0.048), number of total apneas during the night (r = - 0.247, p = 0.036), number of respiratory events during the night (r = - 0.266, p = 0.024), apnea-hypopnea index (r = - 0.287, p = 0.015), respiratory arousal index (r = - 0.267, p = 0.026), time spent in apnea and hypopnea (r = - 0.307, p = 0.01), average oxygen desaturation (r = - 0.265, p = 0.026), and oxygen desaturation index (r = - 0.254, p = 0.031). CONCLUSION: We concluded that EDS seen in some of the OSAS patients might be associated with various pathophysiologic mechanisms including substance P levels.     

Predictors of heartburn during sleep in a large prospective cohort study

BACKGROUND AND AIMS: Nocturnal gastroesophageal reflux, which may result in nocturnal heartburn, has been demonstrated to be associated with a more severe form of gastroesophageal reflux disease (GERD). The aim of this study was to determine the clinical predictors of heartburn during sleep in a large prospective cohort study. METHODS: Study subjects were members of the parent cohorts from which the Sleep Heart Health Study (SHHS) recruited participants. SHHS is a multicenter, longitudinal, cohort study of the cardiovascular consequences of sleep-disordered breathing. As part of the recruitment process, parent cohort members completed a questionnaire that permitted an assessment of the relationships between heartburn during sleep, and patient demographics, sleep abnormalities, medical history, and social habits in nine community-based parent cohorts across the United States. All variables, significant at the p < 0.05 level, were included as independent variables in multivariate logistic regression models with heartburn during sleep status included as the dependent variable RESULTS: A total of 15,314 subjects completed the questions about heartburn during sleep, and of these, 3,806 subjects (24.9%) reported having this symptom. In four increasingly comprehensive multivariate models, increased body mass index (BMI), carbonated soft drink consumption, snoring and daytime sleepiness (Epworth sleepiness scale score), insomnia, hypertension, asthma, and usage of benzodiazepines were strong predictors of heartburn during sleep. In contrast, college education decreased the risk of reporting heartburn during sleep. CONCLUSIONS: Heartburn during sleep is very common in the general population. Reports of this type of symptom of GERD are strongly associated with increased BMI, carbonated soft drink consumption, snoring and daytime sleepiness, insomnia, hypertension, asthma, and usage of benzodiazepines. Overall, heartburn during sleep may be associated with sleep complaints and excessive daytime sleepiness.     

Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension

OBJECTIVE: Obstructive sleep apnea (OSA) and primary aldosteronism are common in subjects with resistant hypertension; it is unknown, however, if the two disorders are causally related. This study relates plasma aldosterone and renin levels to OSA severity in subjects with resistant hypertension, and in those with equally severe OSA but without resistant hypertension serving as control subjects. METHODS: Seventy-one consecutive subjects referred to the University of Alabama at Birmingham (UAB) for resistant hypertension (BP uncontrolled on three medications) and 29 control subjects referred to UAB Sleep Disorders Center for suspected OSA were prospectively evaluated by an early morning plasma aldosterone concentration (PAC) and renin level, and by overnight, attended polysomnography. RESULTS: OSA (apnea-hypopnea index [AHI] > or = 5/h) was present in 85% of subjects with resistant hypertension. In these subjects, PAC correlated with AHI (rho = 0.44, p = 0.0002) but not renin concentration. Median PAC was significantly lower in control subjects compared to subjects with resistant hypertension (5.5 ng/dL vs 11.0 ng/dL, p < 0.05) and not related to AHI. In male subjects compared to female subjects with resistant hypertension, OSA was more common (90% vs 77%) and more severe (median AHI, 20.8/h vs 10.8/h; p = 0.01), and median PAC was significantly higher (12.0 ng/dL vs 8.8 ng/dL, p = 0.006). CONCLUSION: OSA is extremely common in subjects with resistant hypertension. A significant correlation between PAC and OSA severity is observed in subjects with resistant hypertension but not in control subjects. While cause and effect cannot be inferred, the data suggest that aldosterone excess may contribute to OSA severity.     

Central sleep apnea induced by acute ingestion of opioids

OBJECTIVES: Three cases are presented in which patients were using opioids as required for nonmalignant pain management and significant central sleep apnea developed. Patients in the first two cases had no evidence of sleep-related breathing disorders on polysomnography until they ingested an opioid for treatment of chronic pain during the night and severe central sleep apnea developed. The patient in our third case had established obstructive sleep apnea but experienced a significant number of central events after the ingestion of an opioid analgesic, leading to worsening severity of his underlying sleep-related breathing disorder. CONCLUSION: The short-term ingestion of opioid analgesics can precipitate central sleep apnea in patients with chronic pain receiving long-term opiate therapy who otherwise show no evidence of central sleep apnea and have no cardiac or neurologic disease that would predispose them to central sleep apnea.     

Treatment adherence and outcomes in flexible vs standard continuous positive airway pressure therapy

STUDY OBJECTIVES: To compare adherence and clinical outcomes between flexible positive airway pressure (PAP) [C-Flex; Respironics; Murraysville, PA] and standard PAP therapy (ie, continuous positive airway pressure [CPAP]). DESIGN AND SETTING: A controlled clinical trial of CPAP therapy vs therapy using the C-Flex device in participants with moderate-to-severe obstructive sleep apnea. Participants were recruited from and followed up through an academic sleep disorders center. PARTICIPANTS: Eighty-nine participants were recruited into the study after they had undergone complete in-laboratory polysomnography and before initiating therapy. Participants received either therapy with CPAP (n = 41) or with the C-Flex device (n = 48), depending on the available treatment at the time of recruitment, with those recruited earlier receiving CPAP therapy and those recruited later receiving therapy with the C-Flex device. Follow-up assessments were conducted at 3 months. MEASUREMENTS AND RESULTS: The groups were similar demographically. The mean (+/- SD) treatment adherence over the 3-month follow-up period was higher in the C-Flex group compared to the CPAP group (weeks 2 to 4, 4.2 +/- 2.4 vs 3.5 +/- 2.8, respectively; weeks 9 to 12, 4.8 +/- 2.4 vs 3.1 +/- 2.8, respectively). Clinical outcomes and attitudes toward treatment (self-efficacy) were also measured. Change in subjective sleepiness and functional outcomes associated with sleep did not improve more in one group over the other. Self-efficacy showed a trend toward being higher at the follow-up in those patients who had been treated with the C-Flex device compared to CPAP treatment. CONCLUSIONS: Therapy with the C-Flex device may improve overall adherence over 3 months compared to standard therapy with CPAP. Clinical outcomes do not improve consistently, but C-Flex users may be more confident about their ability to adhere to treatment. Randomized clinical trials are needed to replicate these findings.     

The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function

BACKGROUND: Obstructive sleep apnea (OSA) is associated with endothelial dysfunction. In the current study, we assessed the effect of long-term modified Herbst mandibular advancement splint (MAS) treatment on OSA, oxidative stress markers, and on endothelial function (EF). METHODS: A total of 16 subjects participated (11 men and 5 women; mean [+/- SD] age, 54.0 +/- 8.3 years; mean body mass index, 28.0 +/- 3.1 kg/m(2)), 12 of whom completed the 1-year evaluation. Apnea severity, levels of oxidative stress markers, and EF were assessed after 3 months and 1 year of receiving treatment. For comparison, 6 untreated patients underwent two evaluations 9 months apart, and 10 non-OSA individuals were assessed once as a reference group. The results are presented as the mean +/- SD. RESULTS: The mean apnea-hypopnea index (AHI) decreased significantly from 29.7 +/- 18.5 events/h before treatment to 17.7 +/- 11.1 events/h after 3 months of treatment and 19.6 +/- 11.5 events/h after 1 year of treatment (p < 0.005 for both). The mean Epworth sleepiness scale score decreased significantly from 12.4 +/- 6.0 before treatment to 10.2 +/- 6.6 after 3 months of treatment and 7.8 +/- 3.8 after 1 year of treatment (p < 0.001 for both). The mean EF improved significantly from 1.77 +/- 0.4 before treatment to 2.1 +/- 0.4 after 3 months of treatment (p < 0.05) and 2.0 +/- 0.3 after 1 year of treatment (p = 0.055), which were similar to the values of the reference group. Thiobarbituric acid-reactive substance (TBARS) levels decreased from 18.8 +/- 6.2 nmol malondialdehyde (MDA)/mL before treatment to 15.8 +/- 3.9 MDA/mL after 3 months of treatment (p = 0.09) and 15.5 +/- 3.2 nmol MDA/mL after 1 year of treatment (p < 0.05). There was a correlation between the improvement in AHI and in EF or TBARS levels (r = 0.55; p = 0.05). The untreated control group remained unchanged. CONCLUSIONS: The Herbst MAS may be a moderately effective long-term treatment for patients with OSA. EF improved to levels that were not significantly different than reference levels, even though apneic events were not completely eliminated. We think that these data are encouraging and that they justify the performance of larger randomized controlled studies.     

Familial premature coronary artery disease mortality and obstructive sleep apnea

BACKGROUND: Obstructive sleep apnea (OSA) is linked to both coronary artery disease (CAD) and sudden death, but any causal role remains unclear. A family history of premature CAD and related mortality is an independent risk factor for the development of CAD. We hypothesized that OSA is associated with a family history of premature mortality from ischemic heart disease. METHODS: We prospectively studied 588 subjects who underwent polysomnography from May 2000 to June 2004. Demographics, comorbidities, family history of cardiovascular disease, and the ages and causes of death for 10 strata of family members were recorded for all subjects. We excluded those subjects with known causes of premature cardiac death, such as hypertrophic cardiomyopathy and long-QT syndrome. OSA was defined by American Academy of Sleep Medicine criteria (ie, apnea-hypopnea index >or= 5). Premature CAD mortality was defined as death due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age (women). RESULTS: Polysomnography confirmed OSA in 316 subjects and excluded it in 202 subjects. The unadjusted odds ratio (OR) for OSA and a family history of premature CAD mortality was 2.11 (95% confidence interval [CI], 1.10 to 4.31; p = 0.031). After adjusting for each subject's sex, body mass index, and history of CAD, there was a significant and independent association between OSA and family history of premature CAD mortality (OR, 2.13; 95% CI, 1.04 to 4.66; p = 0.046). CONCLUSIONS: Regardless of their own CAD status, people with OSA are more likely than those without OSA to have a family history of premature CAD mortality.