Samuel T. Kuna

Obstructive Sleep Apnea Among Obese Patients With Type 2 Diabetes

OBJECTIVE To assess the risk factors for the presence and severity of obstructive sleep apnea (OSA) among obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Unattended polysomnography was performed in 306 participants. RESULTS Over 86% of participants had OSA with an apnea-hypopnea index (AHI) ≥5 events/h. The mean AHI was 20.5 ± 16.8 events/h. A total of 30.5% of the participants had moderate OSA (15 ≤ AHI <30), and 22.6% had severe OSA (AHI ≥30). Waist circumference (odds ratio 1.1; 95% CI 1.0–1.1; P = 0.03) was significantly related to the presence of OSA. Severe OSA was most likely in individuals with a higher BMI (odds ratio 1.1; 95% CI 1.0–1.2; P = 0.03). CONCLUSIONS Physicians should be particularly cognizant of the likelihood of OSA in obese patients with type 2 diabetes, especially among individuals with higher waist circumference and BMI.

A randomized study on the effect of weight loss on obstructive sleep apnea among obese patients with type 2 diabetes: the Sleep AHEAD Study.

BACKGROUND The belief that weight loss improves obstructive sleep apnea (OSA) has limited empirical support. The purpose of this 4-center study was to assess the effects of weight loss on OSA over a 1-year period. METHODS The study included 264 participants with type 2 diabetes and a mean (SD) age of 61.2 (6.5) years, weight of 102.4 (18.3) kg, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 36.7 (5.7), and an apnea-hypopnea index (AHI) of 23.2 (16.5) events per hour. The participants were randomly assigned to either a behavioral weight loss program developed specifically for obese patients with type 2 diabetes (intensive lifestyle intervention [ILI]) or 3 group sessions related to effective diabetes management (diabetes support and education [DSE]). RESULTS The ILI participants lost more weight at 1 year than did DSE participants (10.8 kg vs 0.6 kg; P < .001). Relative to the DSE group, the ILI intervention was associated with an adjusted (SE) decrease in AHI of 9.7 (2.0) events per hour (P < .001). At 1 year, more than 3 times as many participants in the ILI group than in the DSE group had total remission of their OSA, and the prevalence of severe OSA among ILI participants was half that of the DSE group. Initial AHI and weight loss were the strongest predictors of changes in AHI at 1 year (P < .01). Participants with a weight loss of 10 kg or more had the greatest reductions in AHI. CONCLUSIONS Physicians and their patients can expect that weight loss will result in significant and clinically relevant improvements in OSA among obese patients with type 2 diabetes. Trial Registration clinicaltrials.gov Identifier: NCT00194259.

Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial.

RATIONALE Twenty-eight percent of people with mild to moderate obstructive sleep apnea experience daytime sleepiness, which interferes with daily functioning. It remains unclear whether treatment with continuous positive airway pressure improves daytime function in these patients. OBJECTIVES To evaluate the efficacy of continuous positive airway pressure treatment to improve functional status in sleepy patients with mild and moderate obstructive sleep apnea. METHODS Patients with self-reported daytime sleepiness (Epworth Sleepiness Scale score >10) and an apnea-hypopnea index with 3% desaturation and from 5 to 30 events per hour were randomized to 8 weeks of active or sham continuous positive airway pressure treatment. After the 8-week intervention, participants in the sham arm received 8 weeks of active continuous positive airway pressure treatment. MEASUREMENTS AND MAIN RESULTS The Total score on the Functional Outcomes of Sleep Questionnaire was the primary outcome measure. The adjusted mean change in the Total score after the first 8-week intervention was 0.89 for the active group (n = 113) and -0.06 for the placebo group (n = 110) (P = 0.006). The group difference in mean change corresponded to an effect size of 0.41 (95% confidence interval, 0.14-0.67). The mean (SD) improvement in Functional Outcomes of Sleep Questionnaire Total score from the beginning to the end of the crossover phase (n = 91) was 1.73 ± 2.50 (t[90] = 6.59; P < 0.00001) with an effect size of 0.69. CONCLUSIONS Continuous positive airway pressure treatment improves the functional outcome of sleepy patients with mild and moderate obstructive sleep apnea.

Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes.

STUDY OBJECTIVES To examine whether the initial benefit of weight loss on obstructive sleep apnea (OSA) severity at 1 year is maintained at 4 years. DESIGN Randomized controlled trial with follow-up at 1, 2, and 4 years. SETTING 4 Look AHEAD clinical centers. PARTICIPANTS Two hundred sixty-four obese adults with type 2 diabetes and OSA. INTERVENTIONS Intensive lifestyle intervention with a behavioral weight loss program or diabetes support and education. MEASUREMENTS Change in apnea-hypopnea index on polysomnogram. RESULTS The intensive lifestyle intervention groups mean weight loss was 10.7 ± 0.7 (standard error), 7.4 ± 0.7, and 5.2 ± 0.7 kg at 1, 2, and 4 years respectively, compared to a less than 1-kg weight loss for the control group at each time (P < 0.001). Apnea-hypopnea index difference between groups was 9.7 ± 2.0, 8.0 ± 2.0, and 7.7 ± 2.3 events/h at 1, 2 and 4 years respectively (P < 0.001). Change in apnea-hypopnea index over time was related to the amount of weight loss (P < 0.0001) and intervention, independent of weight loss (P = 0.001). Remission of OSA at 4 years was 5 times more common with intensive lifestyle intervention (20.7%) than diabetes support and education (3.6%). CONCLUSIONS Among obese adults with type 2 diabetes and OSA, intensive lifestyle intervention produced greater reductions in weight and apnea-hypopnea index over a 4 year period than did diabetes support and education. Beneficial effects of intensive lifestyle intervention on apneahypopnea index at 1 year persisted at 4 years, despite an almost 50% weight regain. Effect of intensive lifestyle intervention on apnea-hypopnea index was largely, but not entirely, due to weight loss.

Neural and Anatomic Factors Related to Upper Airway Occlusion During Sleep

Both neural and anatomical factors play an important role in the maintenance of upper airway patency. An abnormality in one or both of these factors is felt to be the underlying cause of obstructive sleep apnea.

Heritability of Performance Deficit Accumulation During Acute Sleep Deprivation in Twins

STUDY OBJECTIVES To determine if the large and highly reproducible interindividual differences in rates of performance deficit accumulation during sleep deprivation, as determined by the number of lapses on a sustained reaction time test, the Psychomotor Vigilance Task (PVT), arise from a heritable trait. DESIGN Prospective, observational cohort study. SETTING Academic medical center. PARTICIPANTS There were 59 monozygotic (mean age 29.2 ± 6.8 [SD] yr; 15 male and 44 female pairs) and 41 dizygotic (mean age 26.6 ± 7.6 yr; 15 male and 26 female pairs) same-sex twin pairs with a normal polysomnogram. INTERVENTIONS Thirty-eight hr of monitored, continuous sleep deprivation. MEASUREMENTS AND RESULTS Patients performed the 10-min PVT every 2 hr during the sleep deprivation protocol. The primary outcome was change from baseline in square root transformed total lapses (response time ≥ 500 ms) per trial. Patient-specific linear rates of performance deficit accumulation were separated from circadian effects using multiple linear regression. Using the classic approach to assess heritability, the intraclass correlation coefficients for accumulating deficits resulted in a broad sense heritability (h(2)) estimate of 0.834. The mean within-pair and among-pair heritability estimates determined by analysis of variance-based methods was 0.715. When variance components of mixed-effect multilevel models were estimated by maximum likelihood estimation and used to determine the proportions of phenotypic variance explained by genetic and nongenetic factors, 51.1% (standard error = 8.4%, P < 0.0001) of twin variance was attributed to combined additive and dominance genetic effects. CONCLUSION Genetic factors explain a large fraction of interindividual variance among rates of performance deficit accumulations on PVT during sleep deprivation.

An Official ATS/AASM/ACCP/ERS Workshop Report: Research Priorities in Ambulatory Management of Adults with Obstructive Sleep Apnea

An international workshop was held to determine the research priorities for incorporating ambulatory management of adults with obstructive sleep apnea into healthcare systems. The workshop identified the barriers preventing incorporation of portable monitor testing into clinical management pathways and determined the research and development needed to address those barriers. The workshop promoted interaction and collaboration among diverse stakeholders who have interest and expertise in the development and evaluation of portable monitor technology and its clinical application. The consensus of the workshop participants was that outcomes-based research studies are needed to demonstrate the efficacy and cost effectiveness of portable monitor testing. Closely related to this objective is the need to develop clinical sleep research networks capable of performing adequately powered studies. Recommendations were developed regarding research study design and methodology that includes the need to standardize technology, identify the patients most appropriate for ambulatory management of obstructive sleep apnea, ensure patient safety, and identify sources of research funding. The evidence resulting from high-quality comparative effectiveness studies that include cost effectiveness as an outcome will allow decision makers to develop healthcare policies regarding the clinical application of portable monitor testing for the ambulatory management of patients with obstructive sleep apnea.

Symptoms of insomnia among patients with obstructive sleep apnea before and after two years of positive airway pressure treatment.

STUDY OBJECTIVES To assess the changes of insomnia symptoms among patients with obstructive sleep apnea (OSA) from starting treatment with positive airway pressure (PAP) to a 2-y follow-up. DESIGN Longitudinal cohort study. SETTING Landspitali--The National University Hospital of Iceland. PARTICIPANTS There were 705 adults with OSA who were assessed prior to and 2 y after starting PAP treatment. INTERVENTION PAP treatment for OSA. MEASUREMENTS AND RESULTS All patients underwent a medical examination along with a type 3 sleep study and answered questionnaires on health and sleep before and 2 y after starting PAP treatment. The change in prevalence of insomnia symptoms by subtype was assessed by questionnaire and compared between individuals who were using or not using PAP at follow-up. Symptoms of middle insomnia were most common at baseline and improved significantly among patients using PAP (from 59.4% to 30.7%, P < 0.001). Symptoms of initial insomnia tended to persist regardless of PAP treatment, and symptoms of late insomnia were more likely to improve among patients not using PAP. Patients with symptoms of initial and late insomnia at baseline were less likely to adhere to PAP (odds ratio [OR] 0.56, P = 0.007, and OR 0.53, P < 0.001, respectively). CONCLUSION Positive airway pressure treatment significantly reduced symptoms of middle insomnia. Symptoms of initial and late insomnia, however, tended to persist regardless of positive airway pressure treatment and had a negative effect on adherence. Targeted treatment for insomnia may be beneficial for patients with obstructive sleep apnea comorbid with insomnia and has the potential to positively affect adherence to positive airway pressure.

Positive Airway Pressure Initiation: A Randomized Controlled Trial to Assess the Impact of Therapy Mode and Titration Process on Efficacy, Adherence, and Outcomes

STUDY OBJECTIVES (1) To determine the efficacy of automatically adjusted positive airway pressure (APAP) with a comfort feature (A-Flex) at reducing apneas and hypopneas in participants with moderate to severe OSA. (2) To determine the relative difference between A-Flex, continuous positive airway pressure (CPAP), and APAP-derived optimal pressure for CPAP (CPAP(APAP)) on adherence to treatment. (3) To determine the relative difference between APAP with A-Flex, CPAP, and CPAP(APAP) on long-term change in functional outcomes. DESIGN Randomized, double-blinded, 3-arm, multicenter trial. SETTING University and Veterans Affairs medical centers. PATIENTS OR PARTICIPANTS 168 participants were randomized, and 140 completed the 180-day study. INTERVENTIONS (1) A-Flex; (2) CPAP; (3) APAP for 14 days and then switched to CPAP at a fixed pressure. MEASUREMENTS AND RESULTS Apnea-hypopnea indices, average and minimum oxygen saturation, time spent < 90% were significantly poorer for A-Flex vs. CPAP at the initiation of study treatment; with the exception of minimum oxygen saturation, these differences were absent at 180 days. A-Flex had lower average leak values at both 3 and 6 months. There were no significant differences between groups in major efficacy, adherence, and outcome (subjective sleepiness, objective vigilance, blood pressure, quality of life) measures. No differences between groups in attitudes toward use were observed at 3 or 6 months; participant ratings for CPAP were significantly higher than A-Flex on treatment satisfaction and benefit, but not different for sleep quality and mask comfort. CONCLUSIONS We found that A-Flex shows equivalency, but non-superiority (except for average leak values), in efficacy, adherence, and functional outcomes compared to CPAP after either 3 or 6 months. CLINICAL TRIAL REGISTRY Positive Pressure Treatment of Obstructive Sleep Apnea, http://www.clinicaltrials.gov, NCT00636181.

A Novel BHLHE41 Variant is Associated with Short Sleep and Resistance to Sleep Deprivation in Humans

STUDY OBJECTIVES Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loophelix family member e41) as causal in a family of short sleepers, who needed just 6 h sleep per night. We evaluated whether there were other variants of this gene in two well-phenotyped cohorts. DESIGN Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase. RESULTS We identified new variants of the BHLHE41 gene in two cohorts who had either acute sleep deprivation (n = 200) or chronic partial sleep deprivation (n = 217). One variant, Y362H, at another location in the same exon occurred in one twin in a dizygotic twin pair and was associated with reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses during sleep deprivation than the homozygous twin. Both twins had almost identical amounts of non rapid eye movement (NREM) sleep. This variant reduced the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro. Another variant in the same exome had no effect on sleep or response to sleep deprivation and no effect on CLOCK/BMAL1 transactivation. Random mutagenesis identified a number of other variants of BHLHE41 that affect its function. CONCLUSIONS There are a number of mutations of BHLHE41. Mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss. Mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation. Thus, clock mechanisms are likely involved in setting sleep length and the magnitude of sleep homeostasis. CITATION Pellegrino R, Kavakli IH, Goel N, Cardinale CJ, Dinges DF, Kuna ST, Maislin G, Van Dongen HP, Tufik S, Hogenesch JB, Hakonarson H, Pack AI. A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans. SLEEP 2014;37(8):1327-1336.