Obstructive Sleep Apnea and Diabetes: A State of the Art Review

doi:10.1016/j.chest.2017.05.009

Chest

Volume 152, Issue 5, November 2017, Pages 1070-1086

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OSA is a chronic treatable sleep disorder and a frequent comorbidity in patients with type 2 diabetes. Cardinal features of OSA, including intermittent hypoxemia and sleep fragmentation, have been linked to abnormal glucose metabolism in laboratory-based experiments. OSA has also been linked to the development of incident type 2 diabetes. The relationship between OSA and type 2 diabetes may be bidirectional in nature given that diabetic neuropathy can affect central control of respiration and upper airway neural reflexes, promoting sleep-disordered breathing. Despite the strong association between OSA and type 2 diabetes, the effect of treatment with CPAP on markers of glucose metabolism has been conflicting. Variability with CPAP adherence may be one of the key factors behind these conflicting results. Finally, accumulating data suggest an association between OSA and type 1 diabetes as well as gestational diabetes. This review explores the role of OSA in the pathogenesis of type 2 diabetes, glucose metabolism dysregulation, and the impact of OSA treatment on glucose metabolism. The association between OSA and diabetic complications as well as gestational diabetes is also reviewed.

Section snippets

Pathophysiology

Intermittent hypoxemia and sleep fragmentation are cardinal features of OSA and are likely in the causal pathway leading to metabolic dysfunction. Several prospective cross-sectional studies have demonstrated an independent association between the severity of OSA and insulin resistance in individuals without type 2 diabetes.9, 10, 11, 12 Short-term, laboratory-based experiments in healthy human subjects have demonstrated that sleep restriction, sleep fragmentation, and intermittent hypoxemia

OSA as a Novel Risk Factor for the Development of Type 2 Diabetes

Longitudinal cohort studies have demonstrated a significant association between OSA and incident type 2 diabetes. To date, a total of 10 studies from various geographic regions around the globe, with a follow-up duration between 2.7 and 16 years, have explored such an association (Table 1).58, 59, 60, 61, 62, 63, 64, 65, 66, 67 Nine of these studies objectively assessed OSA at baseline,59, 60, 61, 62, 63, 64, 65, 66, 67 and one performed OSA assessment at the last visit.⁵⁸ After adjusting for

Treatment

CPAP remains the most efficacious treatment and continues to be considered the gold standard for treating patients with moderate to severe OSA. Randomized controlled trials examining the effect of CPAP on glucose metabolism are summarized in Tables 235, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 3. e-Table 1 summarizes ongoing randomized controlled trials in patients with type 2 diabetes and sleep apnea.

Future Directions

Growing evidence suggests a strong link between OSA and markers of glucose metabolism. Future studies should explore novel interventions or include strategies to maximize adherence with current treatment modalities (ie, CPAP) to treat OSA during the entire sleep period. This will allow an accurate evaluation of the effect of OSA therapy on glucose metabolism and diabetic complications in prediabetes and type 2 diabetes. Epidemiology of OSA in type 1 diabetes, its relation to glycemic control,

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: B. M. is supported by National Institutes of Health grant R01HL119161 and has served on the advisory board of Itamar Medical. S. R. receives a research grant from Merck Sharp and Dohme and honoraria from Sanofi Aventis, Medtronic, Novo Nordisk, and research equipment support from ResMed, Thailand.

Other contributions: We would like to thank Thunyarat Anothaisintawee, MD, PhD, Department of Family Medicine and

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Cited by (373)

Association of lipid-modifying therapy with risk of obstructive sleep apnea: A drug-target mendelian randomization study
2024, Toxicology and Applied Pharmacology
Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA.
A drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods.
Genetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60–0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89–1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93–1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed.
The present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.
Multidimensional sleep health and diabetic retinopathy: Systematic review and meta-analysis
2024, Sleep Medicine Reviews
Diabetic retinopathy (DR) is one of the most prevalent microvascular diabetic complications. Poor sleep health and obstructive sleep apnea (OSA) are risk factors for diabetes and poor glycemic control. Recent studies have suggested associations between poor sleep health/OSA and DR. Furthermore, there have been suggestions of melatonin dysregulation in the context of DR. We conducted a systematic review and meta-analysis exploring the associations between multidimensional sleep health (duration, satisfaction, efficiency, timing/regularity and alertness), OSA and melatonin with DR. Forty-two studies were included. Long, but not short sleep, was significantly associated with DR, OR 1.41 (95%CI 1.21, 1.64). Poor sleep satisfaction was also significantly associated with DR, OR 2.04 (1.41, 2.94). Sleep efficiency and alertness were not associated with DR, while the evidence on timing/regularity was scant. Having OSA was significantly associated with having DR, OR 1.34 (1.07, 1.69). Further, those with DR had significantly lower melatonin/melatonin metabolite levels than those without DR, standardized mean difference −0.94 (−1.44, −0.44). We explored whether treating OSA with continuous positive airway pressure (CPAP) led to improvement in DR (five studies). The results were mixed among studies, but potential benefits were observed in some. This review highlights the association between poor multidimensional sleep health and DR.
Modification of Endotypic Traits in OSA by the Carbonic Anhydrase Inhibitor Sulthiame
2024, Chest
The carbonic anhydrase inhibitor sulthiame reduces OSA severity, increases overnight oxygenation, and improves sleep quality. Insights into how sulthiame modulates OSA pathophysiologic features (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation.
How does sulthiame treatment modify endotypic traits in OSA?
Per-protocol tertiary analysis of a randomized controlled trial with the inclusion criteria as follow: BMI, ≥ 20 to ≤ 35 kg/m²; age, 18-75 years; apnea-hypopnea index (AHI) ≥ 15 events/h; Epworth sleepiness scale score, ≥ 6; as well as nonacceptance or nontolerance of positive airway pressure treatment. Patients were randomized to receive placebo (n = 22), sulthiame 200 mg (n = 12), or sulthiame 400 mg (n = 24) during 4 weeks of treatment. Polysomnography was applied twice at baseline and follow-up. Endotypic traits were determined from polysomnography tracings (PUPBeta). Sulthiame plasma concentration was analyzed. Differences from baseline to follow-up (Δs) were analyzed with the analysis of covariance or Kruskal-Wallis H test and Pearson (r) or Spearman correlations (r_s).
Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain (response to a 1-cycle/min disturbance, LG₁; mean, –0.16 [95% CI, –0.18 to –0.13]; P < .05) in addition to increased ventilation at lowest decile of ventilatory drive (V_min; median, +12 [95% CI, 4-20]; P < .05) and median ventilation at eupneic ventilatory drive (V_passive; median, +4 [95% CI, 0-5]; P < .05). ΔLG₁ correlated with ΔAHI percentage (200 mg: r = 0.65; P < .05). V_min and V_passive correlated with ΔAHI (all sulthiame: r_s = –0.59 and r_s = –0.65; P < .05 for all). The reduction of LG₁ was seen already in the lower sulthiame concentration range, whereas changes in V_min peaked in the higher range.
The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG₁) as well as upper airway collapsibility (V_min and V_passive).
European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu
The Value of Implementing a Digital Approach in the Obstructive Sleep Apnoea Patient Pathway: A Spanish Example
2024, Open Respiratory Archives
Continuous positive airway pressure (CPAP) is the gold standard therapy for obstructive sleep apnoea (OSA). However, non-adherence is common and costly. The COVID-19 pandemic required the use of novel solutions to ensure service provision and quality of care. This retrospective analysis determined the impact and value of a digital versus standard pathway for the management of OSA in Spain.
A time-driven activity-based costing approach was applied to OSA management over 1 year using a standard or digital pathway. The standard pathway included face-to-face appointments at the time of diagnosis, then after 1–3 months and every 6 months thereafter. The digital pathway had fewer face-to-face appointments and utilised telemonitoring. A cost analysis was performed to determine the per-patient cost per healthcare professional (HCP) for a digital pathway for therapy implementation and follow-up compared with the standard pathway.
Compared with the standard pathway, the digital pathway decreased the waiting list time from 18 to 2 months, the overall pathway time from 12 to 6 months, HCP cost per patient from €95 to €85, and number of hospital appointments per patient from 6 to 3.1. Furthermore, CPAP device usage improved from 5.7 to 6.3 h/night and the proportion of individuals defined as adherent increased from 79% to 91%.
Implementation of digital processes using available technology reduced HCP time and costs, and improved adherence to CPAP in people with OSA. Greater utilisation of a digital pathway could improve access to therapy, allow personalised patient management, and facilitate better clinical outcomes.
La presión positiva continua en la vía aérea (CPAP) es el tratamiento de referencia para la apnea obstructiva del sueño (AOS). Sin embargo, su incumplimiento es frecuente y costoso. La pandemia de COVID-19 requirió el uso de soluciones novedosas para garantizar la prestación de servicios y la calidad de la atención. Este análisis retrospectivo determinó el impacto y el valor de un pathway digital frente a un pathway estándar para el manejo de la AOS en España.
Se aplicó el Time-DrivenActivityBasedCosting al tratamiento de la AOS durante 1 año utilizando el pathway estándar o digital. El pathway estándar incluía citas presenciales en el momento del diagnóstico, después de 1 a 3 meses y posteriormente cada 6 meses. el pathway digital tenía menos citas presenciales y utilizaba la telemonitorización. Se realizó un análisis de costes para determinar el coste por paciente y profesional sanitario (HCP) del pathway digital para la implementación y el seguimiento de la terapia en comparación con el pathway estándar.
En comparación con el pathway estándar, el pathway digital redujo el tiempo de la lista de espera de 18 a 2 meses, el tiempo total del pathway del paciente de 12 a 6 meses, el coste del HCP por paciente de 95 a 85 euros, y el número de citas hospitalarias por paciente de 6 a 3,1. Además, el uso del dispositivo de CPAP mejoró de 5,7 a 6,3 h/noche y la proporción de pacientes definidos como adherentes aumentó del 79% al 91%.
La implementación de procesos digitales utilizando la tecnología disponible redujo el tiempo y los costes del HCP y mejoró la adherencia a la CPAP en personas con AOS. Una mayor utilización de un pathway digital podría mejorar el acceso a la terapia, permitir una gestión personalizada del paciente y facilitar mejores resultados clínicos.
Mortality in obstructive sleep apnea syndrome (OSAS) and overlap syndrome (OS): The role of nocturnal hypoxemia and CPAP compliance
2023, Sleep Medicine
Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are two chronic diseases that afflict many individuals worldwide with negative effects on health that may overlap in Overlap Syndrome (OS). The aim of our study was to investigate the differences in mortality between OSAS alone and OS and the risk factors involved.
The study was conducted on patients with OSAS or OS diagnosis that completed 15-year follow-up between 2005 and 2023. Of these, the clinical, functional, sleep and survival data were registered and analysed. Risk factors were found by regression analysis.
501 patients (428 OSAS and 73 OS) were enrolled. Patients with OS had higher mortality than OSAS (p < 0,001). The morality risk factors for the overall population found were age >65 years (odds ratio (OR) = 10.69 (95%CI 3,85–29,69), p < 0,001) and low forced-expiratory volume in 1-s (FEV₁) (OR = 10.18 (95%CI 2,32–44,68), p = 0,002). In patients with OSAS, age and nocturnal hypoxemia (NH) (OR = 2.41 (95%CI 1,07–5,41), p = 0,03) were risk factors, while adherence to nighttime positive airway pressure (PAP) reduced mortality (OR = 0,36 (95%CI 0,15–0,83), p = 0,017). Multivariate analysis confirmed age and FEV₁ as risk factors in OS. Conversely, the risk factors for the overall population under 65 years were NH, which is confirmed in patients with OSAS alone (OR = 4,72 (95%CI 1,07–20,77), p = 0,04) in whom, on the other hand, PAP compliance reduced the mortality risk.
The study suggests that NH is a risk factor for all-cause mortality in sleep disorders by excluding the age; conversely, nighttime PAP improves the survival.
Global Prevalence of Obstructive Sleep Apnea in the Elderly and Related Factors: A Systematic Review and Meta-Analysis Study
2023, Journal of Perianesthesia Nursing
The aims of current meta-analysis was to combine data and statistics on the global prevalence of OSA and related factors in older adults.
A systematic review and meta-analysis.
To find related studies, various databases were searched including Embase, PubMed, Scopus, Web of Science (WoS), MagIran, and SID (two local databases) using appropriate keywords, MeSH and controlled vocabulary, with no time limitation up to June, 2021. Heterogeneity of studies was evaluated using I², and Egger's regression intercept was used to detect publication bias.
39 studies with a total sample size of 33,353 people were included. The pooled prevalence of OSA in older adults was 35.9% (95% confidence interval: 28.7%-43.8%; I² = 98.81%). Considering the high heterogeneity of included studies, subgroup analysis was conducted and yielded the most prevalent in Asia continent with 37.0% (95% CI: 22.4%-54.5%; I² = 97.32%). However, heterogeneity was remained at high level. In the majority of studies, OSA was significantly and positively related to obesity, increased BMI, age, cardiovascular diseases, diabetes, and daytime sleepiness.
Results of this study showed that global prevalence of OSA in older adults is high and is significantly related to obesity, increased BMI, age, cardiovascular diseases, diabetes, and daytime sleepiness. These findings can be used by experts working on the diagnosis and management of OSA in the geriatric population. These findings can be used by experts on the diagnosis and treatment of OSA in the older adults. Due to high heterogeneity, findings should be interpreted with great caution.

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Contemporary Reviews in Sleep MedicineObstructive Sleep Apnea and Diabetes: A State of the Art Review

Section snippets

Pathophysiology

OSA as a Novel Risk Factor for the Development of Type 2 Diabetes

Treatment

Future Directions

Acknowledgments

Lancet Respir Med

Lancet

Chest

Psychoneuroendocrinology

Chest

Free Radic Biol Med

Diabetes Res Clin Pract

Sleep Med

Sleep Med

J Diabetes Complicat

Sleep Med

Sleep Med

Am J Med

Chest

Endocr Pract

Diabetes Metab

Chest

Sleep Med

Chest

Chest

Diabetes Res Clin Pract

J Cardiovasc Magn Reson

Eur J Intern Med

Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr

Am J Respir Crit Care Med

Effects of age on sleep apnea in men: I. Prevalence and severity

Am J Respir Crit Care Med

The occurrence of sleep-disordered breathing among middle-aged adults

N Engl J Med

Prevalence of sleep-disordered breathing in women: effects of gender

Am J Respir Crit Care Med

Increased prevalence of sleep-disordered breathing in adults

Am J Epidemiol

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

N Engl J Med

Sleep-disordered breathing and insulin resistance in middle-aged and overweight men

Am J Respir Crit Care Med

Alterations in glucose disposal in sleep-disordered breathing

Am J Respir Crit Care Med

Meta-analyses of the association of sleep apnea with insulin resistance, and the effects of CPAP on HOMA-IR, adiponectin, and visceral adipose fat

J Clin Sleep Med

Obstructive sleep apnea is independently associated with insulin resistance

Am J Respir Crit Care Med

Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance

J Clin Endocrinol Metab

Sleep restriction for 1 week reduces insulin sensitivity in healthy men

Diabetes

Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study

Ann Intern Med

A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects

J Clin Endocrinol Metab

A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men

J Sleep Res

Slow-wave sleep and the risk of type 2 diabetes in humans

Proc Natl Acad Sci U S A

Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers

J Appl Physiol

Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes

Ann N Y Acad Sci

Three hours of intermittent hypoxia increases circulating glucose levels in healthy adults

Physiol Rep

Hypoxia causes glucose intolerance in humans

Am J Respir Crit Care Med

Sympathetic-nerve activity during sleep in normal subjects

N Engl J Med

Sympathetic neural mechanisms in obstructive sleep apnea

J Clin Invest

Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea

Circulation

The role of the autonomic nervous system in the control of glucagon, insulin and pancreatic polypeptide release from the pancreas

J Physiol

Acute noradrenergic activation induces insulin resistance in human skeletal muscle

Contemporary Reviews in Sleep Medicine
Obstructive Sleep Apnea and Diabetes: A State of the Art Review