Elsevier

Sleep Medicine Reviews

Volume 21, June 2015, Pages 23-38
Sleep Medicine Reviews

Clinical review
Impact of obstructive sleep apnea treatment by continuous positive airway pressure on cardiometabolic biomarkers: A systematic review from sham CPAP randomized controlled trials

https://doi.org/10.1016/j.smrv.2014.07.004Get rights and content

Summary

Reducing cardiometabolic risk may represent an important target for effective obstructive sleep apnea (OSA) treatment. The impact of continuous positive airway pressure (CPAP), the first line therapy of OSA, on metabolic or inflammatory markers is still debated. A systematic literature search using several databases was performed. We provide a systematic analysis of randomized studies comparing therapeutic versus sham CPAP intervention and also include studies using a CPAP withdrawal design. We addressed the impact of CPAP on the following cardiometabolic biomarkers: 1) plasma and urine catecholamines and their metabolites that reflect sympathetic activity; 2) insulin resistance and lipid metabolism biomarkers; 3) oxidative stress, systemic and vascular inflammation biomarkers; 4) liver enzymes highlighting the association between OSA and nonalcoholic fatty liver disease (NAFLD); 5) coagulation biomarkers. The impact of CPAP on sympathetic activity is robust across studies and occurs rapidly. In contrast to sympathetic activity, the well-designed studies included in this review failed to demonstrate that CPAP alters metabolic or inflammatory markers in OSA. CPAP did not change glucose, lipids, insulin resistance levels or the ratio of patients with metabolic syndrome. In unselected OSA patients, it is not realistic to expect a clinically relevant decrease in cardiometabolic biomarkers with CPAP therapy.

Introduction

Obstructive sleep apnea (OSA) is a common clinical condition characterized by repeated episodes of apnea and hypopnea during sleep. Sleep fragmentation and chronic intermittent hypoxia (CIH) induce intermediate mechanisms such as activation of the sympathetic nervous system [1], oxidative stress and systemic inflammation, responsible for cardiometabolic consequences ∗[2], ∗[3] (Fig. 1). OSA is linked with hypertension, arrhythmia, stroke, coronary heart disease, and increased cardiovascular mortality [4]. In addition, OSA is also highly prevalent in patients with metabolic diseases including type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD) [5] and is linked to several features of metabolic syndrome among them hypertension, insulin resistance (IR), abdominal obesity and dyslipidemia [6], ∗[7]. The effective treatment of OSA may thus represent an important target for reducing cardiometabolic risk. However, the impact of continuous positive airway pressure (CPAP), the first line therapy of OSA, on metabolic or inflammatory markers is still debated [8].

Although the effects of CPAP on various biomarkers have been investigated in hundreds of open clinical studies, the real effects of CPAP on cardiometabolic biomarkers are conflicting mainly owing to different study designs and the presence of major confounders. This review is a systematic analysis of randomized studies comparing therapeutic versus sham CPAP intervention and also includes studies using a CPAP withdrawal design ∗[9], [10].

To take account of the intermediary mechanisms involved in OSA pathophysiology (Fig. 1), we will address the impact of CPAP on the following cardiometabolic biomarkers: 1) plasma and urine catecholamines and their metabolites that reflect sympathetic activity; 2) insulin resistance and lipid metabolism biomarkers; 3) oxidative stress, systemic and vascular inflammation biomarkers; 4) liver enzymes highlighting the association between OSA and NAFLD; 5) coagulation biomarkers.

Section snippets

Literature search strategy

We selected only randomized sham-controlled trials i.e., with sham CPAP as the control, addressing the impact of CPAP on cardiometabolic biomarkers. An electronic literature search using the Medline medical research database was conducted. We looked for sham-controlled studies and investigating the effects of CPAP on blood and urinary cardiometabolic biomarkers. First, we used “sham CPAP” as the keyword, then the following keyword associations were used: “subtherapeutic CPAP” AND “randomized

Background: sympathetic activation and intermittent hypoxia

Oxidative stress and inflammation induced by OSA promote activation of the sympathetic nervous system and then endothelial dysfunction, arterial stiffness and atherosclerosis ∗[2], ∗[11], ∗[12]. As shown in Fig. 1, oxidative stress induces inflammation, while inflammation in turn promotes oxidative stress. This vicious circle results in sympathetic activation and endothelial dysfunction leading to atherosclerosis. Impaired arterial vasodilating capacity may contribute to hypertension and

Background: metabolic syndrome and OSA

OSA is associated with all the components of the metabolic syndrome including visceral obesity [27], hypertension, poor glycemic control and lipid metabolism abnormalities. It has been suggested that adipocytes exposed to hypoxia exhibit dysregulated adipocytokine production [28], which may contribute to insulin resistance and metabolic syndrome in OSA patients. We have demonstrated in patients with morbid obesity that chronic intermittent hypoxia is strongly associated with higher systemic

Acknowledgment

We thank Dr Alison Foote (Clinical Research Center, Grenoble University Hospital) for language editing.

References (100)

  • B. Prudon et al.

    Serum urate levels are unchanged with continuous positive airway pressure therapy for obstructive sleep apnea: a randomized controlled trial

    Sleep Med

    (2013)
  • J.W. Weiss et al.

    Nitric oxide and obstructive sleep apnea

    Respir Physiol Neurobiol

    (2012)
  • G.E. Carpagnano et al.

    8-Isoprostane, a marker of oxidative stress, is increased in exhaled breath condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy

    Chest

    (2003)
  • L. Ozturk et al.

    Lipid peroxidation and osmotic fragility of red blood cells in sleep-apnea patients

    Clin Chim Acta

    (2003)
  • P.J. Simpson et al.

    Effects of continuous positive airway pressure on endothelial function and circulating progenitor cells in obstructive sleep apnoea: a randomised sham-controlled study

    Int J Cardiol

    (2013)
  • X. Xie et al.

    Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: a meta-analysis

    Sleep Med

    (2013)
  • M. Lemoine et al.

    Chronic intermittent hypoxia: a breath of fresh air in the understanding of NAFLD pathogenesis

    J Hepatol

    (2012)
  • K. Chin et al.

    Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients

    Am J Med

    (2003)
  • R. von Kanel et al.

    Hemostatic alterations in patients with obstructive sleep apnea and the implications for cardiovascular disease

    Chest

    (2003)
  • R. von Kanel et al.

    Effect of continuous positive airway pressure on day/night rhythm of prothrombotic markers in obstructive sleep apnea

    Sleep Med

    (2013)
  • D.S. Hui et al.

    The effects of nasal continuous positive airway pressure on platelet activation in obstructive sleep apnea syndrome

    Chest

    (2004)
  • M. Kohler et al.

    Mechanisms of vascular damage in obstructive sleep apnea

    Nat Rev Cardiol

    (2010)
  • L. Lavie et al.

    Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link

    Eur Respir J

    (2009)
  • P. Levy et al.

    Sleep apnoea syndrome in 2011: current concepts and future directions

    Eur Respir Rev

    (2011)
  • W.T. McNicholas et al.

    Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities

    Eur Respir J

    (2007)
  • P. Levy et al.

    Sleep, sleep-disordered breathing and metabolic consequences

    Eur Respir J

    (2009)
  • J.L. Pepin et al.

    Obstructive sleep apnoea and metabolic syndrome: put CPAP efficacy in a more realistic perspective

    Thorax

    (2012)
  • M. Kohler et al.

    Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial

    Am J Respir Crit Care Med

    (2011)
  • L. Ayers et al.

    Elevated levels of endothelial cell-derived microparticles following short-term withdrawal of continuous positive airway pressure in patients with obstructive sleep apnea: data from a randomized controlled trial

    Respiration

    (2013)
  • S. Jelic et al.

    Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea

    Circulation

    (2008)
  • R. Tamisier et al.

    14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans

    Eur Respir J

    (2011)
  • J.A. Dempsey et al.

    Pathophysiology of sleep apnea

    Physiol Rev

    (2010)
  • J. Hedner et al.

    Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications

    Eur Respir J

    (1995)
  • J. Heitmann et al.

    Sympathetic activity is reduced by nCPAP in hypertensive obstructive sleep apnoea patients

    Eur Respir J

    (2004)
  • P. Pinto et al.

    Effects of CPAP on nitrate and norepinephrine levels in severe and mild-moderate sleep apnea

    BMC Pulm Med

    (2013)
  • M.A. Arias et al.

    CPAP decreases plasma levels of soluble tumour necrosis factor-alpha receptor 1 in obstructive sleep apnoea

    Eur Respir J

    (2008)
  • A. Alonso-Fernandez et al.

    Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial

    Thorax

    (2009)
  • L. Grote et al.

    Reduced alpha- and beta(2)-adrenergic vascular response in patients with obstructive sleep apnea

    Am J Respir Crit Care Med

    (2000)
  • J.C. Lam et al.

    A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea

    Eur Respir J

    (2010)
  • C.L. Phillips et al.

    Continuous positive airway pressure reduces postprandial lipidemia in obstructive sleep apnea: a randomized, placebo-controlled crossover trial

    Am J Respir Crit Care Med

    (2011)
  • M. Kohler et al.

    CPAP and measures of cardiovascular risk in males with OSAS

    Eur Respir J

    (2008)
  • P.J. Mills et al.

    Effects of nasal continuous positive airway pressure and oxygen supplementation on norepinephrine kinetics and cardiovascular responses in obstructive sleep apnea

    J Appl Physiol (1985)

    (2006)
  • M.A. Arias et al.

    Pulmonary hypertension in obstructive sleep apnoea: effects of continuous positive airway pressure: a randomized, controlled cross-over study

    Eur Heart J

    (2006)
  • A.N. Vgontzas et al.

    Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia

    J Clin Endocrinol Metab

    (2000)
  • M.J. Armstrong et al.

    Extrahepatic complications of nonalcoholic fatty liver disease

    Hepatology

    (2014)
  • Y.T. Chou et al.

    Hyperlipidaemia in patients with sleep-related breathing disorders: prevalence & risk factors

    Indian J Med Res

    (2010)
  • V. Michailidis et al.

    Continuous positive airway pressure treatment: effect on serum lipids in patients with obstructive sleep apnoea

    Open Cardiovasc Med J

    (2011)
  • G.V. Robinson et al.

    Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials

    Thorax

    (2004)
  • S.R. Coughlin et al.

    Cardiovascular and metabolic effects of CPAP in obese males with OSA

    Eur Respir J

    (2007)
  • S.D. West et al.

    Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes

    Thorax

    (2007)
  • Cited by (148)

    • Obstructive Sleep Apnea in Coronary Artery Disease

      2023, Current Problems in Cardiology
      Citation Excerpt :

      These include: Several studies have shown marked increase of circulating catecholamines and sympathetic over-activation in patients with OSA, which has been linked with resistant hypertension in both animal and human observational studies.19-22 This is predominately mediated by hypoxia-mediated chemoreceptor activation as well as oxidative stress-associated endothelial dysfunction.23,24

    • Obstructive sleep apnea

      2022, Handbook of Clinical Neurology
    View all citing articles on Scopus

    The most important references are denoted by an asterisk.

    View full text