An Update on Obstructive Sleep Apnea and the Metabolic Syndrome

Jamie Lam; Mary Ip

Curr Opin Pulm Med.  2007;13(6):484-489.  ?2007 Lippincott Williams & Wilkins
Posted 11/02/2007

Abstract and Introduction

Abstract

Purpose of Review: Patients with obstructive sleep apnea are often overweight or obese, and they frequently exhibit metabolic aberrations, collectively known as the metabolic syndrome, an established cardiovascular risk factor. We review recent data on the relationship between obstructive sleep apnea and metabolic syndrome or its components, including abdominal obesity, insulin resistance, hypertension, and dyslipidemia.
Recent Findings: There is accumulating evidence for an independent association between obstructive sleep apnea and metabolic syndrome or its components. Recent epidemiologic and clinical data suggest a causal role of severe obstructive sleep apnea in development of hypertension, but findings for insulin resistance and dyslipidemia are controversial. Visceral obesity remains a confounding issue in analyses. Animal models and translational studies indicate that obstructive sleep apnea may promote metabolic dysfunction through cycles of intermittent hypoxia; proposed underlying pathophysiologic mechanisms include oxidative stress, sympathetic activation, and inflammation.
Summary: There is suggestive evidence, but independent associations between obstructive sleep apnea and metabolic syndrome or its components are not fully established because of the confounding effect of obesity. Large randomized interventional trials are needed to identify any cause-effect relationship. Long-term follow-up studies would help to clarify the role of treatment of sleep apnea in reducing cardio-metabolic morbidity.

Introduction

Obstructive sleep apnea (OSA) is a prevalent condition worldwide, affecting at least 1-5% of middle-aged individuals in various ethnic populations, and obesity has been demonstrated to be a major risk factor.[1-4] There is growing concern regarding the potential adverse health outcomes attributable to OSA, in particular its impact on cardiovascular disease.[5**] It is now recognized that there is a marked association between OSA and the metabolic syndrome,[6,7,8*,9,10*] a cluster of obesity-related cardio-metabolic factors that are known to increase cardiovascular risk.[11,12] Mechanistically, there is accumulating evidence demonstrating that OSA results in many systemic effects that may contribute, independent of obesity, to the generation of various metabolic aberrations or cardiovascular pathology.[5**,13] This review presents recently reported data on the link between OSA and metabolic syndrome, with a focus on the evidence for an independent causal role of OSA in exacerbating cardio-metabolic risk factors.

Metabolic Syndrome

The metabolic syndrome represents a constellation of metabolic derangements, including central obesity, hypertension, glucose intolerance, and dyslipidemia. It is a well recognized risk factor for cardiovascular disease.[11] The National Cholesterol Education Program Adult Treatment Panel III report[12] recommended the use of five variables, with established diagnostic cut-offs, to define metabolic syndrome: hypertension, insulin resistance or glucose intolerance, low serum high-density lipoprotein (HDL)-cholesterol, elevated serum triglyceride, and abdominal obesity. Any individuals satisfying three of these five criteria would be classified as having the metabolic syndrome. These criteria are clinically identifiable, thus making it easy to recognize the metabolic syndrome in practice.

Using the Adult Treatment Panel III definitions, the Third National Health and Nutritional Examination Survey[14] reported that the age-adjusted prevalence of metabolic syndrome in the USA was 23.7%, with the highest prevalence found among Mexican Americans. With the trend toward increasing body weight in many populations in developed and developing countries,[15] the prevalence of metabolic syndrome and its health-related consequences will certainly increase.

Obstructive Sleep Apnea and the Metabolic Syndrome

Over the years, many studies have investigated the relationship between OSA and various cardio-metabolic parameters. More recently, studies have emerged regarding the relationship between OSA and metabolic syndrome.[6,7,8*,9,10*,16] Compared with non-OSA control individuals, OSA was found to be independently associated with individual metabolic parameters in the metabolic syndrome as well as with an increased prevalence of metabolic syndrome, with an odds ratio of 9.1.[6] A study of similar design found OSA to be independently associated with metabolic syndrome but not with insulin resistance.[9] A community-based study conducted in Chinese adults in Hong Kong[7] identified a fivefold increased risk for having metabolic syndrome in individuals with OSA, and the severity of OSA correlated with number of components of the metabolic syndrome. A marked association of sleep disordered breathing (SDB) and metabolic syndrome was also identified in adolescents.[10*] In a study that included a group of control individuals who were matched for obesity,[17*] however, those with OSA exhibited no increase in the proportion having metabolic syndrome, though they had a comparatively worse metabolic profile. These studies recruited mostly obese individuals, whereas a case controlled study of nonobese Japanese men matched for visceral fat[18*] found OSA to be associated with hypertension, dyslipidemia, and hyperglycemia, suggesting that even nonobese persons with OSA may also be prone to development of metabolic syndrome.

Studies on the effect of treatment for OSA have largely dealt with individual metabolic variables rather than the metabolic syndrome entity. In a randomized placebo-controlled crossover trial conducted in obese patients with severe OSA,[19*] 6 weeks of treatment with continuous positive airway pressure (CPAP) reduced waking blood pressure but did not produce any improvement in the other components of the metabolic syndrome, or in the proportion of patients with metabolic syndrome. The presence of metabolic syndrome in patients with OSA treated with CPAP did not appear to confer additional cardiovascular risk compared with those who did not have metabolic syndrome.[16]

Mechanistically, recurrent obstructive events with cyclic intermittent hypoxia and sleep fragmentation are believed to be the key triggers of various pathogenetic mechanisms in OSA, including sympathetic activation, cellular oxidative stress, and systemic inflammation,[5**,13,20,21] leading to characteristic features of the metabolic syndrome. Intermittent hypoxia followed by reoxygenation may result in increased oxidative stress, which is a fundamental cellular pathogenic process in metabolic and cardiovascular function.[20,21,22*,23] A number of observational studies have demonstrated that OSA is independently associated with increased markers of oxidative stress.[20,21,22*,23,24] Intermittent hypoxia may selectively upregulate inflammatory pathways over adaptive pathways,[25] and generate cytokines and other mediators that modulate metabolic and vascular functions.[26] OSA is associated with heightened sympathetic activation both at night and in the day,[27] and this is believed to be an important mechanism in the pathogenesis of hypertension in OSA.[28] Sympathoadrenal and other neurohumoral activations are also putative mediators of insulin resistance.[29**] The above mechanisms have intricate interactions, with multidirectional positive or negative feedback among them.[13].

Obstructive Sleep Apnea and Obesity/Visceral Obesity

Obesity and visceral obesity are associated with an array of health risks, the most notable of which are type II diabetes and cardiovascular disease, and OSA has recently joined the list. Although OSA also occurs in lean individuals, adiposity is still a major risk factor in various ethnic populations.[2-4] A 10% weight gain was associated with a sixfold increase in the odds of developing sleep apnea, a 10% weight loss predicted a 26% decrease in the apnea-hyponea index (AHI),[30] and every 6 kg/m2 increment in BMI increased the risk for developing OSA by more than fourfold.[31] OSA has also been shown to be closely related to visceral obesity, even more so than BMI.[32] There are ethnic differences in attributable health risks, and therefore the threshold criteria for abdominal obesity recommended by the World Health Organization for Asians are lower than for Caucasians.[33] In the elderly OSA is not as closely associated with obesity.[31] In young children adenotonsillar hypertrophy is a major risk factor, although this has been overtaken by obesity in prepubertal children and adolescents in recent years.[34*]

Visceral fat is now known to be a metabolically active tissue, which produces large amounts of proinflammatory or vasoactive substances,[35] giving rise to metabolic dysregulation and atherogenesis. Hence, the study of the cardio-metabolic consequences attributed to OSA per se is notoriously confounded by coexistent adiposity. On the other hand, OSA may well modulate the expression of adipokines, cytokines, or hormones in adipose tissues, which may contribute systemically to the development of various features of metabolic syndrome and cardiovascular disease.[35,36] The role in OSA of leptin, one of the known adipocytokines, has been explored, but the data are conflicting because of the significant confounding effect of obesity.[5**] In a study including a group of control individuals matched for obesity, serum leptin was significantly higher in those with OSA, suggesting that OSA may indeed be a leptin-resistant state.[17*]

Although obesity is believed to be an etiologic risk factor for OSA, SDB may also feedback to obesity. Sleep disturbance and sleep loss, through as yet ill defined mechanisms, may both adversely affect insulin and glucose homeostasis and predispose to weight gain.[37] Furthermore, OSA may promote weight gain through increased insulin resistance or leptin resistance.[38] Thus, there is potentially a vicious cycle between OSA and metabolic dysfunction.[13]

Obstructive Sleep Apnea and Insulin Resistance/Glucose Intolerance/Diabetes Mellitus

Insulin resistance and visceral obesity are considered to be at the core of the constellation of risk factors that define the metabolic syndrome.[11] Insulin resistance is strongly associated with visceral obesity. OSA exhibits pathophysiologic mechanisms that may potentially contribute to the development of insulin resistance, including autonomic activation, alterations in neuroendocrine function, direct effects of hypoxemia on glucose regulation, and release of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-?.[29**,39,40]

A number of studies have looked at the association between OSA and insulin resistance/glucose intolerance.[29**,39] Epidemiologic data from the Sleep Heart Health Study[41] suggested that patients with mild or moderate to severe OSA have increased risks for fasting glucose intolerance after adjustment for confounding factors. Previous clinical studies including smaller samples of patients have yielded conflicting results, whereas recent studies have more consistently demonstrated an independent association between OSA and insulin resistance in adults,[29**,39-42] although this is by no means a universal finding.[43] In pediatric age groups, the results have also been conflicting.[10*,34*]

Insulin resistance is the hallmark of type II diabetes. A study of 1682 diabetic men in the UK[44*] estimated OSA prevalence at 23%, and OSA was significantly associated with diabetes, independent of age, BMI, and neck size. The Wisconsin Cohort Study[45] reported that 3% of individuals with an AHI below 5 had a diagnosis of type II diabetes, whereas 15% of those with an AHI of 15 or greater had diabetes, at a twofold relative risk after adjustment for age, sex, and body habitus. A 4-year follow up, however, did not confirm an increased incidence of diabetes after controlling for confounding factors, and thus a causal role for SDB in the development of diabetes cannot be established.

Interventional data on OSA and insulin resistance have mostly been observational, involving small samples of individuals. The effect of CPAP treatment on insulin resistance in nondiabetic OSA patients has been conflicting, and most studies failed to demonstrate any significant effect,[40] whereas one study showed improvement mainly in nonobese individuals.[46] Recently, a randomized controlled cross-over study of obese OSA men[19*] did not demonstrate any effect of CPAP treatment for 6 weeks on insulin resistance. Observational studies in OSA patients with diabetes[47,48] suggested that CPAP treatment may result in better glycemic control. These findings must be corroborated by randomized controlled trials before any conclusions can be drawn.

The effect of OSA on glucose homeostasis has been investigated in animal experiments. Exposure to chronic intermittent hypoxia led to an increase in insulin resistance in leptin-deficient obese mice.[49] Sympathetic activation is a putative mechanism in the development of insulin resistance in OSA, but a study of acute intermittent hypoxia in lean mice showed that insulin resistance occurred independent of autonomic activation.[50]

In summary, although there is growing evidence for an independent contribution of OSA to insulin resistance, the picture is far from complete.

Obstructuve Sleep Apnea and Hypertension

OSA is frequently associated with hypertension. The etiology of hypertension in OSA patients is probably multifactorial, with environmental, dietary, and genetic inputs involved.

Several potential mechanisms may mediate the association of OSA with hypertension, including sympathetic activation, resetting of arterial chemoreceptor response, decreased baroreceptor sensitivity, and release of vasoactive mediators with altered endothelial and vascular function, and abnormal salt and water metabolism.[5**,23,27,51,52]

Epidemiologic and large cross-sectional studies have consistently demonstrated an association between OSA and hypertension, independent of obesity.[52] The association was found even in mild OSA,[53] whereas those with moderate OSA had almost three times greater risk for developing hypertension than did control individuals with no documented SDB events.[53] There was also a dose-response association between SDB at baseline and the presence of hypertension at 4 years of follow up, independent of age, sex, BMI, and neck circumference. The findings suggest that SDB is likely to be a risk factor for hypertension and consequent cardiovascular morbidity in the general population.

The evidence for a causal role of OSA in the development of hypertension was consolidated by data from randomized trials comparing therapeutic CPAP with sham or subtherapeutic CPAP,[19*,54-57] which showed a blood pressure lowering effect in the group receiving active treatment. Although association studies have demonstrated a relationship between hypertension and even mild to moderate sleep apnea,[53,58,59] interventional studies have only been able to demonstrate an effect in severe OSA,[54] but not in mild or moderate OSA.[60] Given the high prevalence of mild to moderate OSA in the general population, determining whether treatment of OSA in this group will confer a beneficial effect on blood pressure is important. Evidence for a pre-emptive effect of treatment of OSA on development of hypertension, which will confirm a causal role for OSA, must await the completion of long-term randomized controlled trials. Furthermore, CPAP therapy appeared to produce no effect on blood pressure in OSA patients who were not sleepy[61,62*] Thus, current practice guidelines consider treatment of OSA for its blood pressure lowering effect as 'optional due to inconsistent and variably conclusive evidence.'[63**] In the clinical scenario, the decision is likely to be guided by the severity of OSA and hypertension, and the presence of sleepiness and other cardiovascular comorbidities.

Obstructive Sleep Apnea and Dyslipidemia

Abnormal lipid profiles have frequently been reported in patients with OSA. In the Sleep Heart Health Study of over 6000 men and women,[64] there was an inverse relationship between AHI and HDL-cholesterol levels and a positive association between AHI and triglycerides, especially in younger individuals, on adjustment for confounding factors. Case controlled studies also demonstrated that OSA patients had more adverse lipid profiles than did BMI-matched individuals without OSA,[5**,6,43] although the affected lipid parameters were different.

There are limited interventional data on OSA and dyslipidemia. Pooled data from two randomized controlled trials demonstrated that the group treated with therapeutic CPAP for 1 month experienced a significant decrease in serum total cholesterol, but the difference between changes in the therapeutic CPAP and sham CPAP groups failed to reach statistical significance.[65] An observational study[66] found a small but significant improvement in HDL-cholesterol after 6 months of CPAP therapy, which was most evident in those with abnormal baseline values. The previously cited randomized study[19*] found no changes in lipid profiles between therapeutic and sham CPAP treatment for 6 weeks, however. Studies with larger sample size and longer follow-up periods would be useful in further delineating treatment responses.

Other than affecting the circulating levels, sleep apnea may modulate the functions of lipids. Low-density lipoprotein (LDL)-cholesterol is much more atherogenic in an oxidized form, and individuals with OSA have been reported to exhibit lipid peroxidation, with higher levels of oxidized LDL-cholesterol compared with non-OSA individuals.[67] Furthermore, a lower capacity for HDL-cholesterol to protect LDL-cholesterol from oxidation was found in OSA, and the degree of HDL dysfunction correlated with the severity of OSA and oxidative stress.[68*]

Corroborative evidence is emerging from animal studies. Exposure to intermittent hypoxia caused an upregulation of lipid biosynthesis and dyslipidemia[69,70] and led to lipid peroxidation in the liver in a dose-dependent manner.[71]

Conclusion

With the sweeping obesity epidemic, the prevalence of both OSA and the metabolic syndrome are expected to increase significantly. New insights into the metabolic and cardiovascular risks in OSA are emerging. Because of the common feature of visceral obesity, the association between OSA and metabolic syndrome is not unexpected, but the key issue remains whether OSA itself contributes to the initiation or aggravation of these cardio-metabolic aberrations. A causal role played by SDB in hypertension among those with severe symptomatic OSA is supported by good evidence, but independent associations and cause-effect relationships with insulin resistance and dyslipidemia are controversial. Data on the entire spectrum of SDB, especially in the mild and moderate categories, as well as information on the relationship of OSA and metabolic syndrome in females, are scant. Further interactions with environmental factors and personal susceptibility may contribute to final health outcomes in the individual.[22*] Large randomized trials of longer follow-up duration are required to clarify causal relationships and explore the potential for treatment of OSA to mitigate against cardiovascular morbidity and mortality. Clinically, a high index of awareness and early identification of metabolic risk factors in OSA subjects, and vice versa, would be of benefit in terms of patient care.

References

Papers of particular interest, published within the annual period of review, have been highlighted as:
* of special interest
** of outstanding interest

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Abbreviation Notes

AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; HDL = high-density lipoprotein; LDL = low-density lipoprotein; OSA = obstructive sleep apnea; SDB = sleep disordered breathing.

Reprint Address

Correspondence to: Mary S.M. Ip, MD, University Department of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China Tel: +852 28554455; fax: +852 28162863; e-mail: msmip@hkucc.hku.hk


Jamie C.M. Lam, Mary S.M. Ip, University Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong SAR, China