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Obstructive Sleep Apnoea and the Metabolic Syndrome

Dr Muhammed AslamDepartment of Pulmonary Medicine

DM WIMS Meppadi

• Is there any association between OSA and Metabolic syndrome??

• Is there a causality between these two factors ??

Outline

• Introduction• OSA and the Metabolic Syndrome• OSA and Obesity• OSA and Hypertension• OSA and Insulin Resistance• OSA and Dyslipidemia• Pathogenesis • Effect of Treatment• Conclusion

Introduction• The Metabolic Syndrome- Visceral obesity,

Insulin resistance, Hypertension and Dyslipidemia

• Increased cardiovascular morbidity and mortality in OSA, independent of obesity

Introduction• National Cholesterol Education Program Adult

Treatment Panel III - 3 out of 5 clinically identifiable variables : hypertension, glucose intolerance, low serum HDL ,elevated serum triglyceride and abdominal obesity.

• The WHO and the European Group for the Study of Insulin Resistance recommends insulin resistance or glucose intolerance to be an essential criterion

Prevalence of Metabolic Syndrome

• 8% (India) to 44% (native Americans in the USA) in men

• 7% (France) to 57% (native Americans in the USA) in women

Cameron AJ, Shaw JE, Zimmet PZ. The metabolic syndrome prevalence in worldwide populations. Endocrinol. Metab. Clin. North Am.33,351-375 (2004).

Association Between OSA and the Metabolic Syndrome


• Two case controlled studies on Caucasian men - ninefold and sixfold risk


• Community based Chinese study- fivefold risk • A positive correlation between AHI and the

number of metabolic components present


OSA and Obesity• Positive correlation between the severity of

OSA and the degree of obesity• Sleep apnea patients have a greater amount

of visceral fat compared with obese controls matched for BMI

• Suggesting that central or abdominal obesity are more closely associated with OSA than general obesity.

Vgontzas AN et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J. Clin. Endocrinol. Metab.85(3),1151-1158 (2000).

OSA and metabolic dysfunction is a vicious cycle

Pillar G, Shehadeh N. Abdominal fat and sleep apnea: the chicken or the egg? Diabetes Care. 2008;31(Suppl 2):S303–9

OSA and Hypertension• Studies shown that blood pressure level and

the risk of hypertension increased with increasing AHI levels after correction for confounders such as obesity, age and gender.

• AHI of greater than 15 was associated with elevation of 3.6 mmHg and 1.8 mmHg for systolic and diastolic blood pressure, respectively

Young T, Peppard P, Palta M et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch. Intern. Med.157(15),1746-1752 (1997).

OSA and Hypertension

• A study showed that each additional apneic event per hour of sleep was associated with increases of 0.1 and 0.04 mmHg in systolic and diastolic blood pressure, respectively .

(Lavie P, Herer P, Hoffstein V. Obstructive sleep apnea syndrome as a risk factor for hypertension: population study. BMJ320,479-482 (2000).)

• Prospective longitudinal follow up over 4 years confirmed increased risks of developing hypertension that were dependent on the degree of elevation of AHI at baseline (Peppard etal, NEJM)


• Nasal CPAP treatment in OSA have demonstrated reductions in both systolic and diastolic blood pressure and of decrease in mean arterial blood pressure ranged from 2.5 to 10 mmHg.


• Greater treatment related reductions in ambulatory mean blood pressure among patients with more severe OSA and better effective nocturnal use of CPAP device


• Subjects who do not suffer from sleepiness may also behave differently

• 2 randomized interventional trials did not reveal any decrease in blood pressure, despite treatment of severe OSA although another study of mildly sleepy subjects did show a positive effect

Robinson GV, Smith DM, Langford BA et al. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur. Resp. J.27,1229-1235 (2006)

OSA and Insulin Resistance

• Subjects with OSA may have multiple factors like obesity that promote insulin resistance and glucose intolerance

• Positive and independent association between OSA and insulin resistance/glucose intolerance/diabetes

• The increase in insulin resistance attributable to OSA was observed not only in the overweight or obese, but also in the non obese

Obstructive sleep apnea is independently associated with insulin resistance. Am. J. Respir. Crit. Care Med.165,670-676 (2002).


• 3 months of CPAP treatment reduced insulin resistance in sleepy but not in non sleepy OSA subjects with similar AHI levels


• CPAP was found to improve insulin sensitivity after 2 days as well as 3 months of treatment and the improvement was greater in non obese patients with a BMI of less than 30.


• Using the intravenous glucose tolerance test, non diabetic OSA men were shown to have impaired insulin sensitivity as well as impaired insulin secretion.

OSA and Dyslipidemia

• HDL cholesterol levels were inversely related to AHI levels, independent of obesity, in younger men and women, but not in older men

• Triglycerides levels were positively associated with AHI also in younger men and women only


• Sleep clinic subjects with OSA demonstrated a higher prevalence of dyslipidemia compared with those without OSA, after adjustment for BMI

• Few observational studies reported that nasal CPAP treatment improved lipid parameters

• No consistent data from randomized, controlled studies to support that


• 2 randomized, controlled trials demonstrated that the group receiving CPAP treatment had a 15% reduction in total cholesterol level, but the between group difference failed to achieve statistical significance.

Robinson GV, Pepperrell JC, Segal HC, Davies RJ, Stradling JR. Circulating cardiovascular risk factors in obstructive sleep data from randomized controlled trials. Thorax59(9),777-782 (2004).

PATHOGENESIS OF

CARDIOMETABOLIC DYSFUNCTION IN OBSTRUCTIVE SLEEP APNEA

Sympathetic Activation and Other Neurohumoral Changes

• OSA is postulated to be a chronic stress state with activation of neurohumoral pathways that participate in metabolic regulation.

• Studies of OSA subjects demonstrated elevation of sympathetic activity beyond that attributed to obesity.

• Sympathetic overactivity accompany transient increases in systemic blood pressure in phase with sleep apneic episodes, and sympathoadrenal activation persists in the day


• Sympathetic activation leads to vasoconstriction, modulate angiotensin renin system, insulin and adiponectin

• A study in mice found that intermittent hypoxia resulted in insulin resistance, despite abolition of autonomic nervous system activity

Iiyori N, Alonso LC, Li J et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am. J. Respir. Crit. Care Med.175,851-857 (2007).


• Healthy subjects subjected to sleep restriction in the laboratory setting showed upregulation of the hypo thalamic pituitary adrenal axis and somatotrophic axis

• In a population based study, those reporting short sleep duration were found to have higher ghrelin and lower leptin levels, in keeping with promotion of weight gain.

Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med.1(3),e62 (2004).

Intermittent Hypoxia and Oxidative Stress

• Recurrent intermittent hypoxia with reoxygenation may result in generation of oxidative stress leading to cardiometabolic dysfunction

• OSA subjects have been reported to have increased levels of various oxidative stress markers, such as nitric oxide, 8 isoprostane, reactive oygen species and lipid peroxidation

Inflammation

• Evidence for increased inflammation is observed in OSA, independent of obesity

• Inflammation plays a key role in the pathogenesis of endothelial dysfunction, insulin resistance and lipid peroxidation

• This includes activation of neutrophils, lymphocytes, monocytes and platelets; activation of NFκB, increased circulating levels of proinflammatory or prothrombotic substances and decreased levels of antiinflammatory substances

Role of Adiposity

• In obesity, heightened inflammation occurs in adipose tissue and impacts further upon glucose, lipid and energy metabolism.

• Leptin - regulates bodyweight through the control of appetite and energy consumption

• Human obesity is associated with increased leptin levels, probably reflecting a leptin resistant state

Role of Adiposity

• Adiponectin, is an adipokine with antiinflammatory, antiatherogenic and insulinsensitizing actions

• Hypo adiponectinemia was associated with severe OSA, independent of obesity and visceral obesity

Lam JC, Xu A, Tam S et al. Hypoadiponectinemia is related to sympathetic activation and severity of obstructive sleep apnea. Sleep31(12),1721-1727 (2008).

Effect of Treatment for OSA onMetabolic Syndrome

• Most studies on the effects of abolition of OSA focused on individual metabolic components

• Significant improvements in more than one metabolic parameter were reported

Couglin SR, Mawdsley L, Mugarza JA, Wilding JPH, Calverley PMA. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur. Respir. J.29,720-727 (2007).

Dorkova Z, Petrasova D, Molcanyiova A, Popovnakova M, Tkacova R. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest134,686-692 (2008).

Effect of Treatment

• CPAP therapy reduced several components of the metabolic syndrome in patients who used CPAP for 4 h/night for 8 weeks, including blood pressure, triglyceride levels, and glucose levels, compared with patients with low adherence to CPAP (<4 h/night).

Effect of Treatment

• CPAP for 3 months• Treatment with CPAP vs a placebo was associated

with significant mean decreases in systolic blood pressure, diastolic blood pressure, serum total cholesterol levels, low-density lipoprotein cholesterol levels, triglyceride levels, and glycated hemoglobin.

• Is there any association between OSA and Metabolic syndrome??

• Is there a causality between these two factors ??

Conclusion• OSA is highly associated with the metabolic

syndrome or its core components, partly due to the common feature of obesity, but associations independent of obesity have been demonstrated.

• Available Data suggest that inflammation, neurohumeral alterations including sympathetic activation, and oxidative stress are some of the intermediary mechanisms