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

1. Obstructive Sleep Apnoea and the
Metabolic Syndrome
Dr Muhammed Aslam
Department of Pulmonary Medicine
DM WIMS Meppadi

2. • Is there any association between
OSA and Metabolic syndrome??
• Is there a causality between these two
factors ??

3. 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

4. Introduction
• The Metabolic Syndrome- Visceral obesity,
Insulin resistance, Hypertension and
Dyslipidemia
• Increased cardiovascular morbidity and
mortality in OSA, independent of obesity

7. 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

8. 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).

9. Association Between OSA and the
Metabolic Syndrome

10. Association Between OSA and the
Metabolic Syndrome
• Two case controlled studies on Caucasian men -
ninefold and sixfold risk

11. Association Between OSA and
the Metabolic Syndrome
• Community based Chinese study- fivefold risk
• A positive correlation between AHI and the
number of metabolic components present

12. Association Between OSA and the
Metabolic Syndrome

13. 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).

14. 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

15. 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).

16. 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)

17. OSA and Hypertension
• 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.

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

19. OSA and Hypertension
• 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)

20. 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).

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

23. OSA and Insulin Resistance
• 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.

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

25. 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

26. OSA and Dyslipidemia
• 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

27. OSA and Dyslipidemia
• 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).

28. PATHOGENESIS OF
CARDIOMETABOLIC DYSFUNCTION IN
OBSTRUCTIVE SLEEP APNEA

29. 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

30. Sympathetic Activation and Other
Neurohumoral Changes
• 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).

31. Sympathetic Activation and Other
Neurohumoral Changes
• 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).

32. 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

33. 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

34. 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

35. 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).

38. Effect of Treatment for OSA on
Metabolic 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).

39. 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).

40. 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.

41. • Is there any association between
OSA and Metabolic syndrome??
• Is there a causality between these two
factors ??

43. 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