The Relationship of Weight and Obstructive Sleep Apnea

1. The Relationship of Weight and Obstructive Sleep Apnea Mia Zaharna, MD, MPH Stanford Sleep Center, Fellow

2. Objectives • Background • Discuss Obesity as a risk factor for OSA • Discuss relationship of Obesity and OSA to health effects • Discuss Obesity as a consequence of OSA • Discuss Treatment of OSA and its effect on weight and vice versa • Discuss ways that you can effectively control your weight Mia Zaharna - The Relationship of Weight and Obstructive Sleep Apnea

3. Background • Obesity is the most powerful risk factor for obstructive sleep apnea (OSA) • Obesity is essentially the only reversible risk factor • Potentially modifiable risk factors for OSA also include alcohol, smoking, nasal congestion, and estrogen depletion in menopause. • Data suggest that obstructive sleep apnea is associated with all these factors, but at present the only intervention strategy supported with adequate evidence is weight loss. ( Young et al. 2002)

4. Background: Obesity Prevalence (Young et al. 2002)

5. Background: OSA Prevalence • OSA present in 25-58% of men and 10-37% of women (Young et al 1993), (Young et al 2002) • Prevalence increases in middle age • Symptomatic OSA (OSA with EDS) present in 4% of middle aged men and 2% of women (Young et al 2002) • OSA is associated with neurocognitive dysfunction, cardiovascular disease, insulin resistance, dyslipidemia, motor vehicle and occupational accidents • OSA associated with metabolic syndrome (abdominal obesity, dyslipidemia, impaired glucose tolerance, hypertension) but causal link not proven

6. Obesity and OSA • About 70% of those with OSA are obese (Malhotra et al 2002) • Prevalence of OSA in obese men and women is about 40% (Young et al 2002) • Higher BMI associated with higher prevalence • BMI>30: 26% with AHI>15, 60% with AHI>5 • BMI>40: 33% with AHI>15, 98% with AHI>5 (Valencia-flores 2000)

7. Obesity and OSA • Total body weight, BMI, and fat distribution all correlate with odds of having OSA • Every 10 kg increase in weight increases risk by 2X • Every increase in BMI by 6 increases risk by 4X • Every increase in waist or hip circumference by 13 to 15 cm increases risk by 4X (Young et al 1993)

8. Obesity as a Risk Factor For OSA: Structural Factors • Airway obstruction occurs when the nasopharynx and oropharynx are occluded by posterior movement of the tongue and palate against the posterior pharyngeal wall • Narrower airways are more easily collapsible and prone to airway occlusion • Obese people have extrinsic narrowing of the area surrounding collapsible region of the pharynx and regional soft tissue enlargement (Fleetham 1992) • Increased fat deposits posteriolateral to oropharyngeal airspace at level of soft palate, in the soft palate, and in submental area (Horner et al 1989)

9. Oropharynx in Normal and Obese Patient

10. Obesity as a Risk Factor For OSA: Structural Factors • Distribution of fat is an important correlate • Fat accumulation in the central, android (apple shape), and upper body correlate with metabolic syndrome, atherosclerosis, and OSA • Waist circumference more important than BMI, weight, or total fat content • Increased waist circumference predicts OSA even in non-obese (Grunstein 1993)

11. Obesity as a Risk Factor For OSA: Structural Factors Apple shape is riskier than Pear shape

12. Central Obesity and OSA • Anatomic respiratory effects: reduced upper airway size secondary to mass effect of the large abdomen on the chest wall and tracheal traction (Pillar, Shehadeh 2008) • Endocrine effects: The concept of leptin and ghrelin

13. Leptin • Leptin is an appetite suppressant • Leptin associated with satiety, weight control, and fat distribution (central obesity) • Obese and pts with OSA (independently) have high leptin due to leptin resistance rather than as a result of leptin deficiency • Positive correlation between leptin and AHI in OSA • Sleep deprivation/disordered sleep causes decreased leptin making you feel more hungry (Patel et al 2004) • Treatment of OSA with CPAP decreases leptin (after 2 months) and ghrelin levels (after 2 days) (Harsch et al 2003) • ?? Treating OSA could lead to decreased appetite

14. Ghrelin • Ghrelin is an appetite stimulant • Ghrelin levels increase after weight loss • Ghrelin levels higher in OSA pts • Treatment of OSA may reduce ghrelin levels leading to decreased appetite

15. Leptin and Ghrelin ↑Ghrelin ↓Ghrelin

16. Obesity, OSA, Disease conditions, and Disease mechanisms • Obesity and OSA are associated with common disease conditions with overlapping pathogenesis and disease mechanisms, but causation still unclear DiseasesMechanisms • Heart failure - Leptin • Pulmonary htn - Insulin resistance • Chronic CAD - Hypercoagulability • Cerebrovasc.disease - Inflammation • Hypertension - Sympathetic activity • MI - Genetics • Stroke and TIA

17. Obesity, OSA, Disease mechanisms, and Disease conditions (Gami 2003)

18. Can Obesity be a consequence of OSA? • OSA reduces physical activity and exercise performance • OSA reduces energy metabolism • OSA reduces motivation (from underlying comorbidities like depression: several studies have found correlation between OSA and depression) (Baran 2003) • OSA reduces physical activity from sleepiness (Basta 2008)

20. OSA and exercise performance • Grote and colleagues studied 1149 pts with OSA • BP and HR at rest and during graded bicycle exercise to assess cardiovascular reactivity in those with and w/o OSA • Results: Maximal exercise capacity was less in those with OSA • Conclusions: OSA associated with reduced physical work capacity and modified hemodynamic response to exercise • Aguillard and colleagues studied 32 patients with OSA • Performed PSGs and maximal exercise test which served as an objective indicator of fatigue. Also completed FSS as subjective measure of fatigue • Conclusions: Those with poor quality sleep or inadequate amount of sleep showed higher levels of fatigue both subjectively and objectively

21. OSA and energy metabolism • Reduced leptin and increased ghrelin lead to increased hunger and decreased energy metabolism • Vanuxem and colleagues studied 11 pts with OSA • Asked to perform maximal effort and measured on cycloergometer • Decrease in maximum blood lactate concentration suggesting an impairment of glycolytic metabolism and decrease in the rate of lactate elimination indicating a defect in oxidative metabolism seen in those with OSA • Conclusion: OSA linked to impaired muscle energy metabolism

22. Treatment of Obesity and Impact on OSA • I will focus on dietary weight loss • Medical weight loss with appetite suppressants like sibutramine linked to hypertension and arrythmias so unsuitable in OSA patients • Surgical weight loss such as bariatric surgery for BMI >40 or BMI>35 with comorbidities • Multiple studies have shown significant improvements in AHI with lap band and Roux-en-Y

23. Dietary weight loss can improve OSA • Reduces upper airway collapse by modifying anatomy and function • 13% weight loss decreased nasopharyngeal airway collapsibility in obese patients with OSA after diet. All had decrease in AHI. (Suratt 1987) • Improved pharyngeal and glottic fxn and significant decrease in AHI after 26 kg weight loss in obese patients with OSA (Rubinstein 1988) • 14 pts with BMI>40 showed significant reduction inn neck fat on MRI and significant decrease in AHI (24.3 to 2.9) after 10% weight loss (Hernandez 2009) • In 15 obese pts found 8% weight loss decreased nocturnal oxygen desat index significantly (Kansanen 1998)

24. Dietary weight loss can improve OSA • Impact of weight loss is greater in those with severe OSA (AHI>30) and those higher in BMI • In obese patients, even minimal weight loss can be beneficial • Thought to be related to preferential loss of visceral fat first as oppose to subcutaneous fat which has metabolic advantages • Study of 34 pts with BMI<30 and mild to moderate OSA did not show significant decrease in AHI with weight loss in most of the group (Only 8 pts had decrease of AHI to <5) (Lam 2007)

25. Mean change in AHI by weight change category (Peppard et al 2000)

26. Temporary relief of OSA from weight loss? • Sampol and colleagues studied 24 initially obese pts • Despite initial cure of OSA after dietary weight loss (Ave. BMI from 31.5 to 25.9) , OSA recurred in 50% after mean f/u of 94 months, regardless of whether they had regained weight • This favors a clear multifactorial etiology to OSA

27. Treatment of OSA and its effect on weight • Weight loss may be helped by CPAP in obese with OSA in compliant vs. noncompliant (use >4 hrs) (Loube 1997) • 6 mo. of CPAP could reduce intra-abdominal visceral fat and serum leptin even in absence of weight loss (Chin, 1999) • 2 mo. of CPAP assoc. with reduced serum leptin in absence of weight change (Harsch 2003)

28. Treatment of OSA and its effect on weight • Other studies showed no change in visceral fat, weight, and serum leptin despite adherence to CPAP therapy in obese pts with OSA (Vgontzas, 2008) • Small studies that lacked controls • Lacked info on dietary habits and sleep duration • Some studies suggest possible weight gain with CPAP (Redenius, 2008) • BMI of 228 pts measured pre and post CPAP for one year and compared to pts who did not receive CPAP • CPAP assoc. with weight gain in some. None lost weight.

29. How to manage your weight • Reducing caloric intake is the most common form, but difficult long term • Overall median success rate of only 15% during up to 14 yrs of observation (Ayyad 1999) • Reducing calorie intake is most important: portion of fat vs. protein vs. carbs doesn’t matter in regards to weight loss, satiety, hunger, and satisfaction (Sacks et al. 2009) • Diet + exercise is most effective method of weight loss recommended by most doctors

30. How to manage your weight • Diet alone may be just as good as diet and exercise • Metanalysis of 25 yrs of weight loss research on diet alone, exercise alone, vs. diet + exercise • Concluded: 15-week diet or diet plus exercise program, produces a weight loss of about 24 lbs, with a 15 and 19 lb maintained loss after one year, respectively. (Miller 1997) • Many studies suggest diet + exercise provides about a 20% greater weight loss initially than diet alone

31. How to manage your weight • Exercise alone probably doesn’t work that well (Caudwell 2009) • 58 obese men and women ( Ave BMI = 31.8) were prescribed exercise to expend approximately 500 Kcal per session, five times a week at an intensity of 70 % maximum heart rate for 12 weeks • Significant ave. wt loss of 3.2 kg but large variability (loss of 14.7 kg to gain of 2.7 kg) • Differences were accounted for by calorie intake

32. Exercise is important • Exercise can improve sleep • Study in a group of initially inactive adults showed that moderate intensity exercise for 12 months significantly improved both objective (PSG results) and subjective measures of sleep (King et al. 2008) • Exercise in the long run allows your body to be more efficient at burning calories

33. The Weight Loss Rule + > >

34. Conclusions • Complex interrelationship between weight and OSA • OSA may lead to weight gain and weight gain leads to OSA • Losing weight can improve OSA • Unclear if treating OSA leads to weight loss although some studies show this is the case • Diet and exercise as well as diet alone are good weight loss techniques

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38. Insulin Resistance/DM II • OSA pts have higher fasting bl.glucose, insulin, and HgbA1c than weight matched controls w/o OSA (Vgontzas 2000) • Severity correlates with severity of AHI • Correlation is independent of central obesity • Study showed treatment with CPAP over 4 months improved glucose metabolism (Brooks et al 1994) • Effects of OSA and obesity on insulin resistance are additive

39. Hypercoagulability Obese pts have higher plasma prothrombotic factors like fibrinogen, vWF, factor VII, plasminogen activator 1 (De Pergola, 2002) OSA pts have the above and increased platelet aggregation and blood viscosity (Sanner 2000, Chin 1996, Nobili 2000) Exercise, low fat high fiber diet, and CPAP in OSA pts can reverse abnormal coagulation profiles (De Pergola 2002, Sanner 2000, Chin 1996) Linked to states such as MI, stroke, TIA, CAD, CVD

40. Inflammation • Obesity is an inflammatory state (Roytblat 2000), (Visser 1999) • High CRP and IL-6 • Central obesity has higher markers • OSA is an inflammatory state (Shamsuzzaman 2002) • High CPR, IL-6, TNF • OSA inflammatory state may exist independently of obesity • Linked to states such as MI, stroke, TIA, CAD, Cerebrovascular disease, hypercoagulability

41. Sympathetic activity • Pts with OSA have high sympathetic activity when awake, with further increases in blood pressure and sympathetic activity during sleep • Clinically means increased risk of stroke, htn, cardiovascular disease, TIA, cerebrovascular disease • CPAP decreased blood pressure during sleep

42. Genetics • OSA has genetic linkages • Chrom 2p, 19 p • Obesity has genetic linkages • Chrom 2p, 17p, 12p • Data suggests both shared and unshared genetic factors in OSA and obesity (Palmer 2003)