Chapter 18

Weight-loss treatment for OSA: medical and surgical options

C.L. Chang*,#, N.S. Marshall*, B.J. Yee*,# and R.R. Grunstein*,#

Summary
The public health impact of obstructive sleep apnoea (OSA) is increasingly recognised and will rise in conjunction with the obesity epidemic. Current clinical management of OSA focuses on device-based interventions, which do not correct underlying obesity. Various approaches to weight loss have been tested, including diet and behavioural modification programmes, pharmacological interventions and bariatric surgery. Emergent clinical trials demonstrate that intensive diet and behavioural interventions can reduce weight, and this will substantively reduce OSA severity. However, there is little longterm or subgroup data. Pharmacological interventions alone provide minimal weight loss and potentially unacceptable side-effect profiles as highlighted by the recent withdrawal of sibutramine. Bariatric surgery can markedly reduce obesity and is an effective OSA treatment but there is little good-quality long-term outcome data specific to OSA. The relative effectiveness and safety profiles of various bariatric surgeries, pharmacotherapies or behavioural/diet interventions either in combination or in comparison are unstudied. The multi-comorbidity of OSA lends itself to a multidisciplinary approach incorporating dieticians, physiotherapists, psychologists, exercise physiologists, sleep physicians and surgeons. Keywords: Obesity, obstructive sleep apnoea, pharmacotherapy, surgery, weight loss
*National Health and Medical Research Council Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, and # Sleep Investigation Centre, Edinburgh Building, Royal Prince Alfred Hospital, Camperdown, Australia. Correspondence: C.L. Chang, Woolcock Institute of Medical Research, PO Box M77 Missenden Rd, Camperdown NSW 2050, Sydney, Australia, Email contact_ cat@hotmail.com

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Eur Respir Mon 2010. 50, 302320. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00025409

bstructive sleep apnoea (OSA) is characterised by loud snoring and repetitive closure of the upper airway during sleep with increased respiratory efforts to overcome airway closure, leading to arousals and sleep fragmentation [1]. Risk factors for developing OSA include male sex, age, genetic predisposition (familial and ethnic), cranio-facial anatomical differences, menopause

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and obesity [2]. Of these, obesity has been consistently identified as the strongest risk factor in both population- and clinic-based studies [39]. In the Wisconsin Sleep Cohort, a 1 SD increase in body mass index (BMI) was associated with a four-fold increase in OSA prevalence [3]. Longitudinal observations have confirmed both that weight gain predisposes to a worsening apnoea/hypopneoa index (AHI) and that weight loss works in the opposite direction [1012]. In conjunction with long-standing clinical observations, there is no doubt that obesity is the major modifiable risk for sleep apnoea and offers an excellent target intervention from both a clinical and public health point of view. Obesity is thought to cause OSA through a number of mechanisms. Increased body weight can alter normal sleeping upper airway function in several ways: 1) increased parapharyngeal fat deposition can change airway anatomy; 2) changes in neural compensation and the stability of the respiratory control centres can reduce airway patency and increase collapsibility; 3) reduction in lung volume caused by visceral/abdominal obesity can reduce upper airway traction and increase collapsibility; 4) obesity may be involved in chemoreflex regulation via neurohormonal mediators such as leptin, the level of which decreases as sleep apnoea patients lose weight [1315]. The distribution of body fat (visceral versus non-visceral) is also important and ongoing work suggests visceral adiposity is independently associated with OSA [16, 17]. The current treatment of OSA focuses on alleviation of symptoms by increasing airway patency during sleep through positive airway pressure, oral appliances or changes in sleep position [18]. Continuous positive airway pressure (CPAP) is currently the treatment of choice and when worn correctly at the appropriate dose of pressure, it prevents upper airway obstruction, resulting in improved sleep architecture and daytime symptoms, as well as reduced blood pressure with possible subsequent cardiovascular risk reduction [1922]. Despite proven efficacy, adherence to CPAP treatment is often suboptimal. In studies that used o4 h per night to define adherence, 29 83% of patients were non-adherent [23]. Barriers to adherence included mask discomfort, claustrophobia, nasal congestion, local irritation and psychosocial stigmatisation [23, 24]. Interventions to improve CPAP adherence, such as humidification of the air delivered and cognitive behavioural therapy, only partially alleviate these issues. Oral appliances are less efficacious than CPAP therapy and are only recommended for use in patients with mild-tomoderate OSA who cannot use CPAP [18]. Device-based treatments (whether CPAP or oral appliances) are only efficacious when used. They do not correct the underlying pathophysiology of sleep apnoea. Long-term adherence to current device-based treatment remains poor, so related chronic complications are usually only temporarily forestalled. Thus, disease modification through reduction in weight (the only major modifiable risk factor for OSA) should be central to any long-term management plan. Treatment of excess body weight has wide-ranging benefits beyond OSA. A BMI of .25 kg?m-2 was linearly associated with all-cause mortality in the Prospective Studies Collaboration, which found increased mortality from ischaemic heart disease, stroke, diabetes, chronic kidney disease, neoplastic disease (liver, kidney, breast, endometrial, prostate and colon) and respiratory diseases [25]. This analysis of almost 900,000 adults found a 30% increase in all-cause mortality with each increase of 5 kg?m-2 above a BMI of 25 kg?m-2. Excess body weight is also associated with: considerable morbidity, increased rates of hypertension, dyslipidaemia, diabetes mellitus, gout, heart disease, stroke, dementia, hepatobiliary disease, osteoarthritis, and a variety of cancers [2632]. Weight loss has been shown to reduce risk in many of the above comorbid conditions, reduce overall mortality and improve quality of life [3335]. Therefore, successful weight loss and weight maintenance in obese patients with OSA should result in multifold prognostic benefits beyond those currently achievable with device-based treatment. This chapter examines the current evidence for weight reduction as a treatment for OSA. Current weight loss interventions can broadly be categorised under diet/lifestyle, pharmacotherapy and bariatric surgery. Interpretation of some evidence is complicated by the lack of consistency in how severity of OSA has been reported across studies. This chapter focuses, due to necessity, on AHI or

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respiratory disturbance index (RDI) as measures of OSA severity and BMI as the measure of excess body weight. Most published studies only report OSA severity in terms of RDI or AHI, without including data on other severity measures such as nocturnal oxygen saturation, or patient-centred outcome measures such as quality-of-life. A significant proportion of studies does not objectively re-measure OSA severity after weight loss. Indeed, full channel supervised polysomnography is perhaps under-used even in trials specifically studying weight loss for sleep apnoea. Similarly, most studies report BMI while only a few include additional anthropometric measurements or assess visceral fat content. The most recent advances on this subject are on the effect of diet and behavioural change. This is not an exhaustive systematic chapter, but we have preferentially included studies higher in the evidence-based hierarchy. In the absence of randomised controlled trials, particularly of surgical approaches, we have also reviewed some large cohort studies.

Diet, exercise and behavioural programmes

Introduction and effectiveness in obesity management
Modifications in diet, exercise and lifestyle remain central to achieving weight loss. The aim of dietary therapy is to create an energy deficit by reducing caloric intake to below expenditure. However, there are several well-recognised difficulties in estimating daily caloric requirements due to marked variability in adherence and energy expenditure. Food records are often inaccurate: most people under-report food intake by 1030% while overweight people may under-report food intake by .30% [36]. Energy expenditure is also influenced by sex, age, genetics and behavioural factors, such as non-exercise activity thermogenesis (NEAT) [3739]. Diets of ,800 kCal (3.3 MJ) per day are termed very low calorie diets (VLCD).
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A systematic review of clinical trials addressing weight loss, all of which had a minimum of 1-yr followup, concluded that lifestyle advice and exercise alone resulted in minimal weight loss, and a combination of exercise and diet (whether standard, meal replacement or VLCD) was required for significant weight loss [40]. Regardless of the type of intervention, weight loss tends to plateau at ,6 months on average. VLCD are associated with the greatest weight loss of all behavioural interventions studied.

Effectiveness in obese patients with OSA

Dietary and lifestyle modification with the goal of inducing weight loss have been included in clinical guidelines for the management of OSA for some time [18]. However, until recently there was a paucity of well-conducted studies investigating the effect of dietary- and lifestyle-induced weight loss on OSA. Early case series and treatment cohorts demonstrated that dietary counselling and low caloric diets resulted in substantial weight loss (-9 to -21 kg) with associated improvements in the AHI, nocturnal oxygenation, blood pressure and daytime somnolence [4146]. These studies were nonrandomised and largely uncontrolled. Other potential limitations may have included small size, limited follow-up and a wide variability in the severity of obesity and/or sleep apnoea studied. By 2006, an American Academy of Sleep Medicine Task Force review of medical therapy for OSA could find no studies rated above level II evidence, and only three controlled studies examining the effect of diet-induced weight loss on AHI [47]. A Cochrane review of lifestyle modification (weight loss, sleep hygiene or exercise) for OSA updated in April 2008 identified no randomised controlled trials for inclusion in a planned meta-analysis [48]. Three landmark randomised controlled trials were published in 2009 that addressed the role of diet and lifestyle in the treatment of mild, moderate and severe OSA [4951], providing the first robust evidence for the benefits of weight loss in this population. The findings of these studies are also summarised in table 1.

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Table 1. Prospective randomised controlled trials evaluating the effects of diet and lifestyle modification on weight and obstructive sleep apnoea (OSA) J OHANSSON [49]: moderate-to-severe OSA treated with CPAP Control 33 30 139 Intervention Control F OSTER [51]: OSA plus type II diabetes Intervention 125

T UOMILEHTO [50]: mild OSA Intervention 35

Control

Subjects Baseline characteristics Sex Males Females Age yrs Weight kg BMI kg?m-2 Waist circumference cm ESS AHI total Mean Sa,O2 % Minimum Sa,O2 % ODI o4% % of time Sa,O2 ,90% Intervention 26 9 51.89.0 101.211.9* 33.42.8* 112.58.7* 10.15.0 10.03.0 93.81.5 Not stated Not stated 2.85.2 12-week VLCD plus supervised lifestyle modification 12 months 5 -10.76.5* -3.52.1* -11.66.6* -3.14.0 -4.05.6* 0.81.2* 9 weeks 2 1.11.9 0.30.6 Not stated 13 -211 Not stated
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27 10 50.98.6 92.311.3 31.42.7 105.38.3 9.94.8 9.33.0 94.31.4 Not stated Not stated 1.73.6 Single-session lifestyle counselling 9 weeks 0 -18.74.1* -5.71.1* Not stated -35* -2517* Not stated

33 0 49.97.1 111.713.7 34.82.9 120.58.6 75 3714 Not stated 825 2514 Not stated Usual diet

30 0 47.57.5 113.414.8 34.42.9 120.19.0 95 3717 Not stated 826 2615 Not stated 7-week VLCD plus 2-week bridge diet

60 79 61.36.4 102.017.1 36.55.7 115.712.1 Not stated 23.515 Not stated Not stated 20.213.7 Not stated Three-group support session on lifestyle

12 months 4

12 months 23 -0.60.7 -0.20.3 -0.50.6 Not stated 4.21.4 Not stated

48 77 61.26.6 102.919.6 36.85.8 115.814.4 Not stated 22.918 Not stated Not stated 18.616.1 Not stated 4-month portion-controlled diet plus prescribed exercise 12 months 22 -10.80.7* -3.80.3* -9.30.7* Not stated -5.41.5* Not stated

Follow-up duration Drop-outs Change at follow-up Weight kg BMI kg?m-2 Waist circumference cm ESS AHI total Mean Sa,O2

-2.45.6 -0.82.0 -3.06.0 -2.12.9 0.38.0 -0.31.3

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Data are presented as n or mean SD, unless otherwise stated. BMI: body mass index; ESS: Epworth Sleepiness Scale; AHI: apnoea/hypopnoea index; ODI: oxygen desaturation index; VLCD: very low calorie diet. *: p,0.05 when comparing control and intervention group data.

Mild OSA
In the study by TUOMILEHTO et al. [50], 72 overweight subjects (mean BMI 32 kg?m-2) with mild OSA (AHI 5 15 events?h-1) were randomised to a 12-week VLCD programme (600800 kCal?day-1), with supervised lifestyle modification or with routine, single-session lifestyle counselling. Subjects undergoing other treatment for OSA were excluded. At 1 yr, the treatment group had lost more weight than the control group (-10.7 versus -2.4 kg; p,0.001) and had a greater reduction in BMI (-3.5 versus -0.8 kg?m-2; p,0.001). This was associated with a reduction in AHI of 4 events?h-1, whereas the controls had no significant change in AHI (p50.017). The treatment group also demonstrated improved serum triglyceride levels, and better pharmaceutical discontinuation rates for diabetes, hypercholesterolaemia and hypertension. Randomisation was not stratified for BMI in this study and the treatment group was by chance heavier than the control group at baseline. Despite this, a higher proportion of the treatment group (63 versus 35%) achieved OSA remission with AHI ,5 events?h-1 at 1-yr follow-up (p50.005). The apparent baseline BMI difference between treatment groups did not affect the overall treatment efficacy (p50.818). Moreover, changes in AHI during the 12-month followup were strongly associated with changes in weight. The study by TUOMILEHTO et al. [50] convincingly demonstrated that an intense dietary and lifestyle programme can achieve significant improvements in mild OSA and that the achieved beneficial outcomes can be maintained at 1 yr. Although asymptomatic mild OSA has yet to be conclusively linked with poorer outcomes, it is undoubtedly an important step on the way to moderateto-severe disease [50]. Weight loss can clearly play a role in avoiding disease progression from mild to more severe disease. We await the planned publication of 2and 4-yr follow-up data from this study.

Intervention Intervention Intervention Control Control Control

F OSTER [51]: OSA plus type II diabetes

J OHANSSON [49]: moderate-to-severe OSA treated with CPAP

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T UOMILEHTO [50]: mild OSA

Not stated 1.86.3 Not stated 1335

Not stated -1.74.1 Not stated 2263*

05 Not stated -19 0

56* Not stated -1914* 517*

Not stated Not stated 1.21.3 43.4

Not stated Not stated -5.51.4* 1413.6*

Moderate-to-severe OSA concomitantly treated with CPAP

Moderate and severe OSA in middle-aged people is associated with significant morbidity and mortality [19, 5254]. A Swedish study examined the effect of VLCD in a 9-week, open label, randomised controlled trial [49]. JOHANSSON et al. [49] randomised 63 obese males (mean weight 112.5 kg, mean BMI 34.434.8 kg?m-2) with moderate-to-severe OSA (mean AHI 37 events?h-1), all of whom were treated with CPAP to a 9-week VLCD programme (2.3 MJ?day-1) or usual diet. After 9 weeks, the treatment group lost significantly more weight than the control group (-18.7 versus 1.1 kg; p,0.001), with

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Table 1. Continued

Minimum Sa,O2 % of time Sa,O2 ,90% ODI o4% % patients with AHI ,5

an associated reduction in BMI (-5.7 versus 0.3 kg?m-2; p,0.001). The mean AHI (measured when patients were off CPAP) was substantially reduced in the treatment group: 12 events?h1 (SD 7, range 130) compared with 35 events?h-1 (SD 14, range 1475) in the controls (p,0.001). In the treatment group, 17% of patients no longer had OSA (AHI ,5 events?h-1) and a further 50% had only mild disease (AHI 515 events?h-1). There were also associated improvements in nocturnal oxygen desaturation and subjective symptoms, as quantified by the Epworth Sleepiness Scale (ESS). Interestingly, the study showed that patients with severe OSA derived more benefit from weight loss compared with those with moderate disease at baseline (the changes in AHI from baseline were -38 and -12 events?h-1, respectively), despite little difference in the amount of weight lost. JOHANSSON et al. [49] provided the first high-quality evidence that moderate-to-severe OSA can be substantially modified, at least in the short-term, by traditional weight-loss methods. As weight regain is common in the long-term [40], the obvious limitation of the study by JOHANSSON et al. [49] is the short follow-up duration. Control patients crossed into the same VLCD treatment in phase II of this study and the cohort will complete 1-yr follow-up in April 2010 (personal communication: K. Johansson, Karolinska Institute, Stockholm, Sweden).

OSA with type II diabetes with or without concomitant CPAP

The randomised controlled study by FOSTER et al. [51] looked at the effect of weight loss in patients with OSA and type II diabetes mellitus. This group with known metabolic dysfunction is at high risk of morbidity and mortality and therefore stands to benefit substantially from obesity reduction. As part of the much larger Look AHEAD (Action for HEAlth in Diabetes) study [55], FOSTER et al. [51] randomised 264 obese subjects (mean weight 102.4 kg, mean BMI 36.7 kg?m-2, 59.1% female) with type II diabetes and previously untreated OSA (mean AHI 23.2 events?h-1: 39% mild, 35% moderate, 26% severe) to intense lifestyle intervention with portion-controlled diet and prescribed exercise, or to standard support. The treatment group lost significantly more weight (-10.8 versus -0.6 kg; p,0.001) than the control group at 1 yr and had associated reductions in AHI (-5.4 versus 4.2 events?h-1; p,0.001). At 1 yr, remission of OSA (AHI ,5 events?h-1) was achieved by 13.6% of the intervention group versus 3.5% of the control group. In conjunction, the prevalence of severe OSA had fallen from 28 to 18% in the intervention group versus an increase from 29 to 38% in the controls. The study also found that obese patients with severe OSA benefited more from weight loss compared to patients with only mild disease, in line with the findings of JOHANSSON et al. [49]. Furthermore, despite no change in weight after 1 yr, there was significant worsening of OSA severity in the control group, with a mean increase in AHI of 4 events?h-1. JOHANSSON et al. [49] suggest that untreated OSA in this group of patients may have a relatively rapid natural progression of disease severity. Importantly, despite communicating the diagnosis and severity of OSA to both the patient and their primary care physicians after baseline polysomnography (PSG), ,5% of patients were on CPAP treatment at 1-yr follow-up. This poor treatment uptake rate in a group of patients with co-existing metabolic dysfunction is concerning and underscores the importance of potential disease-altering treatments such as weight loss. It may also reflect the lack of acceptability of CPAP in the community and with other medical practitioners. Follow-up of both treatment and control arms is planned at 4 yrs and may further our understanding of long-term weight maintenance and progression of disease in this population.

Summary
These three randomised controlled studies have provided significant support for diet and lifestyle change in the management of OSA. We now know it is possible to significantly reduce disease severity, alleviate symptoms and perhaps even affect remission with dietary measures in conjunction with a well-structured lifestyle-change programme. Clinically, these results suggest that a structured multi-disciplinary approach with access to trained dieticians, exercise physiologists, obesity physicians and psychologists should be a part of the standard treatment plan in sleep apnoea management. However, the most efficacious and tolerable programme still has to be determined. All three treatment arms involved time- and resource-intensive follow-up,

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as well as highly motivated and carefully selected participants, raising concerns regarding the generalisability of such intervention programmes. Furthermore, significant inter-patient variability in the ability to lose weight was observed in all three studies and females were under-represented or absent in two of the three studies. It is noteworthy that all of the above randomised controlled trials used portable home monitoring rather than full-channel supervised PSG to define OSA. The restrictions of limited channel studies versus gold standard supervised PSG are beyond the scope of this chapter. Practically, this raises the possibility that the AHI measurements in these studies may not match full, in-laboratory PSG measurements as recommended by guidelines [56].

Further research questions

Further study is still required to address the viability of long-term weight maintenance and whether improvements in sleep-disordered breathing are sustained over time. KAJASTE et al. [57] have shown that significant weight maintenance at 24 months after dietary and psychological intervention (-12.6 kg and -9% total body weight from baseline) and associated improvements in sleep apnoea are achievable in this population. However, a long-term cohort (mean follow-up 7.8 yrs) showed that sleep apnoea may recur in some patients without weight regain [41]. Furthermore, the interaction, if any, between CPAP therapy and dietary/lifestyle intervention is poorly studied. Theoretically, concomitant use of CPAP may enhance and maintain weight loss by improving daytime somnolence, but this has yet to be demonstrated. In the study by KAJASTE et al. [57], obese OSA patients who used concomitant CPAP treatment lost a similar amount of weight to those who did not use CPAP and who were undergoing the same weight-loss programme. A further non-randomised controlled study assessing weight after 1 yr of CPAP therapy showed a small increment in BMI with CPAP treatment [58]. Dietary and lifestyle modification in patients with OSA also needs to be tested in younger individuals who are less or more obese, and in those who are unable to tolerate CPAP. Nevertheless, the success of the studies to date indicates that substantial weight loss through diet and lifestyle change is achievable with immediately measurable benefits. Indeed, given the benefits of weight loss to other obesity-related comorbidities, one could argue that more than ever, diet, lifestyle change and weight loss should be at the heart of every sleep apnoea-treatment plan.

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Pharmacotherapy
Introduction
Pharmacological agents may be useful adjuncts to aid weight loss alongside dietary, behavioural and lifestyle modification. Guidelines now recommend consideration of pharmacological agents for obese patients who have failed to achieve weight loss goals through diet and lifestyle changes alone [5961]. Currently approved anti-obesity medications can be divided into two categories: appetite suppressants and lipase inhibitors. Rimonabant, the first of a novel class of drug acting by selective inhibition of the endocannabinoid system, was removed from the market in 2008 due to concerns over psychiatric side-effects [62, 63]. Sibutramine (an appetite suppressant) and orlistat (a lipase inhibitor) are the only two drugs currently licensed for weight reduction. However, clinicians should be aware that sibutramine has recently been temporarily withdrawn from Europe due to a small increase in cardiovascular morbidity in the Sibutramine Cardiovascular OUtcome Trial (SCOUT) and that other regulatory agencies worldwide may follow suit [64].

Sibutramine Introduction and general effectiveness

Sibutramine hydrochloride is the most studied anti-obesity medication in the sleep apnoea population. It is an orally administered serotonin (5-hydroxytryptamine (5HT)) and noradrenaline

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reuptake inhibitor that acts centrally to promote early satiety and maintain energy expenditure during weight loss [65]. In the general, obese population, sibutramine has been shown to induce dose-dependent weight loss [66], enhance the effects of diet and exercise programmes [67], and maintain weight loss when compared to placebo [68, 69]. A meta-analysis examining data from five randomised placebo-controlled trials (n52,188) concluded that, at 4454 weeks, sibutramine causes a mean 4.5 kg (95% CI 3.65.3 kg) greater weight loss than placebo. Groups treated with placebo achieved an average weight loss of 5.5 kg. Thus, a patient treated with sibutramine would expect an average 10 kg weight reduction after 1 yr of treatment when combined with a suitable dietary/ lifestyle programme [70]. Despite consistent results in weight loss, sibutramine has not been shown to reduce mortality or morbidity from obesity-associated diseases. A meta-analysis that pooled the results of 44 studies found slightly decreased levels of fasting glucose and haemaglobin A1C in sibutramine-treated patients but no consistent effect on serum lipid profile [70]. The analysis also showed that heart rate was consistently increased by ,4 beats?min-1 in patients treated with sibutramine. Indeed, the issue of long-term cardiovascular safety continues to plague sibutramine. Short-to-mediumterm studies have suggested that increases in blood pressure and heart rate caused by sibutramine are mostly mild and may be offset by the beneficial effects of sibutramine-induced weight loss [69, 71]. SCOUT is a randomised, double-blinded placebo controlled trial of sibutramine in a population with high cardiovascular risk [72]. More than 10,000 overweight subjects (BMI o27 kg?m-2, or o25 kg?m-2 if truncally obese) who were .55 yrs of age and who had co-existing cardiovascular disease and/or type II diabetes mellitus, were randomised to sibutramine 1015 mg daily or placebo. All subjects underwent 6 weeks of lead-in with 10 mg sibutramine treatment. Although analysis of the lead-in period showed overall small reductions in blood pressure (mean systolic -3 mmHg, mean diastolic -1 mmHg) and a small increase in pulse rate (1.5 beats?min-1), a substantial minority (7.6%) of subjects experienced two consecutive increase of .10 mmHg over initial systolic or diastolic blood pressure and a sustained increase in pulse rate of .10 beats?min-1. Overall, 3.1% of subjects dropped out during lead-in due to adverse drug reactions. Interim analysis of 5-yr data showed that subjects treated with sibutramine had cardiovascular event rates of 11.4% compared with 10% in controls (p50.023), with particular increased risk of non-fatal myocardial infarctions and strokes [73]. At the time of writing, the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) had temporarily suspended marketing authorisation for sibutramine [64], deeming its cardiovascular risks to outweigh its benefits. The USA Food and Drugs Administration (FDA) had contra-indicated the drug in patients with any history of cardiovascular disease (including uncontrolled hypertension), and was withholding further judgment until formal publication of the SCOUT results [74].

Factorial trial of sibutramine and lifestyle modification

The effectiveness of sibutramine and diet/lifestyle change alone and in combination was assessed in a factorial study published in 2005 [67]. WADDEN et al. [67] randomised 224 obese adults (BMI 3040 kg?m-2) to: 15 mg sibutramine per day alone; intensive lifestyle-modification counselling alone; intensive combination therapy (sibutramine plus intense lifestyle-modification counselling delivered by trained psychologists); or brief combination therapy (sibutramine daily plus brief lifestyle-modification counselling delivered by primary care providers). At 1 yr, subjects who received combination sibutramine and intensive lifestyle counselling lost more weight compared to the other groups (meanSD 12.19.8 versus 5.07.4 kg with sibutramine alone, 6.77.9 kg with lifestyle modification alone and 7.58.0 kg with sibutramine and brief lifestyle counselling; p,0.001). WADDEN et al. [67] concluded that the best weight loss results with pharmacotherapy are obtained when medication is used as an adjunct to an intensive diet and lifestyle-change programme and that the effects of these strategies are additive.

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Effectiveness in OSA
There are few trials examining the interaction between sibutramine-induced weight loss and OSA [7577]. Given that OSA is a risk factor for hypertension [78], treatment-resistant hypertension [79] and increased heart rate [80], concerns have been raised about potential adverse cardiovascular effects of sibutramine due to its sympathomimetic activity. The first study examining the short-term side-effects profile of sibutramine in OSA patients was published in 2005 [81]. A total of 19 patients with moderate OSA (mean AHI 28 events?h-1) were randomised to placebo or 15 mg sibutramine at bedtime for 1 month. The small sample size, the shortness of treatment duration and the lack of a concomitant diet and exercise programme reduced the ability of this study to detect clinically relevant adverse outcomes, with the exception of the reported increase of 8 beats?min-1 in heart rate. In our own uncontrolled cohort study, 87 obese males (meanSD weight 11114 kg, BMI 34.22.8 kg?m-2) with symptomatic, moderate-to-severe OSA (AHI 4623.1 events?h-1) underwent a 24-week weight-loss programme with dietary and exercise advice assisted by 1015 mg sibutramine daily [75]. MeanSD weight loss was 8.34.7 kg, and 62 patients (71%) lost o5% of their initial body weight. There were significant reductions in other anthropometric measures of obesity and subjective symptoms (ESS reduced from 13.33.4 to 8.84.6; p,0.0001). Total RDI decreased from 4623.1 to 29.619.3?h-1, and in four subjects the RDI decreased to ,5?h-1 with a significant correlation between % change in RDI and % change in weight (p,0.0001). There was no significant change to systolic or diastolic blood pressure but a small rise of ,6 beats?min-1 in resting heart rate was noted. We concluded that sibutramine can be used effectively as a weightloss agent in closely monitored patients with OSA, and results in improvement in sleep-disordered breathing and symptoms. It is important to note that the expected beneficial effects from a reduction in weight and RDI on blood pressure did not occur in our study and the role sibutramine plays in this is unclear given the uncontrolled nature of the study. We further analysed the body composition (measured by anthropometrics and computer tomography) and metabolic data from the previously discussed cohort [77]. At 6 months, weight loss and improvements in OSA were accompanied by improved markers of insulin resistance and modest improvements in blood cholesterol profile. There were also significant reductions in measures of visceral (-19.6%), subcutaneous abdominal (-15.4%) and liver fat (liver/spleen ratio -19.1%) as well as reduction in percentage of subjects with fatty liver (from 55 to 35%). The improvements in body composition and cardio-metabolic risk factors suggest that sibutramineassisted weight loss may lead to real alterations in clinical outcomes. However, as with the study by MARTINEZ et al. [81], there were no improvements in blood pressure or markers of arterial stiffness. A further study compared the benefits of sibutramine-assisted weight loss with the current gold standard treatment of OSA: CPAP therapy [76]. Some 40 obese patients with severe OSA (meanSD BMI 36.74.2 kg?m-2, mean baseline AHI 5254 events?h-1) underwent either sibutramine plus diet/activity treatment (n522) or conventional CPAP treatment (n518) for 1 yr. The study was not randomised and the participants elected whether they received CPAP or sibutramine treatment. MeanSD weight loss after 1 yr of sibutramine treatment was 5.41.4 kg, amounting to a 5% reduction in initial body weight and a mean decrement in BMI of 2 kg?m-2, compared to no change in weight in the CPAP group (p,0.001). Sibutramine treatment only led to small improvements in AHI (36 events?h-1; p,0.01) and did not change most other respiratory and sleep parameters. Subjective daytime sleepiness, assessed using the ESS, did not change in the sibutramine group but improved in the CPAP group. Furthermore, only CPAP treatment improved nocturnal, daytime and 24-h blood pressure and mean heart rate, while sibutramine-induced weight loss had no impact on these. It may be that the possible beneficial effects of weight loss on cardiovascular parameters were countered by the sympathomimetic effects of sibutramine. Despite this study providing support for the safety of medium-to-long-term

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treatment with sibutramine in sleep apnoea, the much larger long-term safety concerns highlighted by SCOUT may still lead to worldwide withdrawal of this drug.

Other appetite suppressants

Data supporting the use of other anti-obesity medications in patients with OSA is sparse. Fenfluramine works by releasing serotonin (5-HT) to elicit a feeling of satiety and reduce food intake [82]. A small, uncontrolled treatment study examined the effects of fenfluramine hydrochloride in 13 obese patients with OSA [83]. Mean weight loss after 9 months of treatment (6080 mg daily) was 14 kg, with a mean decrease in AHI from 82 to 51 events?h-1. However, in 1997, concerns over the association of fenfluramine and dexfenfluramine with primary pulmonary hypertension and valvular pathologies resulted in the worldwide withdrawal of both drugs [84]. A number of other medications, such as fluoxetine and sertaline (selective serotonin reuptake inhibitors), phentermine and diethylpropion (sympathomimetic agents), and zonisamide and topiramate (anticonvulsants), have known appetite-suppressing effects. However, at present none of these medications are approved for use in weight loss. A controlled release formulation of combination topiramate and phenteramine has recently completed phase III trials and is undergoing assessment by the FDA. A phase II double-blind randomised controlled trial comparing the effects of topiramate/phenteramine versus placebo in obese patients with OSA is in progress (ClinicalTrials.gov NCT00745251). A recently presented abstract of this study indicated a higher degree of weight loss and associated improvements in AHI compared to placebo after 28 weeks of treatment [85].

Orlistat
Following the withdrawal of sibutramine from Europe, orlistat is the only remaining registered drug indicated for weight loss in that market. Orlistat is a gastric and pancreatic lipase inhibitor that reduces dietary fat absorption by ,30%, and was approved for use as an anti-obesity medication in the late 1990s [86]. A recent meta-analysis, including 16 randomised controlled trials using 120 mg orlistat three times daily, found an overall 2.9 kg (95% CI 2.53.2 kg) greater weight reduction than placebo. More subjects in the orlistat group achieved clinically significant (.5%) weight loss and greater reductions in waist circumference compared to placebo [87]. In a 2-yr weight-maintenance trial of 688 overweight-to-obese subjects (BMI 2847 kg?m-2), orlistat 120 mg three times daily taken with an appropriate diet resulted in clinically significant weight loss and reduced weight regain when compared with placebo (10.3 and 6.1 kg, respectively). After the first year, subjects were re-randomised. Those switched from active drug to placebo regained weight and those switched from placebo to active drug lost weight [88]. Orlistat-assisted weight loss has also been shown to have a modest effect on insulin resistance, hypertension and serum cholesterol profile [89, 90]. No specific studies dealing with the effect of orlistat in patients with sleep apnoea exist. As such, effects in OSA patients can only be inferred from general obesity studies.
C.L. CHANG ET AL.

Summary
Current European and North American guidelines recommend adjunctive weight-loss therapies when the expectant result is .510% reduction in weight over placebo [60, 61]. Extra weight loss attributable to anti-obesity medications is often less than this, and most patients remain overweight or obese despite drug treatment. However, even substantial weight loss does not necessarily cause improvements in OSA. Until recently, sibutramine was the most promising pharmaceutical in our arsenal but recent news from SCOUT leaves its future availability questionable. The only currently remaining medication with an acceptable side-effect profile is orlistat, a drug completely untested in OSA.

311

Surgical weight loss

Introduction and general effectiveness
Bariatric surgery can be an effective method to reduce weight in the short term and allow longterm weight maintenance [91, 92]. A Cochrane review updated in 2008 concluded that bariatric surgery is more effective than conventional therapies in the management of obesity, achieving greater weight loss and superior reductions in comorbidities such as diabetes and hypertension [93]. North American, European and British clinical guidelines for the management of obesity all recommend consideration of bariatric surgery for the morbidly obese (BMI .40 kg?m-2) and obese individuals with comorbidities (BMI .35 kg?m-2) who are unable to lose weight despite conventional measures [60, 61, 94, 95]. Bariatric surgery has been shown to reduce mortality, cardiovascular disease-related risk factors and cancer incidence in the prospective, controlled Swedish Obese Subjects (SOS) study [33, 35]. The aim of bariatric surgery is two-fold: to reduce caloric intake and to alter the hormonal and endocrine milieu involved in nutrient absorption [96, 97]. Procedures include gastric banding (with adjustable or non-adjustable bands), gastric bypass (principally Roux-en-Y variations), gastroplasty (principally vertical banded gastroplasty), biliopancreatic diversion or duodenal switch, and a variety of others (biliary intestinal bypass, ilieogastrotomy, jejunoileal bypass etc.). The most commonly available bariatric operations are laparascopic adjustable gastric banding (LAGB), which is purely restrictive, and laparoscopic Roux-en-Y gastric bypass (LYGB), which is both restrictive and malabsorptive [98, 99]. Overall, gastric bypass is more efficacious than gastric banding or gastroplasty, but with longer operative time and perioperative hospitalisation, as well as higher complication rates. Perioperative mortality has been reported as being 0.06% for LAGB and 0.7% for LYGB in a recent meta-analysis [100].

OSA AND WEIGHT LOSS TREATMENT

Effectiveness for OSA

Since the early 1980s, improvements in OSA have been reported in case studies and cohorts of patients who have lost substantial weight following bariatric surgery [101104]. However, these reports were limited by small sample size, selection bias, lack of standardised assessment for severity of sleep-disordered breathing, and lack of complete follow-up data. Furthermore, surgical techniques varied between reports and sometimes within the same series. Larger uncontrolled treatment cohorts with similar methodological caveats continue to be published. A follow-up study of 123 morbidly obese patients who had significant weight loss 1-yr after undergoing LAGB (baseline: -130 kg, BMI 46 kg?m-2; at 1 yr: -99 kg, BMI 35 kg?m-2) found reductions in self-reported snoring frequency and intensity as well as an improvement in daytime sleepiness (mean ESS reduction from 9.1 to 4.0) [105]. The study did not objectively measure sleepdisordered breathing and only 40% of the patients recruited completed follow-up at 1 yr. More recently, RAO et al. [106] reported 1-yr follow-up results for an obese Singaporean cohort (112 kg, BMI 42 kg?m-2) who underwent routine full-channel supervised PSG screening prior to LAGB. Out of a total of 314 patients, 228 (73%) had sleep-disordered breathing, with 21, 18 and 33% having mild, moderate and severe OSA, respectively. A random sample of 46 patients received repeat PSGs at 1 yr. They lost on average 41 kg (BMI -15 kg?m-2) with significant improvements in sleep apnoea severity: the mean reduction in AHI was 25 events?h-1 and 78% had achieved remission (AHI ,5 events?h-1). There were associated improvements in hypertension and glycaemic control. Similarly promising results have been reported following gastric bypass surgery. One study followed 11 morbidly obese individuals with severe symptomatic OSA (baseline BMI 62 kg?m-2, RDI 56?h-1, ESS 14) who lost weight after undergoing gastric bypass surgery [107]. At 6 months, the mean BMI was 40 kg?m-2. There were significant improvements in RDI (23?h-1), nocturnal oxygen desaturation and sleep architecture, as well as a reduction in symptom score (ESS 3).

312

Although 54 patients were approached for follow-up, only 11 completed the protocol. Interestingly, the authors reported that one of the common reasons for drop-out was significant improvement or resolution in OSA symptoms. Another small study, significant for its duration, followed patients for over 2 yrs after gastric bypass. Eight obese patients with moderate-to-severe OSA (mean BMI 49 kg?m-2, mean RDI 55?h-1) were re-evaluated at an average of 28 months post-surgery [104]. Mean BMI was reduced by 31% (post-BMI 34 kg?m-2) and mean RDI was reduced by 75% (14?h-1, seven out of eight patients had improved). Only two patients had a residual RDI of .15?h-1 and the remainder had OSA remission (AHI ,5 events?h-1).

SOS study
To date, the largest study is the SOS study, an ongoing, non-randomised trial investigating the long-term effects of surgical weight loss [28, 33]. Specifically pertaining to OSA, 1,592 patients willing to undergo surgical therapy were matched to an obese control group and the prevalence of sleep-disordered breathing was assessed by survey [108]. Mean weight loss in the surgically treated group was 27.8 kg (-23% from baseline) at 2 years and the mean BMI decreased from 42.2 to 32.5 kg?m-2. The average weight in the control group was essentially unchanged. The weight reduction seen in the surgical group was associated with a significant reduction in frequency of reported apnoeas, snoring and daytime sleepiness. The overall prevalence of persistent snoring was 22% in the surgery group compared to 66% in the controls. Although the general effect of weight loss on symptoms was similar in males and females, males with the greatest degree of weight loss demonstrated a larger improvement in symptoms than their female counterparts.
C.L. CHANG ET AL.

Systematic reviews
The large number of observational cohorts and non-randomised trials has generated two systematic reviews on this subject. The first systematic review by BUCHWALD et al. [109] was published in 2004 and examined the benefits of bariatric surgery on obesity-related comorbidities, including OSA. The authors examined 136 studies involving 150 treatment groups and ,22,000 patients (72% females, mean age 39 yrs). Of these, only 38 treatment groups with 1,195 patients reported sleep-related outcomes. Baseline BMI was 47 kg?m-2 and weight loss after surgery was significant across treatment groups (mean BMI reduction -14.2 kg?m-2). Unfortunately, the analysis combined results from studies of patients with OSA, sleep-disordered breathing and obesityhypoventilation syndrome in data synthesis and examined the composite data as OSA. Furthermore, most included cohorts did not formally assess post-operative disease via PSG. Nevertheless, combined outcome (OSA/sleep-disordered breathing/obesityhypoventilation syndrome) was strongly positive: 84% of patients had reported OSA resolution or improvement. Formal PSG data and AHI were available primarily from patients who underwent gastric bypass surgery (four treatment groups, 92 patients). The overall weight lost from this group was 40 kg with an associated mean reduction in AHI of 34 events?h-1. Gastric banding appeared to provide greater benefit in OSA-related outcome than other types of surgery, with 95% reporting postoperative improvement (gastric bypass 80%, gastroplasty 78%, others 92%). However, these results were not adjusted for amount of weight lost, baseline disease severity or even time lapsed from surgery to re-assessment. Overall, the findings of the review by BUCHWALD et al. [109] were difficult to interpret given the combination of mechanistically different pathologies (central and obstructive apnoea). Absolute benefit was not reported nor was the proportion of patients with significant residual OSA requiring on-going treatment. In the end, the review re-affirmed that considerable weight loss and symptom improvement is possible for patients with sleep apnoea following bariatric surgery but contributed little additional information regarding effect size, the optimal type of surgery, which patients might benefit the most from surgery and the long-term outcomes.

313

The second systematic review by GREENBURG et al. [110], published in 2009, was designed specifically to address some of the above concerns and only included studies that reported both pre-operative and post-operative PSG measures of sleep apnoea severity. 12 observational studies (n5342), five of which were prospective, were reviewed but only six studies yielded individual patient data (n580). Meta-analysed mean BMI decreased by 17.9 kg?m-2 (95% CI 16.519.3 kg?m-2) from 55 to 38 kg?m-2, and the mean AHI decreased by 38 events?h-1 (95% CI 31.944.4 events?h-1) from 55 to 16 events?h-1 after bariatric surgery. No specific bariatric technique seemed more efficacious than any other in reducing weight or AHI. Individual patient data analysis from available studies showed similar reductions in weight (from meanSD 228100 to 14760 kg), BMI (from 49.710 to 32.86.7 kg?m-2) and AHI (from 6840 to 1819 events?h-1) after surgical weight loss. Importantly, residual disease requiring treatment (AHI .15 events?h-1) was still present in 62% of patients after bariatric surgery despite substantial weight loss. Although patients often subjectively noted reduced snoring and daytime somnolence, an AHI of .15 events?h-1 is still associated with significant long-term adverse outcomes [19, 52, 53]. The authors recommended PSG after weight stabilisation to specifically identify these patients. Many patients require less positive airway pressure to eliminate apnoeic events after substantial weight loss [11], so repeat PSG and re-titration of CPAP may also translate into improved comfort and adherence to therapy. A controlled trial randomising obese patients with moderate-to-severe OSA to LAGB or best medical care plus active lifestyle programme, has recently concluded recruitment and follow-up is in progress. The results from the study should provide high-quality evidence on the efficacy of bariatric surgery in OSA (clinical trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR), no. ACTRN12605000161628).
OSA AND WEIGHT LOSS TREATMENT

Summary
Little information is available regarding the optimal time post-surgery to reassess OSA severity. The nadir of weight loss reported following bariatric surgery occurs at ,12 months with subsequent weight regain [33, 100]. Reassessment of OSA severity away from this nadir may underestimate the benefit of bariatric surgery, whilst reassessment at the nadir may overestimate the long-term benefit. Follow-up rates are generally poor and vary from 6 months to .2 yrs in reported cohorts, apart from the SOS study, which unfortunately lacks objective sleep assessments. On average only 2440% of all patients initially included in treatment cohorts undergo repeat sleep apnoea assessments following surgery [104, 105, 107, 111]. Most authors cite significant symptom improvement and lack of funding (insurance approval) as reasons for this problem. This high attrition rate is a possible source of bias and needs to be addressed in any future investigations. The majority of studies addressing surgical weight loss in sleep apnoea available in the literature are small case series or cohorts, without control groups or randomised design. At the time of writing, there were only six prospective studies with PSG data available in the literature (table 2) [106, 107, 111114]. Adverse outcomes are often incompletely described and long-term follow-up data is sparse. As with all interventions, the potential benefits must be balanced against potential adverse events. Without sufficient vigilance and documentation of adverse outcomes, the true nature of this balance is impossible to ascertain. In their 2009 systematic review, GREENBURG et al. [110] justified the lack of randomised controlled trials by suggesting that it may be unethical to randomise patients at future risk from their obesity-related comorbidities to non-surgical treatment. There is now mounting evidence that OSA independently increases peri- and post-operative complications following bariatric surgery [115117]. Given the efficacy of intensive dietary and lifestyle interventions and the small but not insignificant risk of peri-operative morbidity and mortality, advising patients as to the best long-term management for OSA is difficult.

314

AHI BMI AHI events?h-1 kg?m-2 events?h-1

Gastric Not stated 623 Not stated 5613 402 Not stated 237 bypass (311) LAGB 17.7 (1242) 539.5 15435.0 6231.9 377.2 10522.0 1313 LYGB 11 (642) 561.0 Not stated 51.04.0 38.01.0 Not stated 15.02.0

Obesity is incontrovertibly the major modifiable risk factor for OSA; therefore, obesity reduction offers an excellent therapeutic target for treatment of OSA in obese patients. Current standard device-based treatments for OSA do not cause obesity reduction and therefore leave the underlying pathophysiology unchanged. We have reviewed the three major therapeutic approaches to obesity reduction: diet/lifestyle modification, pharmacotherapy and bariatric surgery. If any of these techniques used alone or in combination effectively reduces obesity, it will on average have a corresponding effectiveness in reducing OSA severity. Clinicians should be aware that significant inter-individual variability exists. In some patients, even marked weight loss will not cause a reduction in OSA severity. However, weight loss in these patient should also confer other substantial health benefits and should remain an important treatment goal. The evidence base is not sufficiently advanced to allow specific treatment recommendations for specific patient phenotypes. Tailoring specific obesity-reduction techniques (or combined techniques) to individuals remains a matter of good clinical judgement. Intensive dietary and lifestyle intervention is effective in both increasing weight loss and improving OSA severity. Data supporting bariatric surgery is less methodologically robust but indicates substantial weight loss, usually followed by improvement in OSA. Both of these interventions are resource- and labour-intensive with significant inter-person variability in effectiveness. Pharmacological adjuncts provide only modest additional benefits and are inadequate monotherapy for the morbidly obese patient. Recent data suggest that sibutramine, the most studied anti-obesity medication for OSA, may be associated with an unacceptable rate of cardiovascular adverse events and has been temporarily withdrawn from Europe. Central or visceral adiposity has been identified as a better predictor of OSA than

Change

Conclusion and future directions

Data are presented as n, mean SD or mean (range), unless otherwise stated. BMI: body mass index; AHI: apnoea/hypopnoea index; LAGB: laparoscopic adjustable gastric banding; LYGB: laparoscopic Roux-en-Y gastric bypass.

-33

-48 -36

-22

-16 -18

-42

-23 2518.1 9318.5 325.5 -19

2424.3

-21

Post-operative

348.1 10118.9

Weight kg

BMI kg?m-2

Weight AHI kg events?h-1

24.2 (1830) 5610.1 15222.6 6633.4

Table 2. Prospective studies evaluating the effect of bariatric surgery on obstructive sleep apnoea

13.7 5110.4 14729.0 4833.8 (10.822.2) 12.6 (1240) 45 111 38

Pre-operative

30

71

13

-15

-17

Initial Final Type of Follow-up First author Year recruitment sample surgery months [Ref.] size

LAGB

25 101

11

12

24

100

49 349

2001 2007

2003

2007

2008

R ASHEID [107] DIXON [105] H AINES [111] F RITSCHER [113] L ETTIERI [114] R AO [106]

2009

228

13

25

46

LAGB

LYGB

315

C.L. CHANG ET AL.

BMI kg?m-2

peripheral or subcutaneous adiposity [17, 118, 119]. Visceral adiposity is also strongly associated with metabolic syndrome and adverse cardiovascular outcomes [120, 121]. Thus, weight-loss strategies that particularly focus on visceral adiposity may be preferred over general weight loss. Few studies specifically assess the changes to body fat composition after weight loss in patients with sleep-disordered breathing [77]. The independent effect that exercise (which may reduce visceral adiposity without changing overall weight) may have on sleep apnoea severity is also not well studied. Self-reported exercise, independent of body habitus, is associated with reduced OSA risk and severity in the Winsconsin Sleep Cohort [122]. Small treatment cohort studies have found overall improvements in AHI, quality of life and daytime somnolence after 6 months of supervised exercise training [123, 124]. These results need to be replicated in larger, controlled studies. Further research is required to address these outstanding gaps in evidence and help translate current understanding into clinical practice. It is not yet known how to select an optimal treatment approach for a specific patient. It would also be useful to have a clinically applicable prediction tool to identify patients who will not have improved OSA in conjunction with weight loss. In addition, the long-term sustainability after weight loss of any improvement in OSA is yet to be addressed. Long-term adherence to lifestyle modification is often poor, even when compared to device-based OSA therapy [40]. Although it may be logical to assume that patients who do not adhere to device-based therapy may also adhere poorly to behavioural change, this hypothesis is untested in the literature. The role of dietary counselling and cognitive behavioural therapy has also yet to be specifically assessed in this population but they appear to be useful adjuncts in general weight loss [125, 126]. Females are underrepresented in current OSA-specific diet- and lifestyle-intervention studies. Clinical observations and our interpretation of existing evidence in obesity reduction in OSA patients, leads us to speculate that current obesity-reduction techniques may be more efficacious in males. Future studies of all treatment modalities should be designed to provide better evidence for females with OSA. The future management of weight loss in OSA is likely to be stratified according to severity, with less invasive weight-loss methods being applied to patients with less severe disease and weight. The role of cognitive behaviour therapy as an adjunct to any or all of these approaches is still to be assessed. As with other aspects of medicine, a multidisciplinary approach should be incorporated into the treatment of obesity. Future sleep clinics may need to include dieticians, exercise trainers, behavioural psychologists, obesity physicians, bariatric surgeons, as well as the sleep physician.

OSA AND WEIGHT LOSS TREATMENT

Statement of Interest
None declared.

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