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Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome Ian W Seetho and John PH Wilding Chronic Respiratory Disease published online 3 October 2014 DOI: 10.1177/1479972314552806 The online version of this article can be found at: http://crd.sagepub.com/content/early/2014/10/03/1479972314552806 A more recent version of this article was published on - Oct 31, 2014

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Review Article

Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome

Chronic Respiratory Disease 1–19 ª The Author(s) 2014 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1479972314552806 crd.sagepub.com

Ian W Seetho and John PH Wilding

Abstract Sleep-disordered breathing (SDB) encompasses a spectrum of conditions that can lead to altered sleep homeostasis. In particular, obstructive sleep apnoea (OSA) is the most common form of SDB and is associated with adverse cardiometabolic manifestations including hypertension, metabolic syndrome and type 2 diabetes, ultimately increasing the risk of cardiovascular disease. The pathophysiological basis of these associations may relate to repeated intermittent hypoxia and fragmented sleep episodes that characterize OSA which drive further mechanisms with adverse metabolic and cardiovascular consequences. The associations of OSA with type 2 diabetes and the metabolic syndrome have been described in studies ranging from epidemiological and observational studies to controlled trials investigating the effects of OSA therapy with continuous positive airway pressure (CPAP). In recent years, there have been rising prevalence rates of diabetes and obesity worldwide. Given the established links between SDB (in particular OSA) with both conditions, understanding the potential influence of OSA on the components of the metabolic syndrome and diabetes and the underlying mechanisms by which such interactions may contribute to metabolic dysregulation are important in order to effectively and holistically manage patients with SDB, type 2 diabetes or the metabolic syndrome. In this article, we review the literature describing the associations, the possible underlying pathophysiological mechanisms linking these conditions and the effects of interventions including CPAP treatment and weight loss. Keywords Sleep-disordered breathing, obstructive sleep apnoea, type 2 diabetes, metabolic syndrome

Introduction Sleep-disordered breathing (SDB) encompasses a range of conditions in which repeated apnoeas or hypopnoeas occur during sleep, including snoring, upper airway resistance syndrome and obstructive sleep apnoea (OSA) that can result in perturbations in sleep homeostasis.1 SDB is associated with hypertension, cardiovascular disease, type 2 diabetes and metabolic impairment.2 There is also evidence linking disrupted sleep patterns to other adverse health consequences such as neurocognitive deficits, impaired quality of life and an increased risk of accidents.3 In recent years, progress has been made in understanding how SDB can affect the cardiovascular system, especially blood pressure regulation and why it is associated with dyslipidaemia and abnormal glucose homeostasis. OSA is the most common form of SDB. In OSA, repeated episodes of apnoeas and hypopnoeas occur during sleep with subsequent daytime hypersomnolence.4 These episodes are characterized by recurrent upper

airway obstruction causing intermittent hypoxia, with frequent sleep arousals and fragmented sleep.5 The severity of OSA may be assessed by the number of apnoeas and hypopnoeas per hour during sleep, termed the apnoea–hypopnoea index (AHI). Besides the AHI, the frequency of oxygen desaturation episodes and severity of somnolence symptoms are also used.6 The AHI measures the frequency of reduction in airflow associated with collapse or narrowing of the airways.7 The index classifies the severity of OSA based on the number of obstructive breathing episodes per hour during sleep as: mild AHI: 5–15 events per hour, moderate Department of Obesity and Endocrinology, University of Liverpool, Liverpool, UK Corresponding author: John PH Wilding, Department of Obesity and Endocrinology, University of Liverpool, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK. Email: [email protected]

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OSA: 15–30 events per hour and severe AHI: OSA > 30 events per hour.8 The prevalence of OSA has been increasing, and it has been estimated that 13% of men and 6% of women between the ages of 30 and 70 have moderate to severe forms of OSA (AHI > 15 events per hour of sleep).9 This may be related to the growing obesity prevalence, as it is known that obesity is a risk factor for OSA.10 Obesity may be classified according to the body mass index (BMI), which is calculated as weight (in kilogram)/height (in square metre). According to World Health Organization guidance, adults with a BMI of 25–30 kg/m2 are classed as ‘overweight’, those with a BMI of 30 kg/m2 or more may be referred to as having obesity and those with a BMI of 40 kg/m2 or more may be referred to as having severe (termed ‘morbid’) obesity. It should be noted that the threshold values for the definition of obesity may differ among populations,11 with Asian populations in particular having lower BMI cut-offs. Prevalence estimates of OSA in severe obesity were between 40% and 90%;12 furthermore, OSA severity worsens with increasing levels of obesity.13 OSA severity is correlated with the degree of perturbation in glucose homeostasis, an effect that is independent of obesity.1,14 The prevalence of OSA in type 2 diabetes has been reported with different rates in several population-based studies that are not directly comparable due to differences in populations studied and how OSA was assessed. This has been found to range from 18% of patients in primary care based on an assessment of electronic records,15 23% in a mixed primary and secondary care population of patients with type 2 diabetes who had overnight oximetry testing,16 to as high as 86% in the Sleep Action for Health in Diabetes (AHEAD) study cohort comprising obese subjects with type 2 diabetes who had polysomnography.17 One of the major implications of the global rise in obesity has been an associated rise in the prevalence of the metabolic syndrome.18 The metabolic syndrome, also known as the insulin resistance syndrome, or ‘syndrome X’19 has been variably defined based on clustering of abnormalities of factors including insulin resistance, dyslipidaemia (low high-density lipoprotein (HDL) cholesterol and raised triglycerides), hyperglycaemia and blood pressure,20 with the most recent definition of the syndrome requiring central adiposity as a key feature (Table 1).25 There is also evidence that OSA is associated with the metabolic syndrome, independently of adiposity.2,26 The term

‘syndrome Z’ reflects the close interaction between OSA and cardiovascular disease risk.27 In a study of 529 newly diagnosed OSA patients who had polysomnography, metabolic syndrome based on the National Cholesterol Education Program Adult Treatment Panel definition occurred in about half of the patients; prevalence rates of metabolic syndrome in OSA have previously been reported to be between 23% and 87% using this definition.28 The reduction in time spent sleeping that is typical of OSA may have profound effects on glucose regulation, insulin resistance, appetite and energy balance.29 OSA may induce fatigue and with increasing daytime somnolence, weight-reducing activities are pursued less often with a decrease in energy expenditure that may lead to weight gain, insulin resistance and further worsening of SDB. Understanding the potential influence of OSA on the components of the metabolic syndrome and the mechanisms by which such interactions may contribute to metabolic dysregulation is important because such knowledge may define appropriate targets and lead to more precisely administered preventive actions in addressing health outcomes such as cardiovascular disease, obesity and type 2 diabetes. Whilst there are different forms of SDB, the majority of research studies have focused on OSA and the potential interactions with diabetes, metabolic syndrome and its components. In this article, we review OSA and its association with diabetes as well as components of the metabolic syndrome. We discuss the underlying pathophysiology and also review the effects of OSA treatment on both conditions.

Search strategy A search of Web of Science electronic database for relevant articles was performed using the search terms ‘obstructive sleep apnoea’, ‘sleep-disordered breathing’ with relevant phrases including ‘diabetes’, ‘metabolic syndrome’, ‘type 2 diabetes’ and ‘CPAP’. Only articles published in English were used. Publications referred to in the identified articles were also reviewed and were cited if they provided important data not addressed in subsequent articles.

Compromised metabolism Insulin resistance and type 2 diabetes There is substantial evidence for the association between OSA, insulin resistance and type 2 diabetes.

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Balkau and Charles22 Excluding people with diabetes, presence of insulin resistance or fasting hyperinsulinaemia and two of: hyperglycaemia (fasting plasma glucose and 6.1 mmol/L, but without diabetes); hypertension (systolic/ diastolic blood pressures 140/90 mmHg or treated for hypertension); dyslipidaemia (triglycerides > 2.0 mmol/L or HDL cholesterol < 1.0 mmol/L or treated for dyslipidaemia); central obesity (waist circumference 94 cm in males and 80 cm in females). Hyperglycaemia was defined as fasting plasma glucose 6.1 mmol/ L or impaired fasting glucose in individuals without diabetes.

European Group for the Study of Insulin Resistance (1999)

HDL: high-density lipoprotein; BMI: body mass index.

Alberti and Zimmet21 Impaired glucose regulation or diabetes mellitus and/or insulin resistance together with two or more of: raised arterial pressure (160/90 mmHg) raised plasma triglycerides (1.7 mmol/ L; 150 mg/dL) and/or low HDL cholesterol (0.85 and/or BMI >30 kg/m2) microalbuminuria (urinary albumin excretion rate  20 mg/min) or albumin:creatinine ratio  20 mg/g

World Health Organization (1999)

Table 1. Definitions of metabolic syndrome.

Cleeman and Grundy23 Presence of any three of: central obesity (waist circumference) males > 102 cm females > 88 cm raised blood pressure 130/85); Raised triglycerides 1.7 mmol/L; 150 mg/dL; Low HDLcholesterol (males < 1.03 mmol/L; 40 mg/dL, females < 1.29 mmol/L; 50 mg/dL); fasting hyperglycaemia (6.1 mmol/L; 110 mg/dL).

US National Cholesterol Education Program: Adult Treatment Panel III (2001) Alberti and Zimmet24 Central obesity waist circumference according to ethnicity and any two: raised triglycerides >1.7 mmol/L; 150 mg/dL or on treatment for this reduced HDL cholesterol (males < 1.03 mmol/L; 40 mg/dL, females < 1.29 mmol/L; 50 mg/dL or on treatment for this) raised blood pressure (systolic  130 mmHg and/or diastolic  85 mmHg or on treatment for previously diagnosed hypertension) raised fasting plasma glucose (fasting plasma glucose  56 mmol/L; 100 mg/dL or known type 2 diabetes)

International Diabetes Federation (2005)

Alberti and Eckel25 Presence of any three of: waist circumference according to specific population and country definitions elevated triglycerides (1.7 mmol/L; 150 mg/dL or on treatment for elevated triglycerides) reduced HDL cholesterol (10 oxygen was assessed by placebo CPAP resistance. desaturation of both HOMA and (n ¼ 22) for >4% per hour) euglycaemic 3 months randomized hyperinsulinaemic clamp); lipid profile, adiponectin and hs-CRP Subjects with AHI > Cardiovascular Randomized to Although insulin 15 (13 patients measures (urinary either CPAP or resistance completed microalbumin, no therapy for (HOMA) protocol) catecholamines, 4 weeks followed decreased with blood pressure, by washout for CPAP, the homeostasis model 4 weeks and then difference was for insulin resistance a crossover to not significant. score and endothelial the other Likewise, the function) intervention other cardiovascular measures did not show significant improvements. 61 Men randomized Effects of nasal CPAP Randomized to Therapeutic nasal with moderate-totreatment of OSA on therapeutic nasal CPAP treatment severe OSA insulin sensitivity in CPAP (n ¼ 31) for 1 week (AHI > 15) male subjects without or sham-CPAP improved insulin diabetes mellitus (n ¼ 30) (n ¼ 29 sensitivity in obese completed 12 men (BMI > 25) weeks therapeutic without diabetes, CPAP, n ¼ 30 and the completed 1 week improvement was of sham-CPAP) maintained after 12 weeks of treatment. 50 Subjects with Normalization of the Randomized to CPAP did not OSA (AHI > 15) mean 2-h OGTT; a 8 weeks of CPAP normalize and impaired secondary outcome or sham-CPAP; impaired glucose glucose tolerance was improvement in patients crossed regulation. Insulin the Insulin Sensitivity over to other sensitivity Index therapy after a improved in 1-month washout subjects with severe OSA (AHI  30). 65 Men randomized Visceral abdominal and Real or sham-CPAP No group with AHI > 20 and liver fat, insulin for 12 weeks; at differences at ODI >15 sensitivity the end of the 12 weeks; at (46 completed 12-week blinded 24 weeks, insulin protocol) period all particisensitivity was pants had real improved but not CPAP for an addivisceral abdominal tional 12 weeks or liver fat.

Comondore et al.

Lam et al.

Weinstock et al.

Hoyos et al.

Parameters

CPAP regimen

Findings

Reference 125

130

123

124

131

OSA: obstructive sleep apnoea; CPAP: continuous positive airway pressure; HOMA: Homeostasis Model Assessment; hs-CRP: highsensitivity C-reactive protein; AHI: apnoea–hypopnoea index; BMI: body mass index; OGTT: oral glucose tolerance test; ODI: oxygen desaturation index.

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weeks of treatment in those with moderate obesity.123 Another study by Weinstock et al. found that CPAP did not aid a reversion to normal glucose tolerance in subjects with impaired glucose tolerance. However, there was suggestion of improved insulin sensitivity in those patients with severe OSA (AHI > 30).124 However, West et al. reported that CPAP treatment compared with sham-CPAP treatment in men with OSA and type 2 diabetes improved Epworth Sleepiness Scale (ESS) scores, but did not improve glycaemic control or insulin resistance.125 Individual heterogeneity in terms of glycaemic responses to CPAP suggests most of these studies were probably underpowered to show significant effects on glycaemic control and that the encouraging results seen in uncontrolled observational studies are in general not confirmed in randomized controlled trials. It is possible that for individuals with impaired glucose tolerance, other approaches such as intensive lifestyle intervention may be more effective in preventing progression to type 2 diabetes.126–128 Nevertheless, a recent observational study of OSA patients with type 2 diabetes assessed clinical outcomes and costeffectiveness of CPAP treatment compared with non-treatment. It was found that CPAP use was associated with significantly lower blood pressure, improved glycaemic control and was more costeffective compared with patients who were not treated with CPAP.129 However, this study had limitations because patients were not randomized to the treatments received, by the use of observational data and reliance on clinical outcome findings that were based on clinical entries in patient records. Therefore, no cause-and-effect inferences regarding CPAP treatment and these outcomes can be made. Metabolic syndrome. In order to understand CPAP treatment effects on cardiometabolic profiles, studies have examined the effect of CPAP on the metabolic syndrome components as end points. Randomized controlled trials have evaluated the metabolic syndrome by comparing therapeutic and sham-CPAP (Table 3). A meta-analysis of randomized trials found that there were favourable effects of CPAP treatment in terms of improving blood pressure responses.134 In terms of the effects on lipid profiles, there have been mixed results from different studies although the current evidence suggests that CPAP treatment may decrease total and LDL cholesterol.135 Previous work by Coughlin et al., a randomized crossover trial with sham-CPAP as control did not show any differences

in lipids.132 In other controlled trials, Comondore et al. randomized subjects to 4 weeks of CPAP or no therapy, with crossover after washout for 4 weeks; although no significant difference in lipid levels were found, there appeared to be reduced triglyceride levels.130 Robinson et al. randomized patients to either 1 month therapeutic or sub-therapeutic CPAP and found a trend towards a decrease in total cholesterol after CPAP.136 One randomized crossover trial with 2 months of therapeutic and sham-CPAP showed that treatment with CPAP improved postprandial triglyceride and total cholesterol levels.137 An interventional controlled study in men without diabetes did not find a significant change in weight, body fat, insulin resistance or lipid profiles with 6 weeks of CPAP treatment as opposed to shamCPAP therapy.132 Nevertheless, there were improvements in blood pressure control following CPAP intervention.132 A controlled study by Hoyos et al. evaluated 12 weeks of therapeutic versus shamCPAP on visceral adiposity and insulin sensitivity in males without diabetes and found that there was no significant effect of CPAP on either parameter.131 In a further analysis, it was noted that the 12 weeks of CPAP therapy did not have a significant effect on the number of subjects with metabolic syndrome.133 In another placebo-controlled study by Kritikou et al. compared 2 months of therapeutic and sham-CPAP in non-obese subjects and found no significant difference in metabolic markers including IL-6, TNF, leptin, adiponectin and highly sensitive C-reactive protein. CPAP treatment was not sufficient to alter these factors in this study, although it was noted that the short duration of therapy may have limited metabolic alterations.138 Taken together, the results of studies suggest that CPAP in isolation may not be sufficient for OSA patients with the metabolic syndrome, although there is reasonably consistent evidence for a beneficial effect on blood pressure. It has been proposed that there may be a role for a multifaceted approach for these individuals in order to manage their cardiometabolic risk.126 Thus it is envisaged that measures to promote proper sleep hygiene and weight loss may be important.

Treatment – weight loss It is clear that the promotion of weight loss activities and lifestyle changes has the potential to improve glucose regulation. There is also evidence that supports the role of weight loss in the treatment of OSA.148

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Table 3. Therapeutic versus sham-CPAP studies in metabolic syndrome. Study

Population

Parameters

CPAP regimen

Findings

Coughlin et al.

Randomized controlled trial. 35 OSA subjects randomized (34 completed protocol)

Hoyos et al.

Analysis of results from a randomized controlled trial. 65 Men with OSA randomized (46 completed protocol)

Metabolic syndrome Each group received Significant decreases in (using NCEP-ATP III); 6 weeks of systolic and diastolic blood pressure, therapeutic or blood pressure. No glucose, lipids and sham-CPAP, then change in glucose, insulin resistance treatment crosslipids, insulin over for further resistance or the 6 weeks proportion of patients with metabolic syndrome. Real or sham-CPAP 12 weeks of CPAP Effect on metabolic for 12 weeks therapy had did not syndrome (using affect numbers of international patients with consensus guidelines metabolic syndrome and NCEP-ATP III criteria) (analysis of results from Hoyos et al.131)

Reference 132

133

OSA: obstructive sleep apnoea; CPAP: continuous positive airway pressure; NCEP-ATP III: National Cholesterol Education Program– Adult Treatment Panel III.

These studies are presented in Table 4. In the Wisconsin Sleep Cohort study, subjects were prospectively observed for change in AHI and the development of SDB with weight change; weight control was associated with decreased AHI and a reduced likelihood of OSA.13 These findings are supported by evidence from randomized controlled trials. In the Sleep AHEAD study, obese subjects with type 2 diabetes and OSA were either randomized to a programme of intensive lifestyle intervention comprising behavioural weight loss and physical activity or to diabetes support and education. It was found that the intensive lifestyle intervention reduced weight and AHI over 4 years more than diabetes support and education alone.139 Other randomized trials investigating various lifestyle modifications such as very low-calorie diets (VLCDs) combined with active lifestyle counselling,140 intensive exercise training,142 cognitive–behavioural weight loss, and VLCD143 showed improved OSA severity with these interventions. These effects of lifestyle measures in OSA may potentially be sustained over time.139,141 In a randomized parallel group trial that compared the effects of CPAP, weight loss or both treatments for 24 weeks in adults with obesity, combination therapy with weight loss and CPAP had a beneficial effect in reducing insulin resistance, serum triglyceride levels and blood pressure.145 Concerning the effects of surgical weight loss, in a meta-analysis of bariatric surgery outcomes, Buchwald

et al. reported improvements in glycaemic control, dyslipidaemia, hypertension, blood pressure and OSA following bariatric surgery, but the included studies were often of poor quality with a high proportion of patients lost to follow-up.147 However, a randomized controlled trial investigated whether weight loss by bariatric surgery (laparoscopic gastric banding) was more effective than conventional weight loss therapy (medical consultations and low calorie diets) in the management of OSA. Despite more significant weight loss, it was found that surgical weight loss did not lead to significantly greater improvements in OSA, and, therefore, most patients would still require CPAP treatment postbariatric surgery.146 Hence bariatric surgery alone may not be sufficient to obviate the need for CPAP therapy. In a review that sought to compare surgical and nonsurgical weight loss studies in relation to BMI and AHI, no definitive statement could be made regarding the relative benefits of surgical therapy in OSA mainly because of inherent differences between trials and the need for more comparative studies between surgical and non-surgical methods of treating OSA.149 Nevertheless, in relation to metabolic effects, improved glycaemic control is seen in type 2 diabetes with surgical weight loss approaches.150,151 It is possible that the different pathophysiological mechanisms operating in OSA may not be completely reversed by surgical weight loss alone, despite our knowledge of the potential for amelioration of cardiometabolic risks with weight loss in

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Table 4. Selected studies relating to weight loss in OSA. Lifestyle interventions Study

Population

Study protocol

Key findings

Peppard et al.

690 Randomly selected employed Wisconsin residents

Prospective study of change in AHI and odds of developing moderateto-severe SDB with respect to change in weight

Kuna et al.

264 Obese adults with type 2 diabetes and OSA

Tuomilehto et al.

72 patients (BMI 28–40) with mild OSA completed the protocol

Randomized to either intensive lifestyle intervention with a behavioural weight loss programme (controlled diet, physical activity) or diabetes support and education (three group sessions annually) over 4 years Randomized to either VLCD programme with supervised lifestyle modification or routine lifestyle counselling for 1 year

Tuomilehto et al.

Follow-up study to Tuomilehto et al.140 57 Patients completed the follow-up over 4 years

Assessment of long-term efficacy of lifestyle intervention during 4-year follow-up in OSA subjects who participated in the initial 1 year randomised intervention trial (see Tuomilehto140)

Kline et al.

43 Sedentary and overweight/obese adults with OSA AHI  15

Randomized to intensive exercise training or low intensity stretching regimen

Kajaste et al.

31 Obese male symptomatic OSA patients (ODI > 10)

All subjects had active weight reduction based on the CBT approach (24 months) and a VLCD (6 weeks) and were randomly selected to have either nasal CPAP or without CPAP for the initial 6 months

Relation between weight gain and increased SDB severity. Weight loss was associated with reduced SDB severity and likelihood of developing SDB. Intensive lifestyle intervention produced greater reductions in weight and AHI over 4 years than diabetes support and education. Effects on AHI persisted at 4 years, despite an almost 50% weight regain. VLCD combined with active lifestyle counselling effectively reduced body weight and a significant reduction in AHI compared with the control group. Intervention achieved reduction in the incidence of progression of the OSA compared with the control group. The improvement in OSA that was sustained even 4 years after the active intervention. Compared with stretching, exercise resulted in a significant reduction in AHI and ODI despite non-significant changes in body weight. Weight loss and improvement of OSA was achieved by the CBT weight loss programme. CPAP in the initial phase of the weight reduction program did not result in significantly greater weight loss.

Reference 13

139

140

141

142

143

(continued)

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Table 4. (continued) Lifestyle interventions Study Thomasouli et al.

Chirinos et al.

Population

Study protocol

Systematic review and meta-analysis of 12 randomized controlled trials with lifestyle interventions in adults with OSA. Diet and diet plus CPAP therapy were compared in three studies (n ¼ 261), and intensive lifestyle programmes and routine care were compared in six studies (n ¼ 483) 181 obese patients, moderate-to-severe OSA and CRP >1 mg/ L. 136 completed the study. Intention to treat analysis for 146 subjects

Metabolic bariatric surgery Dixon et al. 60 Obese patients (BMI 35–55), recently diagnosed OSA AHI  20

Buchwald et al.

Systematic review and meta-analysis of 136 fully extracted studies (total 22,094 patients)

Key findings

Reference

To evaluate the impact of diet, exercise and lifestyle modification programmes on indices of obesity and OSA parameters

Intensive lifestyle management can significantly reduce obesity and OSA severity Lifestyle modification combined with CPAP may confer additional benefits in OSA

144

Randomized parallel group 24-week trial that compared the effects of CPAP, weight loss or both in adults with obesity (weight loss interventions included weekly counselling, unsupervised exercise and CBT)

Weight loss with CPAP therapy had an incremental effect in reducing insulin resistance and serum triglyceride levels, compared with CPAP alone. Additionally, combined treatment may result in a larger reduction in blood pressure than either treatment alone.

145

Randomized to a conventional weight loss programme (regular consultations with dietician and physician, with use of VLCDs) or to laparoscopic adjustable gastric banding. Systematic review and meta-analysis to determine the impact of bariatric surgery on weight loss, diabetes, hyperlipidaemia, hypertension and OSA.

Bariatric surgery produced greater weight loss but did not result in a statistically greater reduction in AHI than conventional weight loss therapy.

146

Bariatric surgery produced effective weight loss in morbidly obese individuals with beneficial effects in the majority in terms of diabetes, hyperlipidaemia, hypertension and OSA.

147

AHI: apnoea–hypopnoea index; SDB: sleep-disordered breathing; BMI: body mass index; VLCD: very low-calorie diet; OSA: obstructive sleep apnoea; ODI: oxygen desaturation index; CBT: cognitive–behavioural therapy; CPAP: continuous positive airway pressure; CRP: C-reactive protein.

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obesity and type 2 diabetes by lifestyle modifications. Conceivably, it would be expected that the extent of patient responses to different approaches may differ according to individual circumstance. Thus, a combination of weight loss interventions and CPAP may be complementary in influencing health outcomes for OSA patients.144

Conclusion In summary, there are multiple interacting mechanisms intricately linked with intermittent hypoxia and sleep fragmentation in OSA, which may contribute to the associations between OSA, type 2 diabetes and metabolic dysregulation. These include changes in sympathetic nervous system activity, hormonal changes, inflammation and oxidative stress. The rising rates of obesity and diabetes and the increasing awareness of the potential role of SDB, in particular OSA, to increase cardiometabolic risk means that further investigation of the mechanisms by which OSA drives metabolic risk and potential methods for early screening or assessment are important. Knowledge of these interactions may potentially yield molecular and therapeutic targets, for example, by identification of mechanistic links, which may also improve management of SDB in patients who are at risk, thereby improving health outcomes. Acknowledgements We thank the University of Liverpool, University Hospital Aintree and St Helens & Knowsley Teaching Hospitals, UK.

Conflict of interest The authors declared no conflicts of interest.

Funding This research has received grants from the University of Liverpool, University Hospital Aintree and St Helens & Knowsley Teaching Hospitals.

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