Obstructive Therapy and Metabolic Outcomes

Harneet K. Walia, MDa,b,*, Reena Mehra, MD, MSb,c,d

KEYWORDS Obstructive Metabolic syndrome Obesity Hypertension     Continuous positive airway pressure 

KEY POINTS There are both epidemiologic and experimental data implicating (OSA) as a  key pathophysiologic factor in the evolution of metabolic dysfunction and as a culprit in increasing cardiovascular risk. The metabolic syndrome consists of a constellation of clinical risk factors encompassing truncal  obesity, atherogenic dyslipidemia, elevated blood pressure, low glucose tolerance, and hyperinsu- linemia, which in aggregate set the stage for the development of diabetes mellitus and cardiovas- cular disease. Conceptual frameworks are emerging with respect to the mechanistic underpinnings of OSA  including intermittent hypoxia, sleep fragmentation, systemic inflammation and oxidative stress that contribute to the various facets of metabolic dysfunction. Reversal of the adverse accompanying pathophysiologic effects of OSA can have an impact on  metabolic outcomes. The data suggests that treatment of OSA may ameliorate some of the metabolic parameters of  metabolic syndrome.

INTRODUCTION with projections for a continued increase in fre- quency slated to reach levels in the epidemic Aligned with the obesity epidemic, metabolic realm.1 The metabolic syndrome consists of a dysfunction has evolved into a highly prevalent constellation of clinical risk factors encompassing condition with pervasive, far-reaching public health truncal obesity, atherogenic dyslipidemia (high implications. The metabolic syndrome, a term levels of triglyceride and low levels of high- characterized by a clustering of independent car- density lipoprotein [HDL] cholesterol), elevated diovascular risk factors, has a current estimated blood pressure (BP), low glucose tolerance, and prevalence of 30% in the United States population, hyperinsulinemia in the context of a prothrombotic

Conflicts of Interest Declaration: R. Mehra serves on the Medical Advisory Board for Care Core National, has received funding from the National Institutes of Health for research, and her institution has received positive airway devices from Philips Respironics for research for which she is the Principal Investigator. H. Walia has no conflicts of interest to disclose. R. Mehra was partially supported through funding by the NIH NHLBI 1R01HL109493 and R21HL108226. a Center for Sleep Disorders, Neurologic Institute, Cleveland Clinic, 11203 Stokes Boulevard, 2nd Floor, Cleveland, Ohio 44104, USA; b Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA; c Sleep Disorders Research, Center of Sleep Medicine, Neuro- logic Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA; d Molecular Cardiology Department, Lerner Research Institute, Heart and Vascular Institute, Respiratory Institute, 9500 Euclid Avenue, Cleveland, Ohio, 44195, USA * Corresponding author. E-mail address: [email protected]

Sleep Med Clin 8 (2013) 433–452 http://dx.doi.org/10.1016/j.jsmc.2013.07.009

1556-407X/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved. sleep.theclinics.com 434 Walia & Mehra

state and upregulation of systemic inflammation, mitigate cardiovascular risk, particularly in light which in aggregate set the stage for the devel- of data demonstrating synergism of OSA and opment of diabetes mellitus and cardiovascular metabolic syndrome in increasing .1,2 These risk factors result in serious risk.4 adverse health effects by interacting synergistically to increase cardiovascular morbidity and mortality 1,2 EPIDEMIOLOGY AND INTERRELATIONSHIPS by 2- to 3-fold. Diagnostic evaluation and tar- OF OBSTRUCTIVE SLEEP APNEA, METABOLIC geted intervention coupled with identification of SYNDROME, AND OBESITY critical contributors of metabolic syndrome are paramount in the paradigm of cardiovascular risk Identified relationships of OSA and metabolic syn- reduction. Reduction of cardiovascular risk is of drome are not unanticipated given the overlap of the utmost importance from the standpoint of pub- established associated factors including obesity, lic health imperatives as well as in targeting reduc- diabetes mellitus, and cardiovascular disease. tion of the high economic costs associated with The co-occurrence of metabolic risk factors for cardiovascular disease, namely, estimated direct both type 2 diabetes and cardiovascular disease and indirect costs of $500 billion in 2010 with (abdominal obesity, hyperglycemia, dyslipidemia, $150 billion resulting from loss of productivity and hypertension) suggested the existence of a related to disability and death.3 “metabolic syndrome,” also known as insulin resis- A wealth of both epidemiologic and experi- tance syndrome. According to criteria proposed by mental data have implicated obstructive sleep ap- the National Cholesterol Education Program nea (OSA) as a key pathophysiologic factor in the (NCEP) Adult Treatment Panel III, the metabolic evolution of metabolic dysfunction and as a culprit syndrome is defined by the presence of 3 or more in increasing cardiovascular risk. A singular chal- of the following: (1) abdominal obesity with waist lenge in investigating the interrelationships of circumference greater than 40 inches (102 cm) in obesity, metabolic syndrome, and OSA has been men and 35 inches (88 cm) in women, (2) serum tri- to effectively take into consideration and dissect glycerides of 150 mg/dL, (3) HDL cholesterol less the influence of OSA on metabolic syndrome inde- than 40 mg/dL in men and less than 50 mg/dL in pendent of the effect of obesity. OSA is a highly women, (4) BP greater than 130/85 mm Hg or prevalent disorder affecting approximately 15% drug treatment for hypertension, and (5) fasting of adults, characterized by reduction in upper glucose level greater than 110 mg/dL.5 The preva- airway muscle tone during sleep resulting in repet- lence of metabolic syndrome as defined by NCEP itive complete (resulting apnea) or partial (resulting criteria as per National Health and Nutrition Exam- in hypopnea) upper airway closure in the presence ination Survey (NHANES) data has undergone a of continued thoracoabdominal effort and, often, substantive increase from 22% in NHANES 1988 paradox. OSA results in accompanying physio- to 1994 to 34.5% in NHANES 1999 to 2002.6 Along logic perturbations including intermittent hypoxia, these lines, as expected, an age-dependent in- ventilatory overshoot hyperoxia, intrathoracic crease in the prevalence of metabolic syndrome pressure alterations, autonomic instability, and was also observed. Corroborating data from a sleep fragmentation. These effects then lead to large epidemiologic cohort, the Framingham Heart further adverse effects including increased sys- Study involving 3500 participants without diabetes temic inflammation and elevated oxidative stress. or cardiovascular disease at baseline, demon- The apnea-hypopnea index (AHI) is considered as strated an increase in prevalence of metabolic syn- the disease-defining metric for OSA, and is drome of 26.8% in men and 16.6% in women at defined by the number of and hypopneas baseline, and an almost doubling of prevalence of per hour of sleep. Other measures used to ascer- the metabolic syndrome in both men and women tain the severity of OSA include the oxygen desa- after an 8-year follow-up period.7 A likely contrib- turation index and percentage of sleep time spent uting factor to the noted dramatic increase in prev- in hypoxia. Conceptual frameworks are emerging alence of metabolic syndrome is the concordant with respect to the mechanistic underpinnings of obesity epidemic, which has been observed across OSA that contribute to the various facets of meta- of range of ethnicities.8 bolic dysfunction, which are elaborated in this OSA is also a highly prevalent disorder with article. Furthermore, the effect of the reversal of prevalence estimates of 9% to 24%,9 with a the adverse accompanying pathophysiologic ef- distinct risk-factor profile characterized by fects of OSA on metabolic outcomes is reviewed increased risk in men; positive linear relationships herein. These areas of investigation are of para- with increasing age; and augmented risk related to mount importance in achieving the goal of ef- obesity, owing to mechanical effects on the upper fective treatment of metabolic parameters to airway predisposing to collapsibility, as well as Obstructive Sleep Apnea Therapy and Metabolic Outcomes 435 neurohumoral effects of adipokines and craniofa- metabolic syndrome was further substantiated cial structural alterations resulting in compromise by data from a British study showing a 9-fold of upper airway caliber and function.10 Adverse increased likelihood of metabolic syndrome in effects of OSA, including intermittent hypoxia men with OSA even after consideration of and autonomic nervous system fluctuations, obesity.13 Taken together, accumulating evidence contribute to the increased risk of intermediate points to a steadily increasing prevalence of meta- cardiovascular factors comprising metabolic syn- bolic syndrome and a high prevalence of OSA, drome, as well as a wealth of data supporting with risk-factor profiles derived from a “common relationships between OSA and increased cardio- soil,” and relationships that are strong in magni- vascular morbidity and mortality.11,12 Although tude seemingly demonstrating a consistent obesity can be posited as the culprit connecting pattern of independence from obesity.13 OSA and metabolic syndrome, mounting data indi- cate that this is not entirely the case. Metabolic PHYSIOLOGIC AND BIOLOGICAL syndrome has been noted to be significantly MECHANISMS OF ALTERED METABOLIC associated with moderate to severe OSA in a com- REGULATION IN OBSTRUCTIVE SLEEP APNEA parison with obese controls, suggesting that obesity-independent OSA pathophysiologic path- The mechanisms linking OSA and alterations in ways are contributing to the evolution of metabolic metabolic regulation are likely to be multifactorial. syndrome.13 Amassing evidence also demon- OSA via repetitive upper airway collapse results in strates a relative synergism of the presence of bouts of intermittent hypoxia, hyperoxia, hypercap- OSA and metabolic syndrome, such that the nia, sympathetic nervous system activation, and burden of cardiovascular disease is far greater sleep disruption/fragmentation, which may be with both of these factors compared with either detrimental to glucose and lipid via in- alone.14 It has been posited that OSA, given its termediate mechanisms that include upregulation coaggregation and synergism with metabolic of pathways of systemic inflammation and oxida- syndrome, may represent a salient component of tive stress and abnormalities of the hypothalamic- metabolic syndrome constituting a cluster that pituitary axis. This section focuses primarily on has been termed Syndrome Z.15 The co-occur- the impact of OSA-related intermittent hypoxia, rence of OSA and metabolic syndrome, Syn- sleep fragmentation, and increased systemic drome Z,15 recently has been identified to be inflammation on metabolic function, as gaining a associated with a significantly greater atherogenic firm understanding of these concepts not only is burden and higher prevalence of calcified carotid crucial in setting the stage for the examination of in- artery atheromas when compared with OSA alone terventional trial data targeting reversal of OSA in the absence of metabolic syndrome,16 and is pathophysiology on metabolic outcomes, but also also correlated with intracoronary stenosis de- is instrumental in the interpretation of these data. tected by multislice computed tomography.17 Impact of on Metabolic Function Syndrome Z also appears to be related to alter- ations in cardiac morphology, specifically left ven- Experiments in animal models have shown that tricular hypertrophy and diastolic dysfunction.18 intermittent hypoxia can decrease insulin sensi- Epidemiologic data from the Wisconsin Sleep tivity and induce glucose intolerance.21,22 Some Cohort support strong associations between of these effects may occur via the sympathetic OSA and metabolic syndrome. Age-adjusted and nervous system and altered autonomic function, sex-adjusted associations resulted in a 4-fold the latter of which is impaired in OSA and also in increased odds of metabolic syndrome in those prediabetic persons with impaired glucose meta- with moderate to severe OSA, which persisted bolism.23 Catecholamines also inhibit insulin after adjustment for markers of sympathetic or secretion by activating a2-adrenoreceptors in b neuroendocrine activation (urinary norepinephrine, cells.24 Exposure to intermittent hypoxia in young cortisol, heart-rate variability); after further adjust- healthy adults has been shown to impair insulin ment for obesity this was mitigated to a 2.5-fold sensitivity with a lack of compensatory hyperinsu- increased odds of metabolic syndrome, although linemia, suggesting a concordant suppression of it remained significant.19 Furthermore, in a b-cell function.25 hospital-based urban northern Indian population, Independently of autonomic nervous system those with OSA were 4 times more likely to have activation, in animal models intermittent hypoxia metabolic syndrome than those without OSA, sup- contributes to decreased glucose utilization in porting the notion of consistent relationships oxidative muscle fibers.26 Furthermore, intermit- across different ethnic groups.20 The strong tent hypoxia contributes to increased b-cell prolif- magnitude of association between OSA and eration and cell death, the latter secondary to 436 Walia & Mehra

oxidative stress.27 Increased oxidative stress, response.33 Of note, fasting intravenous glucose increased lipid peroxidation, and upregulation of tolerance testing was used in this study, a tech- nuclear factor kB (NF-kB) and hypoxia-inducible nique considered to be the gold standard in the factor 1 are likely the main mechanisms of insulin assessment of glucose regulation.33 Sleep frag- resistance induced by hypoxia.28 mentation also led to an increase in morning Similar relationships have been confirmed in hu- cortisol levels and a shift in sympathovagal balance man studies examining the effects of intermittent toward an increase in sympathetic nervous system hypoxia on metabolic regulation. Specifically, a modulation and reduction in parasympathetic ac- study randomizing participants to 5 hours of in- tivity, hence shedding light on potential mecha- termittent hypoxia versus normoxia during wake- nistic underpinnings.33 Moreover, chronic sleep fulness supported the notion that hypoxic stress loss related to sleep-disordered is likely in OSA may increase the predisposition for meta- to worsen the metabolic disturbances and may bolic dysfunction by impairing insulin sensitivity, predispose to insulin resistance.34 Experimental glucose effectiveness, and insulin secretion.25 animal studies using intravenous glucose tolerance Moreover, in a large, prospective Japanese study testing before and after an 8-day period of sleep re- involving about 4000 middle-aged individuals, striction and disturbance, in the absence of sleep nocturnal intermittent hypoxia (3% oxygen satura- curtailment, resulted in hyperglycemia and tion dips 15/h on pulse oximetry at baseline) was decreased insulin levels, further corroborating the established as a risk factor for development of type results from human studies.35 More recent experi- 2 diabetes mellitus after a 3-year median follow-up mental data further support this premise, and period (1.7-fold risk of incidental diabetes mellitus extend the length of sleep fragmentation to compared with those without significant hypoxia) 14 days using a sleep interruption model intended after adjustment for multiple confounders.29 In to minimize stressful stimulation to the animal. the Cleveland Family study, measures of hypoxic Findings in the latter work demonstrated not only stress (time spent with <90% O2 saturation) were an impact on peripheral glucose metabolism but the strongest polysomnographic index associated also on appetite, with evidence of hyperphagia in with glucose intolerance.30 the absence of weight gain suggesting alterations in the metabolic rate as a potential culprit.36 Relationship of Sleep Fragmentation with Metabolic Regulation Systemic Inflammation and Oxidative Stress in Obstructive Sleep Apnea as Instigators of Although sleep fragmentation may occur in various Altered Metabolic Function sleep disorders, it is a cardinal feature of OSA and results in alterations in glucose metabolism inde- Inflammation has been proposed as a putative pendent of sleep duration. Both human and animal mechanism of cardiovascular risk in patients with experimental data support the notion of sleep frag- OSA, and it may also impair insulin action in periph- mentation representing an allostatic load on the eral tissues. Intermittent hypoxia and sleep frag- endocrine and autonomic systems, potentially mentation in OSA are postulated to be triggers of resulting in development of metabolic dysregula- the cascade of inflammation in the adipose tissue tion.31 For instance, it is recognized that the initia- and vascular compartment, and thus an array of in- tion of slow-wave sleep coincides with hormonal flammatory products may be released.37 Multiple changes that affect glucose homeostasis.32 As inflammatory markers and mediators, including such, all-night selective suppression of slow- NF-kB, C-reactive protein, tumor necrosis factor wave sleep for 3 consecutive nights has been a, and interleukin-6, are elevated in patients with shown to result in an approximately 25% reduction OSA,38 and these markers have been noted to be in insulin sensitivity without adequate compensa- culprits in inducing insulin resistance.39 The au- tory increase in insulin secretion, thereby leading thors’ group has shown relationships between to reduced glucose tolerance and increased risk markers of systemic inflammation (including solu- of developing diabetes.32 Moreover, 2 days of en- ble interleukin-6 receptor) and increasing severity forced sleep fragmentation resulting in poor sleep of OSA, independent of confounding by obesity quality and reduced slow-wave sleep yielded and apparent diurnal patterns such that morning similar results.32 Nonselective fragmentation of levels were more closely tied to OSA severity, sleep induced by auditory and mechanical stimuli potentially signifying a reflection of overnight across all stages for 2 nights is also associated OSA-related physiologic stress.40 The presence with a decrease in insulin sensitivity and non–insu- of these markers of inflammation in metabolic syn- lin-dependent glucose disposal, the latter referring drome41 support that OSA may play a role in devel- to glucose mobilization independent of an insulin opment of metabolic syndrome. Furthermore, the Obstructive Sleep Apnea Therapy and Metabolic Outcomes 437 adipokines, including leptin, ghrelin, and adiponec- abnormal lipid/lipoprotein serum levels were tin, are altered in patients with OSA and can pro- also noted.45 Data from a smaller randomized mote metabolic syndrome.38 Because of the trial showed an improvement in postprandial tri- close association between inflammation and insu- glycerides and total cholesterol levels in patients lin resistance, it has been suggested that visceral with moderate to severe OSA with CPAP ther- obesity is a potential pathogenic factor in promot- apy.46 A significant improvement in the ratio of ing inflammation and leading to insulin resistance HDL to total cholesterol and levels of total choles- and sleep apnea.42 Elevated oxidative stress is terol, triglycerides, and LDL and non-HDL choles- emerging as a central player in the pathogenesis terol with autoadjusting positive airway pressure of metabolic syndrome, and may represent a unify- (PAP) was noted in a randomized controlled trial, ing factor in progression of disease. In particular, with a significant increase in HDL cholesterol oxidative stress has been identified as a major noted only in more adherent patients.47 It remains mechanism underlying the microvascular and unclear, however, whether the improvement in macrovascular complications in metabolic syn- lipid profiles may be secondary to concomitant drome.43 OSA has been recognized as providing reduction in body mass index, or secondary to the ideal milieu for oxidative stress to occur, given direct reversal of OSA adverse physiologic effects the repetitive intermittent bouts of hypoxemia and with PAP. On the other hand, data from several subsequent episodes of reoxygenation, which studies have suggested that CPAP treatment may lead to generation of free radicals and a state does not improve serum lipid levels. In a random- of enhanced oxidative stress. This resultant state ized, controlled, crossover trial, obese Cauca- of augmented oxidative stress may thus lead to sians with symptoms of OSA underwent the metabolic insults seen in the representative intervention with 6 weeks of therapeutic versus components of metabolic syndrome. sham CPAP without an appreciable change in lipids. In the therapeutic CPAP group, there was EFFECT OF OBSTRUCTIVE SLEEP APNEA no significant change in cholesterol triglycerides, HDL cholesterol, and LDL cholesterol after TREATMENT WITH CONTINUOUS POSITIVE 48 AIRWAY PRESSURE ON LIPID BIOLOGY AND CPAP treatment. Similarly, in a double-blind, VISCERAL ADIPOSITY randomized controlled trial of therapeutic and sham CPAP for 3 months in men with type 2 dia- It has been hypothesized that continuous positive betes and OSA, no significant reduction in total airway pressure (CPAP) via amelioration of cholesterol, HDL cholesterol, or triglycerides breathing disturbances during sleep can improve was observed before and after treatment.49 the lipid profile, such as total cholesterol, low- Visceral adipose mass is considered to be a density lipoprotein (LDL) cholesterol, HDL choles- more accurate measure of dysfunctional adipose terol, triglycerides, and apolipoproteins A, B, and tissue than body mass index when considering C. However, despite mechanistic studies consis- facets of metabolic syndrome. Quantitative radio- tently demonstrating relationships between OSA logic measures of visceral adiposity using stan- and lipid biosynthesis and regulation, the effect dard computed tomography (CT) scans have of CPAP on lipids has revealed conflicting results. been reported as the gold-standard method for Several studies have shown that CPAP treatment assessing visceral adiposity, given its ability to is beneficial for improving the lipid profile of OSA precisely and reliably measure abdominal fat com- patients. A meta-analysis of 2 randomized, partments.50 In a randomized crossover trial placebo-controlled trials in OSA patients com- involving those with moderate to severe OSA, a pared the effect of therapeutic and subthera- significant reduction in visceral fat in addition to peutic CPAP treatment on cholesterol and subcutaneous fat was noted,47 which is contrary triglycerides. There was a significant reduction in to the findings of another randomized trial that total cholesterol levels among patients receiving failed to demonstrate reduction in visceral abdom- therapeutic CPAP for a short treatment duration inal fat over a 12-week period and did not show of 1 month compared with those receiving sub- improvement at 6 months during an uncontrolled therapeutic CPAP, and no significant changes portion of the study.51 Two other recent trials per- were observed in serum triglycerides in either formed over an 8-week period did not show reduc- group.44 A large study of OSA patients showed tion in visceral abdominal fat with CPAP treatment a small but statistically significant increase in of OSA.52,53 HDL cholesterol after 6 months of CPAP therapy. Overall, the effect of CPAP on visceral abdom- Significant improvements in serum levels of HDL inal fat has been inconsistent, with some studies cholesterol, LDL cholesterol, total cholesterol, showing improvement in the amount of visceral and triglycerides in OSA patients with baseline fat. This finding may be attributable to the relatively 438 Walia & Mehra

limited duration of OSA treatment implemented in anticipated and did not achieve the 3-mm Hg these trials.54,55 drop in mean 24-hour ambulatory BP that the trial was powered to detect. In the second study, the OBSTRUCTIVE SLEEP APNEA TREATMENT AND Spanish Sleep and Breathing Group trial of more HYPERTENSION than 350 asymptomatic individuals with severe OSA in which one arm was treated with CPAP, at OSA has been linked with hypertension (HTN), an 1-year follow-up the group treated with CPAP increased prevalence of a nondipping BP pattern, had a significant reduction in SBP and DBP of and increased risk of resistant HTN. Apnea- 1.9 mm Hg and 2.2 mm Hg, respectively. The related arousals and/or hypoxemia can result in most significant reduction in BP was seen in pa- sympathetic nervous system activation, leading to tients who used CPAP for more than 5.6 hours elevated nocturnal or daytime BP. The guidelines per night.58 on HTN detection and treatment recommend Several meta-analyses suggest that the benefi- evaluation of OSA as a cause of difficult-to-treat cial effects of CPAP on BP are detectable in the HTN.56 Numerous studies, ranging from uncon- first few weeks of treatment, this being counterin- trolled studies through clinical observational to ran- tuitive to what one may expect, as the vascular re- domized double-blind trials, have investigated the modeling and other structural cardiovascular effect of CPAP on HTN (Table 1). However, the ef- changes are not expected to be evident in short- fect of CPAP treatment on BP was highly variable, term trials of CPAP treatment, and longer treat- and some individuals do not show any antihyper- ment may be needed to obtain greater reductions tensive benefit other than having manifested a in BP. However, results from randomized trials very high BP response. This variability in response have found significant reductions in BP within a can be explained by multiple reasons: most studies few weeks of CPAP treatment.59–61 were of small sample size; most studies were per- A 2007 meta-analysis of 10 randomized formed in a single center; the methods used for controlled trials did not show any difference in measuring BP such as the 24-hour ambulatory BP SBP or DBP between the PAP and the control monitoring or office BP measurement varied widely group using ambulatory BP monitoring and office between the studies; and studies included patients BP measurements combined.62 In another meta- with and without hypertension, as well as different analysis including 16 trials conducted between types of hypertension and treatment interventions. 1996 and 2006 and a total of 818 patients, a small Furthermore, the method used to diagnose OSA but statistically significant mean net change in varied; the studies had different designs, such as SBP of 2.5 mm Hg and DBP of 1.8 mm Hg was crossover or parallel; studies used different inter- observed. Net reductions in BP were not statisti- ventions such as sham CPAP, subtherapeutic cally different between daytime and nighttime. CPAP, drug therapy, or conservative treatment in This meta-analysis included predominantly obese control participants; and the duration of interven- middle-aged men and comprised studies that tion varied between different studies. Even the were not blinded.63 meta-analyses of randomized trials are limited by In one of the prospective observational studies the trials they included, and many of the trials did with a longer follow-up of 55 patients, a significant not involve the patients most likely to benefit, which decrease was shown only for DBP ( 2.2 mm Hg) may explain the variability of the results. Use of but not SBP or 24-hour mean arterialÀ BP. Sub- CPAP has generally shown a consistent, albeit group analyses, however, showed that 24-hour modest, antihypertensive benefit. Patients who mean BP did decrease significantly in patients are most likely to benefit include those with more with uncontrolled HTN at entry ( 4.4 mm Hg, severe OSA, and higher baseline pretreatment BP P 5 .01) as well as in those with highÀ CPAP compli- levels, and patients more compliant with CPAP use. ance ( 5.3 mm Hg, P 5 .01).64 Two large, randomized controlled trials evalu- A significantÀ decrease in BP was reported by ating the role of CPAP in HTN were recently pub- Pepperell and colleagues61 in 118 patients, with lished.57,58 The first was randomized, multicenter, the largest effect on BP observed with CPAP in se- double-blind, placebo-controlled trial of 340 pa- vere OSA (oxygen desaturation index >33/h, tients, primarily men (81%), which showed a sta- decrease in BP of 5.1 mm Hg), Moreover, use of tistically significant decline in 24-hour arterial BP, therapeutic CPAP for more than 5 hours per night systolic BP (SBP), and diastolic BP (DBP) by 1.5, showed a greater trend toward decreased BP. 2.1, and 1.3 mm Hg, respectively. Mean nocturnal Becker and colleagues65 showed the largest BP decreased by 2.0 mm Hg after 3 months of reduction in BP of about 10 mm Hg SBP, mean treatment in patients with newly diagnosed arterial BP, and DBP in a 9-week double-blind trial HTN.57 This observed reduction was smaller than in patients with moderate to severe sleep apnea. Obstructive Sleep Apnea Therapy and Metabolic Outcomes 439

This drop in BP was seen in patients with thera- BP.74 A small study involving only 11 subjects peutic CPAP treatment with an approximately with an oral appliance showed improvement in 95% reduction in AHI. Despite the reduction in ambulatory BP monitoring after titration.75 A ran- AHI by 50%, in the subtherapeutic control group domized, controlled, crossover trial of 61 patients there was no significant reduction in BP. Coughlin showed significant reduction in mean 24-hour and colleagues48 showed a reduction in mean DBP and awake BP; however, no reduction was SBP and DBP of 6.7 mm Hg and 4.9 mm Hg, seen in SBP.76 Andren and colleagues77 conducted respectively, with CPAP in obese individuals, and a long-term follow-up study of patients with mild there were no changes in metabolic parameters. OSA, and showed that a reduction in SBP and In another randomized study that used ambula- DBP was maintained after 3 years of use of a tory BP measurements in patients with OSA, a mandibular advancement oral appliance. A meta- 12-week CPAP regimen resulted in a reduction in analysis indicated the pooled estimate of mean 24-hour mean BP and DBP by 3.8 and 3.5 mm changes and the corresponding 95% confidence Hg, respectively. In this study, the majority of sub- interval (CI) for SBP, DBP, and mean arterial BP, jects were not sleepy based on the Epworth Sleep- respectively, from each trial were: 2.7 mm Hg iness Scale (ESS) score.66 Whereas some of the (95% CI: 0.8 to 4.6); 2.7 mmÀ Hg (95% CI: trials have shown improvement in BP with CPAP 0.9 to 4.6);À and À 2.40À mm Hg (95% CI: 4.01 in hypersomnolent patients,59 Robinson and col- toÀ 0.80).À À À leagues67 showed no significant improvement in TheÀ clinical significance of SBP and DBP reduc- BP with CPAP in nonhypersomnolent patients, tions of 2 to 4 mm Hg can be put into perspective suggesting a role of hypersomnolence in the path- by data showing a 15% and 42% reduction in the ogenesis of HTN caused by OSA. There have been risk of coronary artery disease and stroke, respec- other randomized trials reinforcing the improve- tively, with a reduction in BP of 5 mm Hg.78 With ment of various BP measurements with CPAP.68 respect to the effect of OSA treatment on BP The effect on BP by CPAP withdrawal has also reduction, there is a clinically significant cardio- been measured, which showed an increase in vascular benefit to OSA treatment in potentially morning SBP and DBP and morning heart rate, reducing adverse cardiovascular outcomes, for along with increases in other clinical features and which hypertension represents a firm risk factor. inflammatory markers of OSA.69 In 2011, Drager Areas of future work should focus on better under- and colleagues70 showed the impact of CPAP on standing the relationships of OSA and nondipping a novel group of patients with pre-HTN and or BP profiles, in particular to examine the potential masked HTN. Thirty-six male patients randomized benefits of chronotherapy for antihypertensive to no treatment and CPAP for 3 months showed a medication in OSA patients. Use of supplemental significant reduction of pre-HTN (from 94% to oxygen as a treatment of OSA-related intermittent 55%) and masked HTN (from 39% to 5%). This hypoxia may also serve to blunt sympathetic finding is important from clinical standpoint, as nervous system surges and reduce BP; therefore most patients with pre-HTN develop HTN later. interventional trials examining this effect are This study is the first to evaluate the effect of BP desired. Along these lines, results of a multicenter, in pre-HTN patients. Overall, CPAP has been randomized controlled trial involving patients from shown to have a modest effect in reducing BP, cardiology clinics with moderate to severe OSA which also is important from the clinical viewpoint randomized to CPAP, supplemental oxygen, or a because it can have a significant effect in reducing healthy lifestyle are forthcoming. Moreover, OSA comorbidity. as a culprit of resistant hypertension and nondip- Most results available on the effect on BP of an ping BP patterns needs to be addressed from oral appliance are based on observational data. the standpoint of ascertaining improvement in Most studies showed a significant improvement in BP profiles in this high-risk group. BP in mild to moderate sleep apnea with use of an oral appliance.71,72 A Chinese study of 46 pa- EFFECT OF POSITIVE AIRWAY PRESSURE tients compared a group wearing an oral appliance AND NON–POSITIVE AIRWAY PRESSURE monitored by ambulatory BP with a nontolerated MODALITIES OF OBSTRUCTIVE SLEEP APNEA oral appliance treatment group.73 There was a sig- THERAPY ON COMPONENTS OF METABOLIC nificant improvement in SBP, DBP, 24-hour and SYNDROME diurnal SBP, and mean arterial pressure in the Uncontrolled Trials oral appliance group in comparison with the other group after 12 weeks of treatment. Another obser- Several uncontrolled trials have focused on the vational study involving 161 patients showed effect of CPAP therapy on OSA and its impact on improvement in SBP, DBP, and mean arterial metabolic syndrome. These studies have been 440 ai Mehra & Walia

Table 1 Studies investigating the effect of CPAP on blood pressure

Authors,Ref. Effect of Treatment Year Type N Male (%) Age (y) Intervention Duration OSA BP on BP Parameters Duran- Randomized 340 81 53.2, 51.7 CPAP and 3 mo AHI >15 History of HTN or on Y in ABP by 1.5 mm Hg Cantolla controlled sham CPAP antihypertensive Y SBP 2.1 mm Hg, YDBP 57 et al, 2010 double- (<1 cm H2O) medications 1.3 mm Hg blind trial Becker et al,65 Randomized 32 60 54.4, 52.3 CPAP and 9 wk AHI 5, None Y 9.9 mm Hg, MBP and 2003 controlled subtherapeutic ESS 10 SBP and DBP Y by trial PAP 10 mm Hg Pepperell Randomized 118 100 51 Therapeutic and 1 mo ESS >9, ODI None Y MAP by 2.5 mm Hg et al,61 2002 controlled subtherapeutic (4%) >10 Effect more pronounced parallel- CPAP (1 cm H2O) in severe OSA group trial Robinson Randomized 35 31 54 Auto PAP and 1 mo ODI Excluded BP No significant difference et al,67 2006 controlled subtherapeutic (4%) >10 <140/90 or not on in mean 24-h BP in crossover CPAP antihypertensive nonhypersomnolent trial patients Hui et al,66 Randomized 28 22/6, 21/7 50.3, 51.2 Therapeutic 12 wk AHI >5 with None Y in 24-h mean BP by 2006 controlled (10.7 cm H2O) symptoms 3.8 mm Hg and DBP parallel- CPAP and of OSA by 3.5 mm Hg group trial subtherapeutic CPAP (4 cm H2O) Coughlin Randomized 34 100 49.0 8.3 CPAP and sham 6 wk AHI >15 Excluded Y in SBP and DBP by 6.7 et al,48 2007 controlled Æ CPAP BP >180/110 and 4.9 mm Hg, no crossover change in metabolic trial parameters Kohler Randomized 41 19/1, 21/0 63.6, 61.8 CPAP or 2 wk ODI Excluded CPAP withdrawal was et al,69 2011 controlled withdrawal CPAP (4%) 10 inadequately associated with trial (subtherapeutic  controlled HTN increase in morning CPAP) office SBP (8.5 mm Hg), morning DBP (6.9 mm Hg) Drager Randomized 36 100 43 CPAP No treatment or 3 mo AHI >30 Pre-HTN CPAP (from 126 5to et al,70 2011 controlled 44 control CPAP treatment (SBP 120–139, 121 7 mm Hg;Æ trial (based on PSG) DBP 80–89), P 5 Æ.001) and a trend masked HTN DBP (from 75 7to (AABP 135>85) 73 8 mm Hg;ÆP 5 .08). SignificantÆ reduction in frequency of pre-HTN (from 94% to 55%; Outcomes Metabolic and Therapy Apnea Sleep Obstructive P 5 .02) and masked HTN (from 39% to 5%; P 5 .04) only in the CPAP group Barbe Randomized 359 100 56 10 CPAP or 1 y AHI >19, SBP >140 or Reduction of in SBP and et al,58 2010 controlled Æ conservative ESS <11 DBP >90 DBP of 1.9 mm Hg and trial treatment 2.2 mm Hg, respectively. Most significant reduction in BP seen in patients who used CPAP for more than 5.6 h per night Faccenda Randomized 68 81 50 CPAP or oral 4 wk AHI >15 24 h BP 1.5 mm Hg reduction et al,59 2001 controlled placebo in DBP crossover trial

Abbreviations: ABP, ambulatory blood pressure (mm Hg); AHI, apnea-hypopnea index; BP, blood pressure (mm Hg); CPAP, continuous positive airway pressure; DBP, diastolic blood pressure (mm Hg); HTN, hypertension; MAP, mean arterial blood pressure (mm Hg); ODI, oxygen desaturation index; OSA, obstructive sleep apnea; PSG, polysomnography; SBP, systolic blood pressure (mm Hg). 441 442 Walia & Mehra

limited by their small sample size, uncontrolled observed in those who used CPAP for more than nature, and varying consideration of primary and 4 hours per day.82 A few studies have assessed secondary outcomes. One of the first studies re- metabolic parameters of individuals undergoing porting the effect of OSA treatment with CPAP treatment for OSA over a more prolonged period on metabolic syndrome assessed this effect on in- of time. Specifically, another study involving a sulin resistance as ascertained by the insulin small sample size but following patients with sensitivity index gleaned from the gold-standard OSA and on CPAP for a 1-year period, demon- hyperinsulinemic euglycemic clamp studies, strated a 45% reduction in prevalence of meta- which were performed in 40 patients over a bolic syndrome and an improvement in HDL 3-month period.79 The degree of apnea was mod- cholesterol as well as waist circumference and erate to severe (AHI >20) and the investigators body mass index; however, no improvement was observed a significant increase in insulin sensitivity noted in fasting blood glucose, triglyceride, or BP after 2 days of CPAP treatment, which persisted at levels.83 A 6-month study of male patients with 3 months and appeared to be most pronounced in moderate to severe OSA treated with autoadjust- the nonobese individuals (ie, those with a body ing CPAP showed that treatment resulted in a mass index <30 kg/m2). These effects were noted reduction in prevalence of metabolic syndrome in the absence of significant changes in body mass from 63.5% to 47.3%, primarily attributable to index. The investigators surmised that the early reductions in BP and triglycerides.84 improvement in insulin sensitivity may be second- In summary, results from uncontrolled interven- ary to reversal of sympathetic nervous system tional studies appear to be somewhat consistent in surges related to OSA, and that the preferential demonstrating improvements in metabolic param- benefit noted in the nonobese may reflect primarily eters, albeit showing discrepancies regarding an obesity-driven source of insulin resistance in which specific components of metabolic syn- obese individuals with a lesser extent of OSA influ- drome show improvement. Data suggest that early ence in this setting. Limitations of this study improvements are noted (as soon as 2 days after included the involvement of only men, with results therapy) and that effects may be more pronounced generalizable as such, and also that only a small in the nonobese. The degree of improvement in proportion of individuals had impaired glucose metabolic function also appears to be related to tolerance.79 the level of CPAP adherence. The results seem Another clinic-based study of primarily men who to be generalizable to primarily men. Of note, were morbidly obese (mean body mass index of 43 some of the studies showed improvement in 8.7 kg/m2) showed an improvement in postpran- body mass index during follow-up, precluding Ædial glucose values as well as a reduction in hemo- one’s ability to effectively ascertain whether im- globin A1c (HbA1c) levels in those with a baseline provements in metabolic function were related to HbA1c level of greater than 7%. Furthermore, direct treatment of OSA or indirect improvement there was a relationship of improved glucose in anthropometrics. Overall these studies were handling relative to PAP usage such that in those limited by smaller sample sizes, mostly shorter individuals using CPAP for greater than 4 hours duration of therapy, limited generalizability, and per day, the reduction in HbA1c level correlated few gold-standard techniques used to assess with the days of CPAP usage; this finding was insulin resistance. not observed in those less adherent with ther- apy.80 Similarly, findings from another study with Randomized Controlled Interventional Trials a small sample size demonstrated a correlation of hypoxemia in patients with OSA and HbA1c There have been 6 randomized controlled trials levels in a group ranging from normal to predia- that have evaluated the role of CPAP in reversing betic and diabetic. Individuals with optimal adher- metabolic abnormalities in patients with OSA ence after 3 to 5 months of CPAP therapy showed (Table 2). These trials have examined populations a significant reduction in HbA1c levels.81 with different ethnic backgrounds and differing Two months of CPAP therapy in a small study background characteristics of subjects, and have showed improvement in cardiovascular risk pro- used varying study designs and eligibility criteria files of patients with severe OSA and concurrent as well as different durations of therapy. metabolic syndrome, resulting in reductions in The largest and, likely, most appropriately BP, total cholesterol levels, insulin resistance powered trial to examine the effects of PAP on measured by Homeostatic Model Assessment— metabolic function was a randomized, crossover, Insulin Resistance (HOMA-IR), tumor necrosis fac- double-blinded, controlled trial based in India tor a, and oxidative stress markers. Similar to other involving 86 participants, with the goal of assess- data, these beneficial effects of therapy were ing the reversal of metabolic syndrome with Table 2 Controlled trials evaluating the role of CPAP in reversing metabolic abnormalities in patients with OSA

Body Mass Authors,Ref. Index Power OSA Predefined Type of Year Age (y) Gender (kg/m2) Number Calculations Study Design Definition Outcome Duration Treatment Findings Weinstock 54 42% males 39 50, n 5 1 80% power Randomized, AHI >15 Primary: 8wkofCPAP CPAP vs sham 13.3% et al,85 Range: with lost to to detect crossover, Normalization or sham CPAP, CPAP improvement 2012 18–75 baseline follow- difference double-blind of mean 2 h CPAP adherence in ISI and impaired up in glucose trial with 1 mo oral glucose followed by 4.8 h/d 28.7% glucose tolerance washout and tolerance alternative reduction in tolerance, status 2 wk run-in testing therapy 2 h insulin USA (anticipating period, the Secondary: after 1 mo level in CPAP 20%–35% latter to assess Improvement washout group in CPAP and adherence in ISI (0, 120) severe OSA 10%–15% (AHI >30) of sham Impaired glucose improved to tolerance normal) normalized after CPAP with moderate OSA and obesity Each hour of active CPAP associated with improvement in insulin sensitivity (0, 120) A subset of participants underwent CPAP treatment for 12 wk without improvement in insulin sensitivity (continued on next page) 443 444

Table 2 (continued)

Body Mass Authors,Ref. Index Power OSA Predefined Type of Year Age (y) Gender (kg/m2) Number Calculations Study Design Definition Outcome Duration Treatment Findings Hoyos 49 12 100% 31.3 5.2 65, 13 Randomized AHI 20 Primary: Change 12 wk CPAP vs No significant et al,51 Æ males, Æ with- parallel-design  in visceral sham CPAP improvement 2012 Australia drawals controlled trial abdominal fat followed by in metabolic post Secondary: 12 wk of outcomes random- Change in CPAP for including ization insulin sensitivity both groups, visceral index and liver mean CPAP abdominal fat fat, body adherence At 24 wk, composition 3.6 h improvement and metabolic of insulin markers sensitivity was noted Sharma 45 84% 33.8 86 80% power to Randomized, AHI 15 Primary: 15% 12 wk Auto PAP vs 11% of the CPAP et al,47 Range: males in detect a 15% crossover  reduction in sham CPAP, group vs 1% 2011 30–65 CPAP first reduction in double-blind metabolic CPAP of the sham 95% metabolic trial with 1 mo syndrome adherence group had males in syndrome washout 4.8 1.4 h reversal of the sham period Æ metabolic CPAP first syndrome ESS (P 5 .003). 14.8 3.7 Decrease in in CPAPÆ systolic and group vs diastolic BP, 14.1 3.5 total in shamÆ cholesterol, group non-HDL, India triglycerides, and glycated hemoglobin. Decrease in BMI, visceral and subcutaneous fat Lam 46.3 100% males, 27.5 3.7 61, n 5 1 90% power Randomized AHI 15 Primary: Change in 1 wk followed Auto CPAP for Early et al,86 10.2Æ China Æ lost to to detect parallel-design  short insulin by 11 wk of 1 wk and improvement 2010 follow- difference controlled trial tolerance test open study fixed PAP in insulin up in insulin for 11 wk vs sensitivity tolerance sham CPAP (P 5 .022) test (Kitt) which was not 1.7 1.5 sustained at mmol/minÆ 12 wk, improvement in insulin sensitivity in subgroup with BMI >25 kg/m2 Coughlin 49 8.3 All males, 36.1 7.6 34, 1 90% power to Randomized, AHI >15 Primary: Metabolic 6 wk CPAP vs sham No change in et al,48 Æ Caucasian, Æ with- detect 20% controlled, syndrome, CPAP, mean HOMA-IR, or 2007 no drawal reduction of blinded HOMA, Change CPAP lipids, mean diabetes metabolic crossover trial in waking BP or adherence systolic and mellitus, syndrome glucose, 3.9 h (range diastolic BP ESS 10, baroreceptor 0–7.4) decreased by UK  sensitivity 6.7 and 4.9 mm Hg, respectively West Range: All males CPAP: 36.6 42, n 5 2 90% power to Randomized >10 oxygen Primary: HbA1c; 12 wk Auto No change et al,49 18–75 with 4.9 lost to detect 0.8 parallel-design saturation also examined CPAP vs in glycemic 2007 diabetes Sham:Æ 36.8 follow- difference double-blind dips of were HOMA placebo index and mellitus 4.6 up in HbA1c trial >4%/h and euglycemic CPAP, mean insulin and Æ hyperinsulinemic usage of resistance sleepiness clamp CPAP 3.6 (HbA1c, (ESS 9), 2.8 h euglycemic UK  Æ clamp, HOMA, adipoonectin)

Abbreviations: AHI, apnea-hypopnea index; BMI, body mass index; CPAP, continuous positive airway pressure; ESS, Epworth Sleepiness Scale; HbA1c, hemoglobin A1c; HDL, high-density lipo- protein cholesterol; HOMA (-IR), Homeostasis Model Assessment (Insulin Resistance); ISI, Insulin Sensitivity Index; OGTT, oral glucose tolerance test; OSA, obstructive sleep apnea. 445 446 Walia & Mehra

3 months of autoadjusting PAP followed by fat with CPAP versus sham CPAP, suggesting 3 months of sham PAP (or vice versa) separated that the reduction in adiposity as a result of by a 1-month washout period to minimize carry- CPAP may have been driving the improvement in over effects.47 The study involved predominantly metabolic parameters in the study by Sharma obese, middle-aged men with moderate to severe and colleagues,47 and could potentially account OSA (overall mean AHI of 48) and excessive day- for the differences in the study results. Alterna- time sleepiness, but without diabetes mellitus. tively, the reduction in visceral fat may have been The sample had a high degree of sleepiness, a result of differential behavioral or lifestyle habits with an ESS score of 14.8 3.7 in the PAP-first rather than a direct effect of CPAP; however, there group versus 14.1 3.4 inÆ the sham-first group. was no evidence of this, based on the social and The PAP adherenceÆ noted in this trial was higher lifestyle habits collected. than that of other studies, namely 4.8 1.4 hours The goal of a parallel-group randomized of daily usage. Autoadjusting PAPÆ treatment controlled trial involving 61 middle-aged, over- compared with sham PAP was associated with a weight, Chinese men with moderate to severe significant reduction in glycated hemoglobin, tri- OSA was to examine the effect of 1 week of auto- glycerides, and total cholesterol, as well as a titrating CPAP versus sham CPAP on short insulin significant increase in HDL cholesterol to total tolerance test (SITT) results and then to perform an cholesterol ratio. The reversal of metabolic syn- extended investigation of effects of 12 weeks of drome (primary outcome) was observed in 13% CPAP.86 Insulin sensitivity, measured by the of participants using autoadjusting PAP therapy, SITT, was shown to be significantly improved after compared with 1% with sham PAP. Concomitant 1 week of CPAP, and the effect was sustained at significant reductions in body mass index, visceral 12 weeks in only a subgroup of overweight/obese fat, and subcutaneous fat were seen in treatment individuals (body mass index>25 kg/m2). The re- with autoadjusting PAP in comparison with the sults are consistent with the observation of early control period. In subgroup analyses, significant improvement of insulin sensitivity in response to improvement in carotid intima-media thickness CPAP noted in uncontrolled trial data; however, was noted among the more adherent patients, the lack of sustained effects may be due to lack suggesting a potential role for PAP therapy in of a control comparison arm. Interestingly, the reversing endothelial damage caused by OSA sustained metabolic improvement in those who and metabolic syndrome.47 were overweight/obese counters the existing Another recent study using a crossover design uncontrolled data.86 involved 50 obese, middle-aged individuals with Two randomized controlled trials based in the moderate to severe OSA (AHI 44 27 in the United Kingdom examined the effect of moderate CPAP-first group and 32 20 in theÆ sham CPAP to severe OSA treatment on components of meta- group) and impaired glucoseÆ tolerance who were bolic syndrome in men.48,49 The first involved randomized to 8 weeks of CPAP followed by middle-aged, obese men without diabetes mellitus sham CPAP (or vice versa) after a 1-month participating in a randomized crossover study, washout period.85 Education on healthy lifestyle with results consistent with lack of reversal of behavior was provided to all participants. Adher- metabolic syndrome with 6 weeks of CPAP versus ence to CPAP was similar to that of the India- sham CPAP (mean CPAP adherence 3.9 hours). based study, at average 4.8 hours of daily usage. Although reductions in SBP and DBP were noted, Overall, there was no improvement in the primary there was no change in the HOMA-IR (measure of outcome, insulin sensitivity, in those on CPAP insulin sensitivity) nor was there improvement in versus sham CPAP; however, in subgroup ana- the lipid profile. Of note, lack of use of a washout lyses those with severe OSA had 13% improve- period to minimize the potential carryover effect ment noted in the Insulin Sensitivity Index (0, of CPAP is a methodologic flaw of this study, 120) and a 28% reduction in the 2-hour insulin and an important aspect to bear in mind when level after CPAP in comparison with those on interpreting results.48 The other randomized, sham CPAP. Moreover, each additional hour of parallel-design United Kingdom–based study active CPAP usage was associated with a signifi- involving middle-aged, obese men with diabetes cant improvement in the Insulin Sensitivity Index, mellitus failed to show evidence of reduction in and this improvement was more pronounced in HbA1c with 12 weeks of autoadjusting CPAP sleepier participants. This study demonstrated a versus sham CPAP. Although the euglycemic hy- dose-response effect for both the severity of dis- perinsulinemic clamp technique was used in this ease and adherence to treatment.85 Contrary to study, the small sample size and lower CPAP the study based in India, there was no reduction adherence, which were also issues with the other in CT-based ascertainment of visceral abdominal United Kingdom study, may have precluded Obstructive Sleep Apnea Therapy and Metabolic Outcomes 447 ascertainment of significant findings.49 Subgroup uncontrolled type 2 diabetes (and a high preva- analyses were performed in both of these studies lence of metabolic syndrome), 12 months of med- with respect to good versus poor CPAP adher- ical therapy plus bariatric surgery achieved ence, with consistency in findings of lack of glycemic control in significantly more patients improvement in metabolic parameters.48,49 than did medical therapy alone.91 Similar to evalu- Contrary to other studies, the parallel-design ating PAP trials in OSA on metabolic function, it is randomized controlled trial involving middle- unclear whether an improvement in metabolic aged, obese Australian men with moderate to se- regulation in treated OSA is a function of direct ef- vere OSA considered visceral abdominal fat as a fects of reversing OSA pathophysiology versus primary outcome after 12 weeks of CPAP versus reduction in body fat, or as a direct or indirect sham CPAP.51 No differences were observed in in- result of OSA treatment. A recently published ran- sulin sensitivity, visceral abdominal fat, and liver domized trial helps to shed light on the answer to fat at 12 weeks. At 24 weeks, after an additional this question.92 The trial involved obese patients 12 weeks of treatment for the entire group (those with moderate to severe OSA randomized to con- randomized to CPAP and sham CPAP), insulin ventional weight loss versus laparoscopic adjust- sensitivity, but not visceral abdominal fat or liver able gastric banding, and examined the AHI as fat, were improved over baseline. These findings well as changes in anthropometrics and metabolic suggest that a longer duration of OSA treatment variables. Despite major differences in weight loss, may be required to observe substantive improve- there was no statistically significant reduction in ments in metabolic function.51 AHI between the 2 groups, nor was there signifi- Two recent meta-analyses have explored the cant improvement in metabolic syndrome, lipid relationship of CPAP with its effect on metabolic profile, or glycemic control. These findings imply outcomes. The first meta-analysis examined 3 that despite weight reduction, if OSA is not parallel-group trials, 2 crossover, randomized adequately ameliorated by intervention (in this controlled trials, and 1 randomized trial of 296 sub- case bariatric surgery), achieving improvement in jects. This meta-analysis did not show any influ- metabolic parameters does not occur. These ence of CPAP on plasma insulin or HOMA-IR, data suggest that addressing OSA pathophysi- adiponectin levels, or HbA1c values.87 The second ology in the face of weight loss is likely a key factor meta-analysis evaluated the impact of CPAP on in improving metabolic function.92 Regarding glycated hemoglobin. This meta-analysis included investigation of the effects of other non-PAP ther- 9 observational studies and randomized trials of apies for OSA on metabolic function such as oral 151 subjects, and treatment durations ranging appliances and upper airway surgery, there are from 41 days to 6 months. The analysis concluded virtually no data that investigate the effects on that CPAP usage in the short term did not show a glucose homeostasis or lipid profiles, underscor- reduction in HbA1c.88 ing the need for future research in these areas.

Effect of Non–Positive Airway Pressure SUMMARY Modalities of Obstructive Sleep Apnea In summary, these uncontrolled and controlled Therapy on Components of Metabolic studies across a vast array of different ethnicities Syndrome and racial backgrounds show that the effects of There are limited data on the direct effect of bariat- OSA treatment on metabolic outcomes have ric surgery as treatment of OSA on metabolic pa- been discrepant, despite adequate biological rameters. Based on a recent systematic review plausibility to support the notion of anticipated involving 69 studies and 13,900 patients, one can benefits of therapeutic interventions for OSA on surmise that irrespective of the type bariatric sur- metabolic regulation. The external validity of exist- gery (ie, Roux-en-Y gastric bypass, laparoscopic ing studies applies primarily to middle-aged, sleeve gastrectomy, or biliopancreatic diversion), obese men. Although the data from the PAP ran- improvement in OSA severity ensued after the bar- domized controlled trials have been inconsistent, iatric intervention.89 Data have also been amassed 3 of the 6 trials conducted to date that demon- from numerous studies highlighting remission of strated improvements in metabolic function, either type 2 diabetes after the bariatric procedures.90 overall or in subgroup analyses, involved larger Furthermore, in a recent single-center, random- sample sizes and were likely more appropriately ized controlled trial comparing intensive medical powered to detect changes in metabolic out- therapy with surgical treatment involving gastric comes.47,85,86 Moreover, 2 of the 3 trials that bypass or sleeve gastrectomy as a means to showed significant metabolic improvements used improve glycemic control in obese patients with crossover designs, which are inherently more 448 Walia & Mehra

efficient and allow for enhanced power given a in OSA reflect lack of improvement in metabolic similar number of participants enrolled in a parameters despite weight loss in the setting of parallel-design trial.47,85 The randomized trial nonsignificant reversal of OSA, thereby suggesting studies involved predominantly obese, sleepy, weight-independent effects of OSA treatment on middle-aged participants, and all except 1 metabolic regulation, adequately powered studies involved primarily male participants, thereby should be focused on addressing and better un- limiting the associated generalizability, and high- derstanding the impact of weight changes on lighting the need to focus future investigations on metabolic function in OSA treatment. The interplay the metabolic function of nonobese individuals or of excessive daytime sleepiness should also be women. Although 2 of the uncontrolled studies investigated, as it seems that sleepier individuals involved a follow-up period of 6 to 12 months, with OSA may potentially derive more metabolic the randomized controlled trials involved follow- benefit from OSA treatment. Questions regarding up periods of 6 to 12 weeks, time frames that optimal duration and the amount of CPAP still may be too short to appreciate metabolic improve- remain unanswered, and will need to be ad- ments. Differences in the usage of static versus dressed in future studies. Future interventional autoadjusting CPAP also characterize these studies should also focus on populations that studies and may also lead to differences in results. have not been examined closely thus far, including For example, if a certain subset of participants was women, nonobese individuals, and those with se- more likely to have positional or rapid eye move- vere OSA, as the latter group may in particular ment sleep–related OSA, perhaps more benefit derive treatment benefit from a metabolic stand- may have been gleaned with autoadjusting than point based on preliminary subgroup analyses of with static CPAP. Varying approaches were used existing trial data. 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