Weight-loss treatment.pdf

8/14/2019 Weight-loss treatment.pdf

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treatment with sibutramine in sleep apnoea, the much larger long-term safety concernshighlighted 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 fenfluraminehydrochloride 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, in1997, 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 reuptakeinhibitors), phentermine and diethylpropion (sympathomimetic agents), and zonisamide andtopiramate (anticonvulsants), have known appetite-suppressing effects. However, at present noneof 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 isundergoing assessment by the FDA. A phase II double-blind randomised controlled trialcomparing the effects of topiramate/phenteramine versus placebo in obese patients with OSA is inprogress (ClinicalTrials.gov NCT00745251). A recently presented abstract of this study indicated ahigher degree of weight loss and associated improvements in AHI compared to placebo after28 weeks of treatment [85].

Orlistat

Following the withdrawal of sibutramine from Europe, orlistat is the only remaining registereddrug indicated for weight loss in that market. Orlistat is a gastric and pancreatic lipase inhibitorthat 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 controlledtrials using 120 mg orlistat three times daily, found an overall 2.9 kg (95% CI 2.53.2 kg) greaterweight 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 a2-yr weight-maintenance trial of 688 overweight-to-obese subjects (BMI 2847 kg ?m -2 ), orlistat120 mg three times daily taken with an appropriate diet resulted in clinically significant weight lossand reduced weight regain when compared with placebo (10.3 and 6.1 kg, respectively). After thefirst year, subjects were re-randomised. Those switched from active drug to placebo regainedweight and those switched from placebo to active drug lost weight [88]. Orlistat-assisted weightloss has also been shown to have a modest effect on insulin resistance, hypertension and serumcholesterol 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.

Summary

Current European and North American guidelines recommend adjunctive weight-loss therapieswhen 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 remainoverweight or obese despite drug treatment. However, even substantial weight loss does notnecessarily cause improvements in OSA. Until recently, sibutramine was the most promisingpharmaceutical in our arsenal but recent news from SCOUT leaves its future availability questionable. The only currently remaining medication with an acceptable side-effect profile isorlistat, a drug completely untested in OSA.

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Surgical weight loss

Introduction and general effectiveness

Bariatric surgery can be an effective method to reduce weight in the short term and allow long-term weight maintenance [91, 92]. A Cochrane review updated in 2008 concluded that bariatricsurgery is more effective than conventional therapies in the management of obesity, achievinggreater 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 allrecommend consideration of bariatric surgery for the morbidly obese (BMI . 40 kg?m -2 ) andobese individuals with comorbidities (BMI . 35 kg?m -2 ) who are unable to lose weight despiteconventional measures [60, 61, 94, 95]. Bariatric surgery has been shown to reduce mortality,cardiovascular disease-related risk factors and cancer incidence in the prospective, controlledSwedish Obese Subjects (SOS) study [33, 35].

The aim of bariatric surgery is two-fold: to reduce caloric intake and to alter the hormonal andendocrine 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 duodenalswitch, 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 isboth restrictive and malabsorptive [98, 99]. Overall, gastric bypass is more efficacious than gastricbanding or gastroplasty, but with longer operative time and perioperative hospitalisation, as wellas higher complication rates. Perioperative mortality has been reported as being 0.06% for LAGBand 0.7% for LYGB in a recent meta-analysis [100].

Effectiveness for OSASince 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, thesereports were limited by small sample size, selection bias, lack of standardised assessment forseverity of sleep-disordered breathing, and lack of complete follow-up data. Furthermore, surgicaltechniques varied between reports and sometimes within the same series.

Larger uncontrolled treatment cohorts with similar methodological caveats continue to bepublished. A follow-up study of 123 morbidly obese patients who had significant weight loss 1-yrafter undergoing LAGB (baseline: -130 kg, BMI 46 kg?m -2 ; at 1 yr: -99 kg, BMI 35 kg?m -2 ) foundreductions in self-reported snoring frequency and intensity as well as an improvement in daytimesleepiness (mean ESS reduction from 9.1 to 4.0) [105]. The study did not objectively measure sleep-disordered breathing and only 40% of the patients recruited completed follow-up at 1 yr. Morerecently, R AO 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. Outof a total of 314 patients, 228 (73%) had sleep-disordered breathing, with 21, 18 and 33% havingmild, moderate and severe OSA, respectively. A random sample of 46 patients received repeat PSGsat 1 yr. They lost on average 41 kg (BMI -15 kg?m -2 ) with significant improvements in sleep apnoeaseverity: 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 ), nocturnaloxygen desaturation and sleep architecture, as well as a reduction in symptom score (ESS 3).

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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 significantimprovement or resolution in OSA symptoms.

Another small study, significant for its duration, followed patients for over 2 yrs after gastricbypass. Eight obese patients with moderate-to-severe OSA (mean BMI 49 kg ?m -2 , mean RDI55?h -1 ) were re-evaluated at an average of 28 months post-surgery [104]. Mean BMI was reducedby 31% (post-BMI 34 kg ?m -2 ) and mean RDI was reduced by 75% (14 ?h -1 , seven out of eightpatients had improved). Only two patients had a residual RDI of . 15?h -1 and the remainder hadOSA remission (AHI , 5 events?h -1 ).

SOS study

To date, the largest study is the SOS study, an ongoing, non-randomised trial investigating thelong-term effects of surgical weight loss [28, 33]. Specifically pertaining to OSA, 1,592 patientswilling 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 treatedgroup was 27.8 kg (-23% from baseline) at 2 years and the mean BMI decreased from 42.2 to32.5 kg?m -2 . The average weight in the control group was essentially unchanged. The weightreduction 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 was22% in the surgery group compared to 66% in the controls. Although the general effect of weightloss on symptoms was similar in males and females, males with the greatest degree of weight lossdemonstrated a larger improvement in symptoms than their female counterparts.

Systematic reviews

The large number of observational cohorts and non-randomised trials has generated twosystematic reviews on this subject. The first systematic review by B UCHWALD et al. [109] waspublished 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 , 22,000patients (72% females, mean age 39 yrs). Of these, only 38 treatment groups with 1,195 patientsreported sleep-related outcomes. Baseline BMI was 47 kg ?m -2 and weight loss after surgery wassignificant across treatment groups (mean BMI reduction -14.2 kg ?m -2 ). Unfortunately, theanalysis combined results from studies of patients with OSA, sleep-disordered breathing andobesityhypoventilation 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 syn-drome) 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 bypasssurgery (four treatment groups, 92 patients). The overall weight lost from this group was 40 kgwith an associated mean reduction in AHI of 34 events ?h -1 . Gastric banding appeared to providegreater benefit in OSA-related outcome than other types of surgery, with 95% reporting post-operative improvement (gastric bypass 80%, gastroplasty 78%, others 92%). However, theseresults were not adjusted for amount of weight lost, baseline disease severity or even time lapsedfrom 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). Absolutebenefit was not reported nor was the proportion of patients with significant residual OSArequiring on-going treatment. In the end, the review re-affirmed that considerable weight loss andsymptom improvement is possible for patients with sleep apnoea following bariatric surgery butcontributed little additional information regarding effect size, the optimal type of surgery, whichpatients might benefit the most from surgery and the long-term outcomes.

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The second systematic review by GREENBURG et al. [110], published in 2009, was designedspecifically to address some of the above concerns and only included studies that reported bothpre-operative and post-operative PSG measures of sleep apnoea severity. 12 observational stud-ies (n5 342), five of which were prospective, were reviewed but only six studies yielded indi-vidual patient data (n 5 80). Meta-analysed mean BMI decreased by 17.9 kg ?m -2 (95% CI16.519.3 kg?m -2 ) from 55 to 38 kg?m -2 , and the mean AHI decreased by 38 events ?h -1 (95% CI31.944.4 events?h -1 ) from 55 to 16 events ?h -1 after bariatric surgery. No specific bariatric tech-

nique seemed more efficacious than any other in reducing weight or AHI. Individual patientdata analysis from available studies showed similar reductions in weight (from mean SD228 100 to 147 60 kg), BMI (from 49.7 10 to 32.8 6.7 kg?m -2 ) and AHI (from 68 40 to18 19 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 substantialweight 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 weightloss [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 bestmedical care plus active lifestyle programme, has recently concluded recruitment and follow-up isin 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).

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 withsubsequent 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 overestimatethe long-term benefit. Follow-up rates are generally poor and vary from 6 months to . 2 yrs inreported 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 repeatsleep apnoea assessments following surgery [104, 105, 107, 111]. Most authors cite significantsymptom improvement and lack of funding (insurance approval) as reasons for this problem. Thishigh 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 literatureare 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-updata is sparse. As with all interventions, the potential benefits must be balanced against potentialadverse events. Without sufficient vigilance and documentation of adverse outcomes, the truenature of this balance is impossible to ascertain. In their 2009 systematic review, G REENBURG 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-surgicaltreatment. There is now mounting evidence that OSA independently increases peri- andpost-operative complications following bariatric surgery [115117]. Given the efficacy of intensivedietary and lifestyle interventions and the small but not insignificant risk of peri-operativemorbidity and mortality, advising patients as to the best long-term management for OSA isdifficult.

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Conclusion and futuredirectionsObesity is incontrovertibly the major modifi-able risk factor for OSA; therefore, obesity reduction offers an excellent therapeutictarget for treatment of OSA in obese patients.Current standard device-based treatments forOSA do not cause obesity reduction andtherefore leave the underlying pathophysiol-ogy unchanged. We have reviewed the threemajor therapeutic approaches to obesity reduction: diet/lifestyle modification, phar-macotherapy and bariatric surgery. If any of these techniques used alone or in combina-tion effectively reduces obesity, it will onaverage have a corresponding effectiveness inreducing OSA severity.

Clinicians should be aware that significantinter-individual variability exists. In somepatients, even marked weight loss will notcause a reduction in OSA severity. However,weight loss in these patient should alsoconfer other substantial health benefitsand should remain an important treatmentgoal. The evidence base is not sufficiently

advanced to allow specific treatment recom-mendations for specific patient phenotypes.Tailoring specific obesity-reduction techni-ques (or combined techniques) to indivi-duals remains a matter of good clinical judgement.

Intensive dietary and lifestyle intervention iseffective in both increasing weight loss andimproving OSA severity. Data supportingbariatric surgery is less methodologically robust but indicates substantial weight loss,usually followed by improvement in OSA.Both of these interventions are resource- andlabour-intensive with significant inter-personvariability in effectiveness. Pharmacologicaladjuncts provide only modest additionalbenefits and are inadequate monotherapy for the morbidly obese patient. Recent datasuggest that sibutramine, the most studiedanti-obesity medication for OSA, may beassociated with an unacceptable rate of car-diovascular adverse events and has beentemporarily withdrawn from Europe.

Central or visceral adiposity has beenidentified as a better predictor of OSA than

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peripheral or subcutaneous adiposity [17, 118, 119]. Visceral adiposity is also strongly associatedwith metabolic syndrome and adverse cardiovascular outcomes [120, 121]. Thus, weight-lossstrategies 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 patientswith sleep-disordered breathing [77]. The independent effect that exercise (which may reducevisceral adiposity without changing overall weight) may have on sleep apnoea severity is also notwell 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 foundoverall improvements in AHI, quality of life and daytime somnolence after 6 months of supervisedexercise 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 translatecurrent understanding into clinical practice. It is not yet known how to select an optimaltreatment approach for a specific patient. It would also be useful to have a clinically applicableprediction tool to identify patients who will not have improved OSA in conjunction with weightloss. In addition, the long-term sustainability after weight loss of any improvement in OSA is yetto be addressed. Long-term adherence to lifestyle modification is often poor, even when comparedto 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 isuntested in the literature. The role of dietary counselling and cognitive behavioural therapy hasalso yet to be specifically assessed in this population but they appear to be useful adjuncts ingeneral 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 OSApatients, leads us to speculate that current obesity-reduction techniques may be more efficaciousin males. Future studies of all treatment modalities should be designed to provide better evidencefor females with OSA.

The future management of weight loss in OSA is likely to be stratified according to severity, withless invasive weight-loss methods being applied to patients with less severe disease and weight. Therole of cognitive behaviour therapy as an adjunct to any or all of these approaches is still to beassessed. As with other aspects of medicine, a multidisciplinary approach should be incorporatedinto 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.

Statement of InterestNone declared.

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