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The new england journal of medicine established in 1812 june 12, 2014 vol. 370 no. 24

CPAP, Weight Loss, or Both for Obstructive Sleep Apnea Julio A. Chirinos, M.D., Ph.D., Indira Gurubhagavatula, M.D., Karen Teff, Ph.D., Daniel J. Rader, M.D.,

Thomas A. Wadden, Ph.D., Raymond Townsend, M.D., Gary D. Foster, Ph.D., Greg Maislin, M.S., M.A., Hassam Saif, M.D., Preston Broderick, M.A., Jesse Chittams, M.S., Alexandra L. Hanlon, Ph.D.,

and Allan I. Pack, M.B., Ch.B., Ph.D.

A B S T R A C T

From the Philadelphia Veterans Affairs Medical Center ( J.A.C., I.G.), Perelman School of Medicine, University of Pennsyl- vania–Hospital of the University of Penn- sylvania ( J.A.C., I.G., D.J.R., T.A.W., R.T., G.M., H.S., P.B., A.I.P.), Monell Chemical Senses Center (K.T.), Temple University School of Medicine (G.D.F.), and Univer- sity of Pennsylvania School of Nursing ( J.C., A.L.H.) — all in Philadelphia. Ad- dress reprint requests to Dr. Chirinos at the Division of Cardiology, University of Pennsylvania, Rm. 8B111, University and Woodland Aves., Philadelphia, PA 19104, or at [email protected].

Background

Obesity and obstructive sleep apnea tend to coexist and are associated with inflam- mation, insulin resistance, dyslipidemia, and high blood pressure, but their causal relation to these abnormalities is unclear.

Methods

We randomly assigned 181 patients with obesity, moderate-to-severe obstructive sleep apnea, and serum levels of C-reactive protein (CRP) greater than 1.0 mg per liter to receive treatment with continuous positive airway pressure (CPAP), a weight-loss intervention, or CPAP plus a weight-loss intervention for 24 weeks. We assessed the incremental effect of the combined interventions over each one alone on the CRP level (the primary end point), insulin sensitivity, lipid levels, and blood pressure.

Results

Among the 146 participants for whom there were follow-up data, those assigned to weight loss only and those assigned to the combined interventions had reductions in CRP levels, insulin resistance, and serum triglyceride levels. None of these changes were observed in the group receiving CPAP alone. Blood pressure was re- duced in all three groups. No significant incremental effect on CRP levels was found for the combined interventions as compared with either weight loss or CPAP alone. Reductions in insulin resistance and serum triglyceride levels were greater in the combined-intervention group than in the group receiving CPAP only, but there were no significant differences in these values between the combined-intervention group and the weight-loss group. In per-protocol analyses, which included 90 par- ticipants who met prespecified criteria for adherence, the combined interventions resulted in a larger reduction in systolic blood pressure and mean arterial pressure than did either CPAP or weight loss alone.

Conclusions

In adults with obesity and obstructive sleep apnea, CPAP combined with a weight- loss intervention did not reduce CRP levels more than either intervention alone. In secondary analyses, weight loss provided an incremental reduction in insulin resis- tance and serum triglyceride levels when combined with CPAP. In addition, adher- ence to a regimen of weight loss and CPAP may result in incremental reductions in blood pressure as compared with either intervention alone. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT0371293.)

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A vailable clinical data derived largely from observational studies link obstructive sleep apnea1 to proatheroscle- rotic risk factors, including insulin resistance,2 dyslipidemia, hypertension,3 and inflammation.4 Obesity and obstructive sleep apnea are strongly associated.5-8 Like obstructive sleep apnea, obe- sity is linked to insulin resistance,6 dyslipidemia,9 hypertension,9,10 and inflammation.10 However, the relative causal roles that obstructive sleep ap- nea and obesity play in these abnormalities is un- clear.6,11,12 The interrelationships between obesity and obstructive sleep apnea are complex and bi- directional, and they cannot be confidently dis- cerned in observational studies. Randomized tri- als have shown the beneficial effects of weight loss on cardiovascular risk factors. However, even mod- est reductions in body weight are associated with changes in obstructive sleep apnea, with a 10% reduction in body weight predicting an approxi- mate change of 26 to 32% in the apnea–hypop- nea index (AHI).13 Previous trials assessing the effects of weight loss on cardiovascular risk fac- tors have neither assessed the effect of sleep-dis- ordered breathing nor included a controlled in- tervention for obstructive sleep apnea. Conversely, trials of continuous positive airway pressure (CPAP) therapy have not included a control intervention for obesity. Furthermore, the incremental benefit of a weight-loss intervention plus CPAP as com- pared with each intervention alone in reducing cardiovascular risk factors is unknown. We eval- uated the incremental effect of CPAP combined with a weight-loss intervention over the effect of each intervention alone on subclinical inflamma- tion, insulin resistance, dyslipidemia, and blood pressure in patients with obesity and obstructive sleep apnea.

M e t h o d s

Study Design

In this randomized, parallel-group, 24-week tri- al, we compared the effects of CPAP, weight loss, or both CPAP and weight loss in adults with obe- sity (body-mass index [the weight in kilograms divided by the square of the height in meters], ≥30), moderate-to-severe obstructive sleep apnea (AHI, ≥15 apnea or hypopnea events per hour), and a serum level of C-reactive protein (CRP) greater than 1.0 mg per liter. Detailed criteria for

inclusion and exclusion are provided in Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Potential participants were screened with the use of a home-based sleep monitor (ApneaLink, ResMed) for 1 or 2 nights. If this test yielded an AHI score of 10 or more events per hour, we per- formed 12-channel diagnostic polysomnography in the sleep laboratory for a full night. Patients with a polysomnogram that showed an AHI of 15 or more events per hour were randomly assigned to a study group. Randomization was conducted with a permuted-block design, with stratification according to sex, status with respect to statin use, and enrollment site (the Hospital of the Univer- sity of Pennsylvania or the Philadelphia Veterans Affairs Medical Center).

The study was approved by the institutional re- view boards of the University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center. Participants provided written informed consent. ApneaLink devices and CPAP machines were pro- vided at no cost by ResMed, which had no role in study design, data accrual or analysis, or manu- script preparation. The first and last authors vouch for the accuracy and completeness of the data and for the fidelity of the study to the protocol.

Interventions

In the CPAP and combined-intervention groups, participants underwent an overnight in-laborato- ry sleep study to allow for individual calibration of the CPAP therapy each participant would re- ceive. Nightly CPAP therapy was provided there- after through a fixed-pressure or autoadjusting CPAP device (ResMed). Adherence to CPAP ther- apy was monitored weekly by means of a wireless router attached to the CPAP device (ResTraxx, ResMed).

Participants in the weight-loss group and those in the combined-intervention group had individual weekly counseling sessions. The goals for caloric intake were set at 1200 to 1500 kcal per day for participants weighing less than 114 kg and at 1500 to 1800 kcal per day for those weigh- ing 114 kg or more. Dietary composition was aligned with recommendations from the National Cholesterol Education Program (NCEP). Self- selected foods within the framework of the NCEP diet were prescribed for the first 2 weeks. For weeks 3 to 19, a more structured diet was pre-

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scribed, including two to three liquid-meal re- placements per day.14 Unsupervised exercise was initiated at week 4, starting with four 15-minute weekly sessions that increased progressively to four 50-minute weekly sessions by week 15. This target for level of activity was chosen because of its association with long-term maintenance of weight loss. Cognitive-behavioral strategies, in- cluding self-monitoring, goal setting, stimulus control, problem solving (to address problems with adherence to recommendations on diet and exercise), and relapse prevention, were used to facilitate and maintain weight loss.15

Study Assessments and End Points

Assessments were performed at baseline and at 8 and 24 weeks after the initiation of therapy. Serum levels of CRP and lipoproteins were mea- sured after an overnight fast. Insulin sensitivity was assessed with the use of the frequently sam- pled intravenous glucose-tolerance test, which allowed for calculation of the insulin sensitivity index with Bergman’s minimal model.16 (Analytic methods are described in detail in the Supple- mentary Appendix.)

The primary end point was the serum CRP level. Secondary end points included insulin sen- sitivity and atherogenic dyslipidemia (determined by measuring serum levels of triglycerides, high- density lipoprotein [HDL] cholesterol, low-densi- ty lipoprotein [LDL] cholesterol, and LDL-particle concentration). Exploratory end points included systolic blood pressure, mean arterial pressure, pulse pressure, and HDL-particle concentration.

Statistical Analysis

Our primary analysis was based on a modified intention-to-treat population, defined for the pur- poses of the study as all participants who were randomly assigned to a study group and for whom there was at least one observation after random- ization. Additional per-protocol analyses were per- formed to investigate the causal relation between obstructive sleep apnea or obesity and underlying metabolic abnormalities. These analyses were based on the principle that any incremental ben- efit of weight loss combined with effective CPAP treatment, as compared with the benefit of effec- tive CPAP treatment alone, can be attributed to effects of obesity that are independent of the ef- fects of obstructive sleep apnea. Conversely, any

incremental benefit of effective CPAP therapy combined with weight loss, as compared with weight loss alone, can be attributed to effects of obstructive sleep apnea that are independent of the effects of obesity. For these assumptions to be valid, the estimation of between-group differ- ences requires actual reductions in body weight and obstructive sleep apnea. Accordingly, our per- protocol analyses were restricted to participants who met minimum requirements for weight loss (at least 5% of baseline weight) and adherence to CPAP therapy (use for an average of at least 4 hours per night on at least 70% of the total number of nights). On the basis of previous studies evaluat- ing the effects of CPAP therapy alone17 and weight loss alone18 on CRP levels, we powered the trial to detect standardized between-group differenc- es in the change from the baseline CRP level of at least 0.53 mg per liter in the modified intention- to-treat population and at least 0.79 mg per liter in the per-protocol population, with 90% power, allowing for a type I error rate of 0.05.

The effects of the interventions on end points were analyzed with the use of general linear mixed models, with all measurements available at 24 weeks used to estimate intervention effects.19 Restricted maximum-likelihood estimation was used, and an unstructured covariance matrix was specified to adjust for within-participant cluster- ing resulting from the repeated-measures design. Individual measures of growth were modeled as a function of randomly assigned group, time, and the interaction between group and time.

The primary comparisons of interest were the 24-week change in the CRP level among partici- pants in the modified intention-to-treat popula- tion who were assigned to the combined interven- tion as compared with the changes among those assigned to CPAP alone and those assigned to weight loss alone. To account for two primary comparisons, a Bonferroni-adjusted significance level was set at 0.025 for each comparison. All other analyses were considered secondary, with a nominal significance level of 0.05. Accordingly, any nominally significant P values in secondary analyses should be interpreted conservatively, giv- en an increased type I error rate introduced by multiple comparisons. Considering the number of comparisons made for a total of 10 end points, up to two significant tests of incremental bene- fit (P<0.05) would be expected on the basis of

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chance alone in each of the study populations ana- lyzed (the modified intention-to-treat and per- protocol samples). Although this study was not designed to compare the effects of CPAP alone and weight loss alone, we also provide the results of exploratory analyses for these pairwise com- parisons. Data on the CRP level were log-trans- formed because of their skewed distribution. Analyses were performed with SAS software, version 9.2 (SAS Institute).

R e s u l t s

Study Participants

A total of 544 persons were screened and 181 underwent randomization (Fig. 1). Baseline char- acteristics were similar among the three groups (Table 1). Of the 181 participants, 35 dropped out of the trial before the follow-up visit at 8 weeks, and an additional 10 participants dropped out after that visit; a total of 136 participants com- pleted the study. The modified intention-to-treat analyses included the 146 participants who un- derwent at least one assessment for the study end points after the initiation of therapy.

The decline in body weight was similar in the weight-loss and combined-intervention groups (6.8 kg and 7.0 kg, respectively); there was no discernible decline in body weight in the CPAP group (Fig. S1A in the Supplementary Appendix). The average duration of CPAP use was 4.0 hours per night, with no significant differences between the CPAP and combined-intervention groups. Among all three groups, the adherence criteria for inclusion in the per-protocol analyses were met by 90 participants: 39 in the CPAP group, 27 in the weight-loss group, and 24 in the combined- intervention group. (Table S2 in the Supplementary Appendix shows the baseline characteristics of participants who met the prespecified adherence criteria.)

CRP Levels

The combined interventions did not have a signifi- cant incremental effect on CRP levels, as com- pared with either weight loss alone or CPAP alone, in either the modified intention-to-treat popula- tion (Fig. 2A) or the per-protocol population (Fig. 2B). In both the modified intention-to-treat pop- ulation and the per-protocol population, the lat- ter comprising participants who met prespecified

adherence criteria, the CRP level was significantly reduced at 24 weeks in the weight-loss and com- bined-intervention groups but not in the CPAP group, and the reduction in the CRP level was greater in the weight-loss group than in the CPAP group.

Insulin Sensitivity

In the modified intention-to-treat analyses, insu- lin sensitivity increased in the weight-loss and combined-intervention groups at 24 weeks but not in the CPAP group. The increase in insulin sensitivity was significantly greater in the com- bined-intervention group than in the CPAP group (Fig. 3A), but the difference between the com- bined-intervention group and the weight-loss group was not significant. The results of the per-proto- col analyses were similar (Fig. 3A).

Dyslipidemia

In the modified intention-to-treat population, the reduction in serum triglyceride levels at 24 weeks was greater in the combined-intervention group than in the CPAP group; there was no significant difference in the change in triglyceride levels be- tween the combined-intervention group and the weight-loss group (Fig. 3B). The results were simi- lar in the per-protocol population (Fig. 3B). Se- rum triglyceride levels were significantly reduced at 24 weeks in the weight-loss and combined- intervention groups but not in the CPAP group.

Changes in LDL cholesterol levels at 24 weeks did not differ significantly among the three study groups in either the modified intention-to-treat population or the per-protocol population (Fig. S1B in the Supplementary Appendix). In the modi- fied intention-to-treat population, a reduction in LDL cholesterol levels was observed in the weight- loss group. In the per-protocol population, LDL cholesterol levels were reduced in the combined- intervention group and the weight-loss group but not in the CPAP group. Changes in HDL cholesterol levels from baseline to 24 weeks were similar among the three study groups (Fig. S1C in the Supplementary Appendix). There was no significant change in HDL cholesterol levels at 24 weeks in any of the study groups. The find- ings for LDL-particle and HDL-particle concen- trations (Fig. S1D and S1E in the Supplementary Appendix) were similar to those for LDL and HDL cholesterol levels, respectively.

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Blood Pressure

In the modified intention-to-treat population, sys- tolic blood pressure was reduced at 24 weeks in all three study groups (Fig. 3C), with no signifi- cant between-group differences. In the per-pro- tocol population, the reduction in systolic blood pressure at 24 weeks was greater in the combined-

intervention group (14.1 mm Hg) than in the weight-loss group (6.8 mm Hg) and the CPAP group (3.0 mm Hg) (Fig. 3C). Mean arterial pres- sure also decreased in all three study groups in the modified intention-to-treat population, with no significant between-group differences (Fig. S2A in the Supplementary Appendix). In the per-pro-

181 Underwent randomization

544 Patients were assessed for eligibility

363 Were excluded 44 Were not interested in continuing study

319 Met exclusion criteria 151 Had an AHI <15 events/hr 37 Had a CRP value of <1 mg/liter 22 Were excluded for safety reasons 19 Did not pass motor vehicle questionnaire 17 Had blood pressure >160/95 mm Hg 13 Had a BDI score ≥29 points 10 Were lost to follow-up 7 Had a BMI <30 5 Had fasting blood glucose >125 mg/dl

38 Had other reasons

61 Were assigned to the weight-loss group

58 Were assigned to the CPAP group

55 Started treatment 56 Started treatment

62 Were assigned to the combination group

57 Started treatment

46 Were included in the 8-wk assessment

50 Were included in the 8-wk assessment

42 Were included in the 24-wk assessment

48 Were included in the 24-wk assessment

46 Were included in the 24-wk assessment

136 Completed the study

Figure 1. Numbers of Patients Who Were Screened, Randomly Assigned to a Study Group, and Included in Analyses.

AHI denotes apnea–hypopnea index, BDI Beck Depression Inventory (in which scores range from 0 to 63, with high- er scores indicating more severe depression), BMI body-mass index (the weight in kilograms divided by the square of the height in meters), CPAP continuous positive airway pressure, and CRP C-reactive protein. To convert the val- ues for glucose to millimoles per liter, multiply by 0.05551.

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Table 1. Baseline Characteristics of the Study Participants.*

Characteristic Weight Loss

(N = 61) CPAP

(N = 58)

CPAP and Weight Loss

(N = 62) P Value

Age — yr 48.3 49.8 49.0 0.75

Male sex — no. (%) 36 (59) 35 (60.3) 33 (53.2) 0.70

Race — no. (%)† 0.95

White 33 (54) 34 (59.6) 36 (59.0)

Black 25 (41) 23 (40.4) 25 (41.0)

Mixed or other 3 (5) 1 (1.72) 1 (1.61)

Height — cm 172.5±10 170.2±14.2 165.9±23 0.09

Weight — kg 114.5±21.9 115.1±21.7 111.5±28.1 0.68

Body-mass index‡ 38.1±5.8 39.8±7.1 38.4±6.4 0.29

Cholesterol — mg/dl

Total 188.1±46.1 196.4±46 177.1±44.4 0.07

HDL 43.1±11.7 43.1±10.6 40±12.6 0.23

LDL 116.7±35 123.8±31.1 107±32 0.02

Cholesterol particle size — nm

LDL 20.5 (0.73) 20.5 (0.71) 20.5 (0.65) 0.96

HDL 8.7 (0.32) 8.8 (0.41) 8.7 (0.31) 0.62

Triglycerides — mg/dl 130±72.3 133.1±63.4 145.3±98.5 0.53

Hypertension — no. (%) 25 (41) 26 (45) 24 (39) 0.79

Insulin sensitivity index§ 1.4±0.82 1.2±1.03 1.4±1.14 0.63

Apoprotein — mg/dl

A-I 120.6 (31.2) 125.7 (25.86) 118.7 (32.69) 0.45

B 87.3 (29.98) 92.5 (26.23) 85.1 (24.06) 0.33

High-sensitivity C-reactive protein — mg/liter 0.74

Median 4.4 4.7 4.3

Interquartile range 1.9–8.5 2.5–8.2 2.1–9.3

Blood pressure — mm Hg

Systolic 126.5±10.02 129.9±14.87 123±19.91 0.053

Diastolic 78.9±7.5 80.1±8.98 76.8±13.71 0.22

AHI — events/hr¶ 39.7±20.3 41.2±20.96 47.1±26.86 0.17

Oxygen desaturation index — no. of events/hr

>3% drop from baseline 22.6±18.8 25.5±22.1 27.6±25.7 0.47

>4% drop from baseline 18.3±17.4 20.7±20.4 23.3±24.7 0.44

Sleep time with SpO2 <90% — % 5.0±8.4 6.9±13.8 8.7±15.6 0.29

Mean SpO2 during sleep — %

Nadir 78±14.8 76.7±11.1 73.7±20.7 0.34

Mean 94.8±1.8 94.7±2.3 94.1±2.4 0.17

Arousal index — no. of arousals/hr of sleep 31.7±15.8 37±20.5 39.6±20.1 0.07

Score on Epworth Sleepiness Scale‖ 9.3±4.3 9.8±4.6 8.9±4.8 0.55

Current or former smoker — no. (%) 21 (34) 20 (35) 12 (19) 0.11

Medication use — no. (%)

Statin 12 (20) 12 (21) 13 (21) 0.99

Antihypertensive medication 25 (41) 24 (41) 21 (34) 0.63

* Plus–minus values are means ±SD. Spo2 denotes oxygen saturation level as measured by pulse oximetry. To convert values for low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol to millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129.

† Race was self-reported. ‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. § The insulin sensitivity index was calculated with the use of values from frequently sampled glucose tolerance tests.

Higher levels indicate greater insulin sensitivity. ¶ The apnea–hypopnea index (AHI) is the number of apnea and hypopnea episodes per hours of sleep time. ‖ Scores on the Epworth Sleepiness Scale range from 0.0 to 24.0, with higher scores indicating more daytime sleepiness.

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tocol population, the reduction in mean arterial pressure was significantly greater in the combined- intervention group than in either the weight-loss group or the CPAP group. In the modified inten- tion-to-treat population, pulse pressure was sig- nificantly reduced at 24 weeks only in the com- bined-intervention group, and there were no significant between-group differences (Fig. S2B in the Supplementary Appendix). In the per-pro- tocol population, the reduction in pulse pressure was greater in the combined-intervention group and weight-loss groups than in the CPAP group.

Sensitivity Analyses

We performed sensitivity analyses in which the baseline value was carried forward for partici- pants in the modified intention-to-treat popula- tion who had missing follow-up data because of early withdrawal from the study (Table S4 in the Supplementary Appendix). These analyses showed within-group changes that were less pronounced than those observed in the primary analysis, but the trends were similar.

Adverse Events

Nasal or sinus congestion, nostril irritation, or other upper respiratory symptoms were reported

in 10 participants in the CPAP group, 9 partici- pants in the weight-loss group, and 10 partici- pants in the combined-intervention group. Other adverse events were much less common (Table S5 in the Supplementary Appendix). No serious ad- verse events occurred that were related to the study interventions or to study participation.

D i s c u s s i o n

In this randomized trial, CPAP combined with weight loss did not have a significant incremen- tal effect on CRP levels, as compared with either CPAP alone or a weight-loss intervention alone. Secondary analyses, which should be interpreted conservatively, showed that weight loss had an incremental effect on insulin resistance and se- rum triglyceride levels, as compared with CPAP, but no significant incremental effects on these end points were observed with combination ther- apy as compared with the weight-loss intervention alone. In exploratory analyses, the combination of CPAP and the weight-loss intervention was as- sociated with a larger reduction in blood pressure than was either intervention alone among partici- pants who adhered to the therapeutic regimen.

As reported in previous studies, weight loss

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Figure 2. Changes from Baseline in CRP in the Modified Intention-to-Treat and Per-Protocol Populations.

Panel A shows changes in CRP levels in the modified intention-to-treat population, and Panel B shows changes in CRP levels in the per-protocol population. The per-protocol population consisted of participants who met prespeci- fied adherence criteria. I bars represent 95% confidence intervals. P values without brackets are for the change from baseline in each group. P values with brackets are for between-group differences at week 24.

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significantly reduced CRP levels, insulin resis- tance, dyslipidemia, and blood pressure.20-22 In contrast, CPAP therapy did not have a significant effect on CRP level, insulin sensitivity, or dyslip- idemia, even among participants who adhered to the therapy. Cross-sectional observational stud- ies4,23 and prospective observational studies24-27 have yielded conflicting results regarding the role of obstructive sleep apnea in inflammation, but the two largest observational studies did not show a reduction in CRP levels after 9 to 12 months of CPAP therapy in patients with obstructive sleep apnea.26,27 Similarly, short-term observational studies28,29 have suggested an improvement in insulin resistance with CPAP therapy30; however, a crossover trial,31 in which insulin resistance was measured with the use of homeostatic model assessment, an indirect index of hepatic insulin sensitivity, did not show changes in insulin re- sistance after 6 to 12 weeks of CPAP therapy, even among participants who adhered to the treat- ment regimen. Using the frequently sampled in- travenous glucose-tolerance test, which measures whole-body insulin sensitivity,32 we found that CPAP monotherapy did not improve insulin sen- sitivity or enhance the improvement in insulin sensitivity associated with weight loss. In con- trast, weight loss, with or without CPAP, increased insulin sensitivity. CPAP monotherapy for 24 weeks also did not improve dyslipidemia in our trial, a finding that is consistent with the results of a recent randomized trial, which showed no sig- nificant changes in total cholesterol levels after 24 weeks of CPAP therapy.33

Unlike the other cardiovascular risk factors we assessed, blood pressure decreased in the CPAP, weight-loss, and combined-intervention groups. In analyses including only participants who met the prespecified adherence criteria, a larger reduction was seen in the combined-

intervention group than in either the weight-loss group or the CPAP group. Despite the causal re- lationship between obstructive sleep apnea and hypertension that has been reported in animal models and the epidemiologic association34 be- tween obstructive sleep apnea and hypertension in humans, improvements in blood pressure with CPAP therapy in clinical studies have been absent or remarkably small,35-37 estimated at approxi- mately 1.3 to 3.0 mm Hg in systolic or diastolic blood pressure. However, to the degree that ob- structive sleep apnea and CPAP activate similar or overlapping pathophysiological pathways lead- ing to hypertension, it was not possible to clearly separate their direct effects without the inclusion of randomly assigned CPAP and weight-loss in- terventions, alone and in combination. Our find- ings suggest that both obstructive sleep apnea and obesity have an independent causal relation to hypertension.

Our study has limitations. We did not include a sham CPAP intervention. However, both sham CPAP and the absence of treatment for obstructive sleep apnea are considered to be adequate controls for an active CPAP intervention.38 In addition, sham CPAP is not a perfect placebo, since it may result in significant reductions in the number of apnea events, increases in the number of hypopnea events, and a small impairment in sleep quality.39 We did not include any group in which no therapy was implemented because of ethical considerations and because its inclusion was not needed to test our hypotheses. Our 24-week attrition rate was high (25%). We did not assess ambulatory blood pres- sure. Finally, our findings cannot be extended to populations with diabetes mellitus or mild obstruc- tive sleep apnea because of our exclusion criteria.

In conclusion, we found that CPAP therapy combined with a weight-loss intervention did not have a significant incremental effect on CRP lev- els, as compared with either intervention alone. The weight-loss intervention combined with CPAP therapy had an incremental effect on insulin re- sistance and serum triglyceride levels, as com- pared with CPAP alone, but no significant incre- mental effects were detected for combination therapy as compared with the weight-loss inter- vention alone, even among participants who ad- hered to the therapeutic regimen. In an analysis that included only participants who adhered to the regimen, the combined interventions result- ed in a larger reduction in blood pressure than

Figure 3 (facing page). Changes from Baseline in the Insulin Sensitivity Index, Serum Triglyceride Levels, and Systolic Blood Pressure in the Modified-Intention- to-Treat and Per-Protocol Populations.

Panel A shows changes in the insulin sensitivity index, Panel B changes in serum triglyceride levels, and Panel C changes in systolic blood pressure. I bars represent 95% confidence intervals. P values without brackets are for the change from baseline in each group. P val- ues with brackets are for between-group differences at week 24. To convert the values for triglycerides to milli- moles per liter, multiply by 0.01129.

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either CPAP or weight loss alone. Our study shows that a weight-loss intervention is effective as a central component of the strategies used to im- prove the cardiovascular risk-factor profile in pa- tients with obesity and obstructive sleep apnea.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

Supported by grants from the National Heart, Lung, and Blood Institute (HL-R01080076, to Dr. Chirinos; and P01 HL094307, to Dr. Pack).

Dr. Wadden reports receiving fees for serving on advisory boards for Novo Nordisk, Nutrisystem, and Orexigen, consult- ing fees from Boehringer Ingelheim, and grant support from Weight Watchers, Novo Nordisk, and Nutrisystem. Dr. Foster reports receiving fees for serving on advisory boards for ConAgra Foods, Tate and Lyle, and UnitedHealth Group and re- ports being an employee of Weight Watchers. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank Dr. Frederick F. Samaha, who led the design of this trial and its initial implementation but who died unexpectedly, and the members of the data safety and monitoring board (Arshed Quyyumi, M.D., chair; and Robert Basner, M.D., Atul Malhotra, M.D., and Diane Catellier, Ph.D.).

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