Three month continuous positive airway pressure (CPAP) therapy decreases serum total and LDL cholesterol, but not homocysteine and leptin concentration in patients with obstructive sleep apnea syndrome (OSAS)

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Corresponding author:

Corresponding author: Marta Kumor, MD, PhD, Department of Internal Diseases, Pneumonology and Allergy, Medical University of Warsaw, Banacha St. 1a, 02–097 Warsaw, Poland; tel.: +48 22 599 15 70; mobile: +48 602 791 359; fax: +48 22 599 1560, +48 22 599 1561; e-mail: marta_kumor@vp.pl Received on 2 August 2010

Marta Kumor, Piotr Bielicki, Tadeusz Przybyłowski, Renata Rubinsztajn, Jan Zieliński, Ryszarda Chazan

Department of Internal Diseases, Pneumonology and Allergy, Medical University of Warsaw, Poland Head: Prof. R Chazan, MD, PhD

Three-month continuous positive airway pressure (CPAP)

treatment decreases total and LDL-cholesterol levels but does not affect serum homocysteine and leptin levels in patients with

obstructive sleep apnoea syndrome (OSAS) without co-existent ischaemic heart disease (IHD)*

* This paper is part of a doctoral thesis defended at the Medical University of Warsaw, Poland, on 18 February 2009.

This research project has been funded from the Committee for Scientific Research grant 2 P05B 050 29.

Abstract

Introduction: Continuous positive airway pressure (CPAP) treatment reduces cardiovascular morbidity and mortality in patients with obstructive sleep apnoea syndrome (OSAS). Homocysteine and leptin may play a role in the development of ischaemic heart disease (IHD) in these patients. The aim of the study was to assess the effects of 3-month CPAP treatment on the risk factors of IHD in patients with OSAS without co-existing IHD (OSAS without IHD) and on OSAS with co-existing IHD (OSAS with IHD).

Material and methods: CPAP treatment was commenced in 42 patients with OSAS without IHD and in 23 patients with OSAS with IHD. Baseline and end-of-treatment levels of homocysteine, leptin, C-reactive protein (CRP), fibrinogen, lipids parameters and visceral obesity related parameters were determined.

Results: No significant changes in the levels of homocysteine, leptin, fibrinogen or CRP in either of the study groups were observed at the end of the treatment. No changes in lipid parameters or the degree of obesity were observed in the OSAS with IHD group. A significant reduction in total and LDL-cholesterol levels were observed in the OSAS without IHD group (202.5 ± 38.5 mg/dl v. 186.7 ± 33.5 mg/dl, p = 0.001 and 127.3 ± 32.9 mg/dl v. 116.4 ± 26.9 mg/dl, p = 0.02, respectively). There were no significant changes in body mass index (30.4 ± 3.8 kg/m² v. 30.6 ± 3.6 kg/m², p = 0.5) or the amount of visceral fat, as measured by waist circumference (108.5 ± 8.0 cm v. 107.0 ± 7.5 cm, p = 0.09) and waist-to-hip ratio (1.03 ± 0.04 v. 1.01 ± 0.03, p = 0.07).

Conclusions: Three-month CPAP treatment did not affect the levels of homocysteine or leptin in patients with OSAS, although there was a significant reduction in lipid parameters in patients with OSAS without co-existent IHD, which confirms the beneficial effect of this method of treatment on the risk factors of IHD.

Key words: obstructive sleep apnoea syndrome, CPAP, homocysteine, leptin, lipids

Pneumonol. Alergol. Pol. 2011; 79, 3: 173–183

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Introduction

Obstructive sleep apnoea syndrome (OSAS) is the second most common chronic respiratory disease [1] and a significant risk factor for such cardiovascular diseases as hypertension, ischaemic heart disease (IHD), stroke and heart failure [2, 3].

In Poland, based on a study by Pływaczewski et al. conducted in 676 individuals aged 41 years or more, the prevalence of OSAS among the inhabi- tants of Warsaw, Poland, has been estimated at 8.7% in men and 2.5% in women [4].

OSAS is an independent risk factor for hypertension, as confirmed by such epidemiological studies as the Sleep Heart Health Study (n = 6424) or the Wisconsin Sleep Cohort Study (n = 805) [5, 6].

There is also evidence to suggest premature cardiovascular mortality in this group of patients [7].

So far, the causal relationship between OSAS and cardiovascular disease has not been unequivo- cally established. Some of the mechanisms that may be responsible for this include excessive sti- mulation of the sympathetic system, increased re- activity of peripheral chemoreceptors and excessive pressor response to hypoxaemia [8]. Resear- chers also take into account potential relationships between: sleep-disordered breathing and en- docrine dysfunction [9], endothelial injury [10]

and increased platelet aggregation [11]. Other factors identified in this group of patients also seem to have a considerable direct or indirect effect.

These factors include male sex, age, smoking, hypertension [12], visceral obesity [13], dyslipida- emias [14–17], insulin resistance and impaired glucose tolerance [18] and abnormal secretion of leptin [19].

Many studies have confirmed the benefits of continuous positive airway pressure (CPAP) treatment on cardiovascular risk factors in the form of reduced total cholesterol levels [20, 21], reduced triglyceride levels [14], elevated HDL-cholesterol levels [17], reduced visceral obesity [13], reduced leptin levels [22], reduced activity of the sympathetic system [23], reduced blood pressure [24], reduced insulin resistance [25] and improved glucose tolerance [26].

The relationship between mild hyperhomocysteinaemia and premature development of IHD, myocardial infarction, hypertension and atherosclerosis has been confirmed several years ago [27].

The mechanism in which homocysteine causes atherosclerosis is most likely associated with endothelial injury, platelet activation and increased blood coagulability [28].

The results of studies investigating the role of this amino acid in the pathogenesis of cardiovascular disease in patients with OSAS are often con- flicting [20, 29–32].

Many abnormalities promoting atherosclerosis that are observed in the blood of patients with hyperhomocysteinaemia are also found in patients with OSAS, such as elevated levels of endothelin-1 (ET-1) [33], free oxygen radicals [10], adhesion molecules ICAM-1 and VCAM-1 [34], C-reactive protein (CRP) [35] as well as elevated haematocrit, elevated fibrinogen level and increased platelet aggregation [11].

Given the inconclusiveness of the reports published so far and the existence of premises suppor- ting a common pathomechanism of atherosclerosis in the case of OSAS and hyperhomocysteinaemia, it seems justified to make attempts to establish whether homocysteine levels in patients with OSAS co-existing with IHD are significantly higher than in controls and how CPAP affects homocysteine levels and therefore cardiovascular risk.

The aim of our study was to assess the effect of 3-month CPAP treatment on selected biochemical risk factors of IHD with particular focus on leptin and homocysteine in a group of patients with OSAS without IHD and in a group of patients with OSAS and IHD.

Material and methods

We enrolled men presenting to the Sleep-Di- sordered Breathing Clinic and to the Cardiology Clinic at the Independent Public Central Teaching Hospital in Warsaw, Poland. All the patients provided informed consent to participate in the study. The study had been approved by the Medical University of Warsaw Bioethics Committee (Deci- sion KB/173/2003).

The degree of sleepiness was assessed on Epworth Sleepiness Scale (ESS) [36]. Excessive daytime sleepiness was defined as an ESS score of 9 or more. The inclusion and exclusion criteria are given in Table 1.

Physical examination additionally included a determination of the waist-to-hip ratio (WHR) using a standard method according to which waist circumference (in centimetres) is measured halfway between the lower costal margin and the iliac crest and hip circumference (in centimetres) is the widest dimension at the level of the greater trochanter [37].

Based on these two values WHR was calculated. The degree of obesity was assessed using body mass index (BMI) calculated from the following

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formula: body mass in kg/(height in m)², according to the World Health Organization (WHO) classification [38]. Metabolic syndrome was diagnosed in accordance with the International Diabetes Fede- ration (IDF) definition adopted in 2005 [39].

Diagnosis of obstructive sleep apnoea syndrome

Polysomnography (PGS) studies were conducted using the Alice 4 Diagnostic Sleep System (Re- spironics, USA), which offers the possibility of si- multaneous recording of 20 variables. Upon the completion of the sleep study the results of an au- tomated analysis by the software provided by the manufacturer were verified by qualified sleep study laboratory staff.

The sleep studies were conducted between 11 pm and 6 am the next day in a specially isolated room. An ELEMIS audiovisual system was used for continuous monitoring of the patients undergoing the sleep study. The sleep studies were supervi- sed by a doctor or a trained medical student of the Medical University of Warsaw. The diagnosis of OSAS was based on the local guidelines of the Medical University of Warsaw Polysomnography Laboratory with an apnoea-hypopnoea index (AHI) exceeding 10 (Table 1).

Diagnosis of ischaemic heart disease A 12-lead electrocardiogram (ECG) was obtained in all the patients. The severity of angina in patients with the diagnosis of IHD was assessed in accordance with the Canadian Cardiovascular So- ciety (CCS) classification [40]. The cardiovascular risk assessment was performed with the use of the Systematic Coronary Risk Evaluation (SCORE) Risk

Charts for high cardiovascular risk areas, such as Poland [41].

In order to rule out IHD in the group of patients with OSAS treadmill exercise testing was performed at the Ergospirometry Laboratory of the Department of Internal Diseases, Pneumonology and Allergy, Medical University of Warsaw. One patient from the OSAS group had a positive exercise test. In the remaining cases the test was di- scontinued due to achieved pulse limit, muscle fatigue, blood pressure rise or dyspnoea.

Cardiopulmonary exercise testing was performed on a mobile treadmill according to Bruce’s protocol [42] with the use of the START 2000 system (MES, Poland).

All the patients had 40 ml of venous blood drawn in the morning after an overnight fast. The blood samples for determination of homocysteine and leptin were placed in ice immediately after collection and centrifuged at 3000 revolutions per second for 20 minutes. The resulting plasma was frozen at –70°C for further determination of homocysteine and leptin. The remaining determinations were performed at the Central Laboratory of the Independent Public Central Teaching Hospital using appropriate methods.

Leptin was determined by radioimmunoassay (RIA) using the commercial Leptin RIA Kit (LIN- CO Research Inc.) and homocysteine by enzyme immunoassay using the Axis Homocysteine EIA kit (BIO RAD).

The value of positive airway pressure was selected manually — during subsequent polysomnography or using an auto-CPAP device in accordance with the manufacturer-programmed algorithm.

Following the above, the patients were provided with a CPAP or an auto-CPAP device (GoodK- night 420S [Tyco Healthcare, Puritan Bennett, Table 1. Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria

Both groups Both groups

— age 30–65 years — lack of consent

— male — drugs affecting homocysteine concentration

OSAS and IHD group — introduction of hypolipaemic treatment

— AHI > 10 + typical symptoms of OSAS — nontreated thyroid insufficiency or AHI > 30 regardless symptoms of OSAS — renal failure

— diagnosis of IHD: history and/or positive stress test, — diabetes

positive coronarography — contraindications to CPAP therapy OSAS and IHD

Pure OSAS group — unstable IHD

— AHI > 10 + typical symptoms of OSAS — cardiac failure

— no IHD

All abbreviations in the text

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France], HC 600 [Fisher & Pykel, New Zealand], S8 Escape [ResMed, UK], GoodKnight 420E [Tyco Healthcare, Puritan Bennett, France], REMstar auto [Respironics, USA], S8 Autospirit [ResMed, UK] or Magellan [MAP, Germany]).

The surveys, history, physical examination and biochemistry were repeated after the three- month CPAP treatment. Three attempts to contact the patient by telephone were made to invite them to the follow-up visit. Compliance was assessed by using special magnetic cards or by reading the number of hours the patient used the device from the device counter.

Statistical analysis

The study data were analysed using STATI- STICA version 8.0 (StatSoft Inc.; www.statsoft.com). Comparisons of independent groups, due to parameters assuming nominal or ranked values, were performed using non-parametric te- sts (Mann-Whitney test). Values in tables referring to nominal variables are given as means ± standard deviations (SD). Relationships between two nominal variables, between two ranked variables or between a nominal and a ranked variable were calculated using Spearman’s rank correlation test.

In cases where both variables were qualitative or binary variables, the chi-square test for contingen-

cy tables was used and, in a special case for “2 by 2” tables (two rows and two columns), depending on the calculated expected values, also a chi-square test version with Yates’ correction. Dependent variables were compared using two methods: the sign test and the Wilcoxon test. The sign test was used for ranked, nominal and binary variables, while the Wilcoxon test for ranked and nominal variables only.

Results

Of all the patients presenting to the Sleep-Di- sordered Breathing Clinic and to the Cardiology Clinic who provided informed consent and met the eligibility criteria a total of 65 consecutive men (Table 2) were preliminarily qualified for the study. CPAP treatment was commenced in 42 patients with OSAS without IHD and in 23 patients with OSAS and IHD. Following 3 months of CPAP treatment 24 patients from the group with OSAS without IHD and 16 from the group of OSAS and IHD returned for the follow-up visit (Table 3). PSG results for the study groups are shown in Table 4.

After 3 months 61% of the patients treated with CPAP returned for the follow-up visit. In this group, levels of leptin, homocysteine and the remaining biochemical parameters were determined at baseline and after treatment completion. The

Table 2. Characteristics of studied groups (n = 65)

Variables Pure OSAS OSAS and IHD p

(n = 42) (n = 23)

Age (years) 49.5 ± 8.4 54.0 ± 6.8 p = 0.02

Weight [kg] 94.7 ± 11.9 94.4 ± 17.5 ns

BMI [kg/m²] 30.1 ± 3.3 31.5 ± 5.6 ns

Waist circumference [cm] 107.7 ± 10.6 110.5 ± 14.1 ns

WHR (n < 1.0) 1.020 ± 0.063 1.037 ± 0.039 ns

AHI (h^-1) 48.7 ± 19.6 46.5 ± 21.8 ns

NS — the difference not statistically significant; other abbreviations in the text

Table 3. Characteristics of subjects treated with continuous positive airway pressure (CPAP)

(n = 24) (n = 16)

Age (years) 50.0 ± 9.8 54.2 ± 6.9 ns

Weight (kg) 94.1 ± 10.7 92.3 ± 12.6 ns

BMI [kg/m²] 29.9 ± 2.8 30.3 ± 4.2 ns

WHR (n <1.0) 1.019 ± 0.06 1.037 ± 0.04 ns

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mean duration of CPAP treatment in the OSAS and IHD group was 97 ± 8.8 days (90–113 days) and the mean duration of CPAP use during the night (compliance) was 4.4 ± 1.8 hours (1.3–7.1 hours).

The mean AHI recorded with a CPAP device sensor was 2.7 ± 2.1 per night (0.5–7.5/h), treatment pressure ranged from 8 to 12 cm H2O with the mean value of 10.2 ± 1.2 cm H2O.

During the three months of treatment, in the OSAS and IHD group, no statistically significant changes in diet, physical activity, coffee consump-

tion or alcohol consumption were observed. After the 3-month CPAP treatment in this group the obesity-related parameters did not change significantly (Table 5). The changes in metabolic parameters were non-significant (Table 6). Of the 42 patients from the OSAS without IHD group who had star- ted CPAP treatment 24 returned for the follow-up visit. Patients on stable doses of statins (n = 4) and those in whom treatment of hypercholesterolaemia had changed (n = 2) were not included in the statistical analysis.

Table 4. Results of standard nocturnal polisomnography in studied groups (n = 40)

(n = 24) (n = 16)

AHI (h^-1) 48.3 ± 20.3 45.4 ± 21.5 ns

AI (h^-1) 30.3 ± 20.8 25.0 ± 17.6 ns

Desaturation index (h^-1) 47.0 ± 25.7 43.1 ± 27.9 ns

Mean SaO2 (%) 91.6 ± 4.7 89.3 ± 5.8 ns

Minimal SaO2 (%) 77.2 ± 7.9 73.6 ± 17.7 ns

T SaO2 < 90% (min) 75.0 ± 83.4 106.9 ± 124.4 ns

Table 5. Comparison of anthropometrics in subjects treated with continuous positive airway pressure (CPAP) (OSAS and IHD group)

Variables Before CPAP therapy After 3-month CPAP therapy p

Weight [kg] 92.6 ± 12.2 93.5 ± 11.3 ns

BMI [kg/m²] 30.4 ± 3.8 30.6 ± 3.5 ns

WHR (n < 1) 1.04 ± 0.04 1.03 ± 0.03 ns

Table 6. Leptin and homocysteine and other biochemical variables before and after 3 month of continuous positive airway pressure treatment (CPAP) (OSAS and IHD group)

Variables Before CPAP therapy After CPAP therapy p

Leptin [ng/ml] 10.6 ± 4.7 10.3 ± 4.5 ns

Uric acid [mg/dl] 6.2 ± 1.2 6.2 ± 1.5 ns

Glucose [mg/dl] 94.2 ± 13.6 97.7 ± 13.0 ns

Oral glucose tolerance test [mg/dl] 122.2 ± 37.5 116.1 ± 45.1 ns

Fibrinogen [mg/dl] 350.4 ± 88.2 368 ± 105.4 ns

Homocysteine [μmol/l] 12.4 ± 3.8 10.9 ± 3.2 ns

CRP [mg/dl] 2.0 ± 1.6 2.2 ± 1.6 ns

Total cholesterol [mg/dl] 212 ± 47.2 192.5 ± 24.7 ns

HDL cholesterol [mg/dl] 47.4 ± 10.5 45.2 ± 11.7 ns

LDL cholesterol [mg/dl] 129.3 ± 45.9 110.0 ± 20.2 ns

Triglyceride [mg/dl] 185.5 ± 106.6 188.7 ± 82.3 ns

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Table 8. Leptin, homocysteine and other biochemical variables in pure OSAS group before and after continous positive air- way pressure (CPAP) therapy

Variables Before CPAP therapy After 13-month CPAP therapy p

Leptin [ng/ml] 8.9 ± 5.5 9.4 ± 5.3 ns

Uric acid [mg/dl] 5.9 ± 1.4 5.5 ± 1.1 ns

Glucose [mg/dl] 89.3 ± 12.5 92.1 ± 10.8 ns

Oral glucose tolerance test [mg/dl] 122.3 ± 39.8 115.6 ± 36.7 ns

Fibrinogen [mg/dl] 311.3 ± 53.9 327.8 ± 71.4 ns

Homocysteine [μmol/l] 11.65 ± 2.4 11.3 ± 3.7 ns

CRP [mg/dl] 2.7 ± 2.9 1.4 ± 1.1 p = 0.05

Total cholesterol [mg/dl] 202.5 ± 38.5 186.7 ± 33.5 p = 0.001

HDL cholesterol [mg/dl] 43.6 ± 9.1 42.5 ± 12.2 ns

LDL cholesterol [mg/dl] 127.3 ± 32.9 116.4 ± 26.9 p = 0.02

Trigliceride [mg/dl] 161.4 ± 79.0 133.4 ± 79.8 ns

PO2 [mm Hg] 79.8 ± 9.7 85.3 ± 11.9 p = 0.05

The mean duration of CPAP treatment in the OSAS without IHD group was 93 ± 10.4 days (80–

119 days) and the mean duration of CPAP use during the night (compliance) was 5.2 ± 1.5 hours (1.3–7.3 hours). The mean AHI recorded with a CPAP device sensor was 2.6 ± 1.5 per night (0.3–

6.3/h), treatment pressure ranged from 6 to 15 cm H2O with the mean value of 9.6 ± 2.4 cm H2O.

In the OSAS without IHD group, over the three months of CPAP treatment, there were no statistically significant changes in the diet, physical activity, coffee consumption or alcohol consumption with the exception of red wine (p = 0.04), whose consumption had increased. Also, there were no changes in body mass (p = 0.6), BMI (p = 0.5), WHR (p = 0.07) and waist circumference (p = 0.09) (Table 7).

The survey data showed that the prevalence of nocturia decreased from 66.6% to 33.0% (p = 0.04). Sleepiness, as measured with the ESS, signi- ficantly decreased (13 ± 4 v. 8 ± 4, p = 0.0008).

Following three months of treatment there was a significant reduction in total and LDL-cholesterol levels. The reduction in CPR and the increase in arterial blood partial pressure were at the bor-

derline of statistical significance (p = 0.05 for both parameters) (Table 8).

Discussion

We found no significant changes in the levels of homocysteine, leptin, fibrinogen, CRP and glucose following three months of CPAP treatment in either of the study groups. Based on the available reports the assessment of the effect of CPAP treatment on homocysteine levels is equivocal. Robin- son et al. [20] did not observe any significant effect of one-month CPAP treatment on homocysteine levels (n = 52). Similar findings were obtained by Ryan et al. [3] following six weeks of treatment (8.4 ± 3.6 v. 9.9 ± 4.7 μmol/l). Also Barceló et al.

[16] observed no changes in homocysteine levels following 12 months of CPAP treatment in a group of 27 patients with OSAS.

On the other hand, Jordan et al. [43] observed an approximately 30% reduction from baseline in homocysteine levels in a group of 12 patients with OSAS following an average of 149 ± 48 days of CPAP treatment (p < 0.005). The authors reported

Table 7. Anthropometric in pure OSAS group before and after continuous positive airway pressure (CPAP) therapy (n = 24)

Variables Before CPAP therapy After 13-month CPAP therapy

Weight [kg] 94.7 ± 11.2 95.3 ± 3 ns

BMI [kg/m²] 30.3 ± 2.8 30.6 ± 3.6 ns

WHR (n < 1) 1.03 ± 0.04 1.01 ± 0.03 ns

Waist circumference [cm] 108.5 ± 8.0 107.5 ± 7.5 n

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no changes in medication, diet, smoking, vitamin B6 and B12 levels in the study group and stated that homocysteine levels did not correlate with BMI, although the paper did not provide any data on BMI changes from baseline. It should be noted that the study group was very small and heteroge- nous: 7 patients were hypertensive and 2 diabetic.

Furthermore, the paper did not provide any infor- mation on blood-pressure-lowering and lipid-lowering medication. No data were provided on the number of hours of CPAP treatment at night. In addition, the duration of treatment was longer than that in our study, which could also have affected the significant reduction in homocysteine levels.

Similar results were obtained by Steiropoulos et al [21], but in a larger group of patients with OSAS without co-morbidities (n = 39). Homocy- steine levels were compared following six months of CPAP treatment in a group of patients effectively treated (n = 20; compliance > 4 hours per night) and patients using CPAP for less than 4 hours per night (n = 19). The control group consisted of patients with OSAS who had refused CPAP treatment and in whom homocysteine levels were determined six months later (n = 14). The study showed a significant reduction in homocysteine levels in patients receiving CPAP treatment, both in the subgroup receiving more than 4 hours of CPAP per night (12.3 ± 1.9 μmol/l v. 10.9 ± 1.5 μmol/l) and in the subgroup receiving less than 4 hours of CPAP per night (14.7 ± 5.8 μmol/l v. 12.7 ± 3.5 μmol/l).

There were no changes in homocysteine levels in patients who had refused CPAP treatment. It seems that the reduction in homocysteine levels could have resulted from a longer duration of treatment with CPAP than that in our study.

Following three months of CPAP treatment in our study, both in the OSAS and IHD group and in the OSAS without IHD group, there were no significant changes in leptin levels. Chin et al. [13]

found that already after 3–4 days of CPAP treatment leptin levels significantly decreased (p <

0.01) and this trend was maintained at 1 and 6 months of treatment, both in the group with BMI reduction and in the group without BMI reduction.

However, Ip et al. [14] observed a significant reduction in leptin levels following six months of CPAP treatment (n = 9) (10.4 ± 4.5 ng/ml v. 6.9 ± 1.8 ng/ml, p = 0.01) with no change in BMI. In our study, following three months of CPAP treatment we did not observe any significant changes in leptin levels, which could be a result of the increase in BMI from baseline. Because the difference was not statistically significant, this hypothesis cannot be conclusively confirmed. In a group of 13 pa-

tients Harsch et al. [19] found no changes in leptin levels following 2 days of CPAP treatment but did observe a significant reduction following 8 weeks (p = 0.004). The difference was higher in the subgroup of patients with BMI values below 30 kg/m² compared to the subgroup of patients with BMI values exceeding 30 kg/m² (p = 0.02).

Sanner et al. [44] found no change in leptin levels following six months of treatment with va- rious methods (CPAP or BiPAP [bi-level positive airway pressure], n = 68; or mandibular advance- ment devices [MAD], n = 11; or conservative treatment, n = 7) in a group of 86 patients with OSAS (7.3 ± 5.0 ng/ml v. 7.5 ± 4.8 ng/ml). Only in the successfully treated subgroup, in which AHI values during treatment were 1.6 ± 1.3 h^–1), where BMI values did not change significantly, there was a significant decrease in leptin levels (8.5 ± 5.0 ng/

ml v. 7.4 ± 5.1 ng/ml, p < 0.05). In the unsuccess- fully treated subgroup, leptin levels there was a significant increase in leptin levels (5.0 ± 4.0 ng/

ml v. 7.7 ± 4.1 ng/ml, p = 0.01).

On the other hand, however, Barceló et al. [45]

observed no changes in leptin levels in 12 obese patients with OSAS at 3 and 12 months of CPAP despite successful treatment (compliance 5.7 ± 1.4 hours per night). Statistically significant differen- ces were only observed in the subgroup of patients with BMI below 27 kg/m² (11.0 ± 1.9 ng/ml v. 10.5

± 1.8 ng/ml at 3 months v. 9.2 ± 1.5 ng/ml at 12 months, p < 0.01). The paper did not say whether BMI had changed during that period. No changes were also observed in obesity-related parameters (body mass, BMI, WHR).

In the group of patients with OSAS and IHD, we did not observe any changes in lipid parameters either. We did observe significant reductions in total and LDL-cholesterol levels in the group of patients with OSAS without IHD (202.5 ± 38.5 mg/

dl v. 186 ± 33.5 mg/dl, p = 0.001 and 127.3 ± 32.9 mg/dl v. 116.4 ± 26.9 mg/dl, p = 0.02, respec- tively).

Robinson et al. [20] found a trend towards reduced total cholesterol levels (p = 0.06) after one month of CPAP treatment compared to the group managed with subtherapeutic pressure, although the difference was not statistically significant.

However, in the successfully treated group, total cholesterol decreased by 0.28 mmol/l from baseline, which resulted in a 15% reduction of cardiovascular risk.

Börgel et al. [17] observed a significant increase in HDL-cholesterol levels of 5.8% from 46.9 ± 15.8 mg/dl to 49.0 ± 15.3 mg/dl (p < 0.05) following six months of CPAP treatment in 127 patients

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on stable doses of lipid-lowering drugs during the observation period.

Steiropoulos et al. [21] found a significant reduction of total cholesterol (p = 0.021) and of the total-to-HDL-cholesterol ratio (p = 0.018) following six months of CPAP treatment. No such changes were observed in the group of patients with OSAS who had refused CPAP treatment. Ip et al. [14]

observed a significant reduction in triglyceride levels from 1.9 ± 0.9 mmol/l to 1.2 ± 0.5 mmol/l (p

< 0.05) following six months of CPAP treatment (n = 9) with no changes in the levels of the remaining lipids.

The failure to demonstrate changes in homocysteine and leptin levels in patients with OSAS receiving CPAP treatment, which is in contrast to some of the published reports, may result from certain limitations of our study. Despite our efforts, out of the 65 who had commenced CPAP treatment only 40 patients returned for the follow-up visit at 3 months (61.5% of the study subjects). However, similarly low compliance levels may be found in the literature. Difficulties in preserving compliance during PAP treatment have been reported by many authors. According to Roux et al. [46], abo- ut 70% of patients who are offered CPAP accepts this method of treatment. In post-hospitalisation observation 58–80% discontinue CPAP [47, 48].

It may well be that our results were affected by the size of the study groups after three months of treatment. This limitation resulted from the de- sire to eliminate all the confounders that could affect the study results, particularly confounders that could affect homocysteine levels and lipid profiles.

To this end, patients with changes in their lipid- lowering regimen during CPAP treatment and patients diagnosed with diabetes mellitus, renal failure or hypothyroidism were excluded from the study.

Moreover, although polysomnography studies could have been performed at three months to con- firm the efficacy of CPAP treatment, we intentio- nally decided against it, as all the patients had been provided with CPAP devices offering the possibility to record the duration of treatment and, in the majority of patients, the possibility to record AHI (45 out of the 65 who had commenced CPAP treatment). The analysis of data retrieved from the auto- CPAP devices, which had been provided to all the patients at baseline, showed that the treatment had been effective. Furthermore, the additional polysomnography studies would have generated significant cost to be incurred by the polysomnography laboratory.

We also did not take the opportunity to per- form follow-up measurements in patients who had

refused CPAP treatment and decided to undergo surgery or not to receive any treatment. This group was, however, very small (n = 15) and we conc- luded that it would not have contributed significantly to the study results.

Conclusions

1. Three-month CPAP treatment did not affect blood levels of homocysteine or leptin in patients with OSAS.

2. Three-month CPAP treatment significantly reduced lipid parameters in patients with OSAS without co-existent IHD but not in patients with OSAS and IHD, which confirms the beneficial effect of this method of treatment on the risk factors of IHD.

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