Revista Portuguesa de Pneumologia Revista Portuguesa de Pneumologia
Rev Port Pneumol 2017;23:193-202 - Vol. 23 Num.4 DOI: 10.1016/j.rppnen.2017.02.010
Original article
Effects of positive airway pressure therapy on cardiovascular and metabolic markers in males with obstructive sleep apnea
A. Felicianoa,b,, , M.J. Oliveirac, A. Cysneirosa, C. Martinhoa, R.P. Reisb,d, D. Penquee, P. Pintof,g,h, C. Bárbaraa,g,h
a Pneumology in Thorax Department, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
b Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
c Serviço de Pneumologia, Centro Hospitalar de Vila Nova de Gaia e Espinho, EPE, Vila Nova de Gaia, Portugal
d Cardiology Unit, Hospital Pulido Valente, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
e Proteomics Laboratory, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal
f Sleep and Non Invasive Ventilation Unit, Thorax Department, Centro Hospitalar Lisboa Norte, Lisboa, Portugal
g Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
h Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
Received 21 October 2016, Accepted 25 February 2017

Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular/metabolic complications. Some analytical parameters (homocysteine, glycemic and lipidic profiles) are recognized markers of these consequences. Limited data is available on the association of these markers and OSAS's severity/response to positive airway pressure therapy (PAP).

Material and methods

In this prospective study we analyzed polysomnographic and analytical data of male patients admitted to sleep laboratory. The aim was to evaluate metabolic/cardiovascular markers in snorers and OSAS patients, to relate with sleep parameters and PAP response. One-hundred and three patients were included, and 73 (71%) were OSAS patients. OSAS patients were similar to snorers except for higher body mass index (BMI) and dyslipidemia. Severe OSAS patients showed higher glycemia, HbA1c, insulin, and insulin resistance, and lower HDL cholesterol in comparison to mild–moderate (p<0.05, p<0.05, p<0.001, p<0.001, p<0.05, respectively). Glycemic profile and triglycerides were slightly correlated with OSAS severity. 46 OSAS patients were submitted to 6 months of PAP, with a statistical decrease in mean values of homocysteine, glycemia, total and LDL cholesterol (p<0.05, p<0.05, p<0.05, respectively), and in glycemia and LDL cholesterol in severe group only (p<0.05, p<0.05, respectively).


This study demonstrated an association between glucose metabolism parameters and triglycerides with OSAS severity underlying the complexity of the process leading to cardiovascular/metabolic complications in this disorder. Moreover, homocysteine, glycemic and lipidic profiles changed significantly after 6 months of PAP therapy in OSAS, supporting its cardiovascular and metabolic protective effect.


Our study has reinforced the importance of analytical cardiovascular/metabolic evaluation as complementary tool of diagnosis/treatment response in OSAS.

Obstructive sleep apnea, Lipid metabolism, Glucose metabolism, HOMA-IR, Homocysteine, PAP

Obstructive sleep apnea syndrome (OSAS) is a common sleep and chronic respiratory disorder,1,2 associated with cardiovascular3–5 and metabolic (such as obesity,6 dyslipidemia7 and type 2 diabetes)8 complications. It has been difficult to determine if these are due to OSAS or to associated risk factors. Sleep fragmentation and intermittent hypoxia are some mechanisms contributing to OSAS complications,9,10 which improve with positive airway pressure treatment (PAP). However, the impact of PAP on other mechanisms involved is still not well characterized. Some oxidative stress biomarkers have been associated to OSAS morbidity.11 Still controversy remains regarding the best diagnostic/prognostic marker. An example is homocysteine (Hcy), which is considered a “promising” marker.12 Hcy is an intermediate product in the biosynthesis of methionine and cysteine,13 and is determinant of the methylation cycle.14 Hcy levels in adults follow a circadian variation,15 being lower in the morning. Studies reported Hcy as an independent risk factor for atherosclerosis,16,17 cerebral, and cardiovascular diseases (CVD),13,18–24 being related with their prognosis.18 The proposed mechanisms are its adverse effects on vascular structure and function,25 hypercoagulability state,23 and depletion of nitric oxide.26 Moreover, dyslipidemia, diabetes, cancer, renal, and thyroid dysfunction13,23 are associated with elevated Hcy. Also, older age, male gender, various drugs, tobacco/coffee/alcohol, and vitamins deficiency.13,23 Hcy has been proposed as an OSAS biomarker regarding its relationship with CVD. Studies show higher levels of Hcy in OSAS with27–30 or without31,32 pre-existing cardiac disease. Moreover there are contradictory studies reporting the effect of PAP on Hcy levels.29,33–37

The aim of this study was to analyze Hcy levels in snorers and OSAS patients, its correlation with OSAS severity, and response to PAP. Additionally, glycemic and lipid parameters were also evaluated.

Material and methods

This prospective study included one hundred three consecutive male subjects with suspicion of OSAS, who were evaluated at a Sleep Clinic. Demographic data included age, body mass index (BMI), Epworth sleepiness scale, and medical history. Exclusion criteria were female gender (to avoid hormonal influence), other sleep disorders, neuromuscular, renal, and thyroid disease, heart failure, cancer, acute disease, and previous PAP.

All patients underwent an overnight polysomnography (PSG) using Embla S7000 System (Embla, USA) with a technician monitoring. Sleep recording and events were manually analyzed according to standard criteria.38 The respiratory disturbance index (RDI), oxygen desaturation index (ODI), percentage of time with saturation under 90% (T90) and lowest oxygen saturation (SpO2) were calculated. Based on RDI5 obstructive events/h of sleep, patients were diagnosed as OSAS (n=73) and grouped into mild (RDI 5–14.9), moderate (RDI 15–29.9), and severe (RDI30). Later, in pre/post OSAS treatment analysis, mild and moderate patients were combined (RDI<30), in order to evaluate the extreme of disease spectrum.

To calculate the sample size we focused in the main objective, that is Hcy analysis before/after PAP treatment. The sample size was calculated with PS software, version 3.1.2. It was planned a study of a continuous response variable from matched pairs of study subjects. Prior data indicated that the difference in the response of matched pairs was normally distributed with standard deviation 2. If the true difference in the mean response of matched pairs is 0.95, the sample size need to be of 37 pairs of subjects to be able to reject the null hypothesis that this response difference is zero with probability (power) 0.8 (i.e. beta 0.20). The type I error probability associated with this test of this null hypothesis is 0.05 (i.e. alfa 0.05).

According to criteria,39 PAP therapy with automatic devices (S9, Resmed, Australia) was prescribed for 46 patients in severe disease or in disease of any severity when associated with excessive diurnal sleepiness and/or cardio/cerebrovascular complications. These patients were evaluated at six months for compliance registration. As described,41 more than 4h use/night for at least 70% of nights was considered as acceptable compliance. After PAP initiation, no more indications (excluding healthy lifestyle) were given, assuming a real life scenario.

Venous blood samples were collected after PSG and a 12-h fasting period, into EDTA-coated polypropylene tubes. At six months of PAP a second morning blood sample was collected. The collected blood was processed between 1 and 2h to determine Hcy (chemiluminescence (CLIA), ADVIA Centaur xp, Siemens). Additionally, parameters of glycemic profile were determined, such as glucose (Enzyme UV Hexoquinase – ADVIA 2400 Siemens), haemoglobin A1c (HbA1c) (HPLC – Variant II BioRad), insulin (chemiluminescence (CLIA), ADVIA Centaur xp, Siemens) and insulin resistance (calculated by homeostatic model assessment of insulin resistance – HOMA-IR). Parameters of lipid profile were, also, determined such as total cholesterol (CHOD-PAP (enzymatic colorimetric) ADVIA 2400, Siemens), low-density lipoprotein (LDL) cholesterol (by calculation), high-density lipoprotein (HDL) cholesterol (HDL Plus 2nd generation elimination/catalase ADVIA 2400, Siemens), and triglycerides (Enzymatic colorimetric (GPO) ADVIA 2400, Siemens). The HOMA-IR was determined by the product between fasting plasma glucose and insulin concentration, which has a reasonable linear correlation with the gold standard of insulin resistance measurement (hyperinsulinemic–euglycemic clamp).40

All subjects underwent restriction of alcohol, tea, coffee, chocolate, beetroot, banana, avocado, tomato, plum, pineapple, kiwi, orange, nut, hazelnut, vanilla candies, and confectionery during the three days prior to PSG. Patients underwent 24h urine collection (into a hydrochloric acid container and stored at 4°C) for catecholamines determination (adrenaline, nor-adrenaline, and dopamine) (HPLC – BioRad).

The study protocol was approved by the local ethics committees and all patients gave written informed consent.

Statistical analyses were performed using SPSS for windows software (SPSS 20 Inc., Chicago, IL, USA). All variables were tested for normality of the distribution using Kolmogorov–Smirnov test. Continuous variables with normal distributions were expressed as means ± standard deviation (SD) and categorical variables in numbers (percentages). Pearson's analysis was performed for correlations between parametric variables. Independent-samples T-test was used for comparisons between independent groups for values that were normally distributed and paired-samples T-test was used to compare variables normally distributed before and after PAP treatment. Categorical variables were compared using X2 test. Results were considered statistically significant when p value was <0.05.


Clinical and analytical evaluation of snorers and OSAS patients are shown in Table 1. There were no statistically significant differences regarding demographic and analytical parameters. Instead, the existence of known dyslipidemia and BMI were higher in OSAS patients (p<0.001, p=0.001, respectively). HOMA-IR, total cholesterol, and urinary noradrenaline were higher than normal range in OSAS patients and Hcy was higher than normal range in both groups.

Table 1.

Initial evaluation of study participants: demographics, comorbidities, polysomnography data, glycemic and lipidic profiles, homocysteine, and urinary catecholamines (BMI: body mass index; EPW: Epworth sleepiness scale; LDL: low-density lipoprotein; HDL: high-density lipoprotein; HOMA-IR: homeostasis model assessment; OSAS: obstructive sleep apnea syndrome; RDI: respiratory disturbance index; SD: standard deviation; T90: desaturation time under 90%; U: urine).

  Total  Snorers  OSAS  Snorers vs. OSAS (pMild-Mod OSAS  Severe OSAS  Mild-Mod vs. Severe OSAS (pMild-Mod OSAS before PAP  Severe OSAS before PAP  Mild-Mod vs. severe OSAS before PAP (p
  N=103  N=30  N=73    N=46  N=27    N=22  N=24   
Age (years) (media/SD)  46/8  45/10  46/8  0.354  46/8  47/7  0.737  47/9  47/7  0.931 
Smoking history (n/%)  69/67.0  21/70.0  48/65.8  0.681  29/63.0  19/70.4  0.531  14/63.6  17/70.8  0.612 
Alcohol consumption (n/%)  66/64.1  15/50.0  51/69.9  0.057  30/65.2  21/77.8  0.265  15/68.2  18/75.0  0.617 
BMI (kg/m2) (media/SD)  29.4/3.8  27.4/3.3  30.2/3.7  0.001  28.9/3.0  32.3/3.8  <0.001  29.4/2.4  32.0/3.7  0.006 
Cardiac disease (n/%)  55/53.4  13/43.3  42/57.5  0.193  23/50.0  19/70.4  0.092  12/54.5  17/70.8  0.263 
Respiratory disease (n/%)  15/14.6  2/6.7  13/17.8  0.188  7/15.2  6/22.2  0.571  3/13.6  6/25.0  0.382 
Dyslipidemia (n/%)  49/47.6  4/13.3  45/61.6  <0.001  22/47.8  23/85.2  0.026  10/45.5  20/83.3  0.030 
Diabetes (n/%)  7/6.8  1/3.3  6/8.2  0.374  2/4.3  4/14.8  0.115  0/0  3/12.5  0.099 
EPW scale (media/SD)  9.5/4.8  9.3/5.1  9.5/4.7  0.843  9.7/4.7  9.2/4.8  0.694  11.7/4.1  9.5/5.0  0.103 
RDI (events/h) (media/SD)  20.4/23.3  2.8/1.3  27.6/24.2  <0.001  11.9/6.1  54.3/19.5  <0.001  12.2/6.2  55.0/19.3  <0.001 
T90 (%) (media/SD)  5.6/13.2  1.6/8.1  7.2/14.5  0.047  1.0/2.3  17.9/19.6  <0.001  1.2/2.0  16.4/18.2  <0.001 
Sleep efficiency (%) (media/SD)  79.2/14.4  77.3/14.4  79.1/14.5  0.407  80.4/14.7  79.1/14.0  0.703  75.2/18.6  77.2/13.8  0.675 
Lowest SpO2 (%) (media/SD)  84.1/7.5  88.5/4.6  82.3/7.7  <0.001  85.3/5.4  77.1/8.3  <0.001  83.3/6.6  77.7/7.8  0.012 
ODI (dessaturations/h) (media/SD)  16.8/22.5  2.2/2.9  22.8/24.2  <0.001  8.1/5.7  47.8/23.2  <0.001  8.9/6.0  48.1/23.8  <0.001 
Glucose (mg/dL) (media/SD)  101.0/25.8  101.2/31.3  100.9/23.4  0.951  95.9/17.2  109.4/29.8  0.017  97.3/20.2  109.4/31.0  0.128 
Glycosylated haemoglobin (%) (media/SD)  5.8/0.8  5.8/1.0  5.8/0.8  0.957  5.6/0.5  6.1/1.0  0.012  5.6/0.7  6.2/1.0  0.036 
Insulin (mU/L) (media/SD)  14.7/8.6  12.7/6.8  15.5/9.1  0.124  12.4/6.8  20.9/10.1  <0.001  11.3/5.0  20.8/10.4  <0.001 
HOMA-IR (media/SD)  3.8/2.8  3.3/2.8  4.0/2.8  0.241  3.1/2.2  5.7/2.9  <0.001  2.8/1.7  5.6/2.9  <0.001 
Total cholesterol (mg/dL) (media/SD)  192.1/37.7  185.9/41.3  194.6/36.1  0.290  194.2/38.4  195.3/32.4  0.092  191.6/42.7  193.7/30.0  0.852 
LDL cholesterol (mg/dL) (media/SD)  121.0/31.6  117.2/33.4  122.6/30.9  0.435  122.1/30.6  123.5/32.0  0.854  123.8/32.6  122.0/28.2  0.850 
HDL cholesterol (mg/dL) (media/SD)  44.7/10.1  44.7/10.4  44.7/10.0  1.000  46.8/11.3  41.2/6.0  0.019  44.6/12.3  41.0/5.5  0.190 
Triglycerides (mg/dL) (media/SD)  134.6/79.3  121.0/68.0  140.2/83.3  0.265  128.8/79.4  159.7/87.6  0.126  120.0/57.1  160.7/88.7  0.074 
Homocysteine (μmol/L)  15.2/3.4  14.7/3.3  15.3/3.5  0.399  15.3/3.8  15.3/2.9  0.997  14.9/3.1  15.6/2.6  0.436 
Adrenaline (μg/24h U) (media/SD)  19.9/15.5  17.7/16.3  20.8/54.2  0.765  13.8/12.3  32.7/87.4  0.152  14.2/13.1  34.7/92.6  0.308 
Noradrenaline (μg/24h U) (media/SD)  85.7/180.4  64.6/28.1  94.3/213.4  0.45  63.1/35.5  147.5/345.4  0.103  62.0/35.4  149.7/365.9  0.269 
Dopamine (μg/24h U) (media/SD)  434.6/771.5  373.9/197.0  459.5/908.5  0.611  340.9/202.1  661.5/1465.5  0.147  334.7/220.4  657.2/1550.0  0.339 

Concerning OSAS patients, there were no statistically differences between mild–moderate (46, 63%) and severe (27, 37%) regarding demographic parameters. Instead, dyslipidemia and BMI were higher in severe OSAS patients (p<0.05, p<0.001, respectively). Glycemia, HbA1c, insulin, and HOMA-IR were higher and HDL cholesterol was lower in severe group (p<0.05, p<0.05, p<0.001, p<0.001, p<0.05, respectively). Moreover, HbA1c, HOMA-IR, triglycerides, and urinary catecholamines were higher than normal range in severe OSAS patients and total cholesterol and Hcy in both groups.

Some metabolic parameters were slightly correlated with OSAS severity. Glycemia, HbA1c, and triglycerides were positively correlated with RDI (p<0.05, Pearson correlation). Glycemia and HbA1c were negatively correlated with lowest SpO2 (p<0.05, Pearson correlation). Instead, insulin and HOMA-IR were positively correlated with RDI, T90, and ODI (p<0.001, Pearson correlation) and negatively correlated with lowest SpO2 (p<0.001) (Table 2).

Table 2.

Correlation between variables of polysomnography and glycemic and lipidic profiles, homocysteine, and urinary catecholamines (LDL: low-density lipoprotein; HDL: high-density lipoprotein; HOMA-IR: homeostasis model assessment; ODI: oxygen desaturation index; RDI: respiratory disturbance index; T90: desaturation time under 90%; U: urine).

  Glucose (mg/dL)Glycosylated haemoglobin (%)Insulin (mU/L)HOMA-IR
  r  p  r  p  r  p  r  p 
RDI (events/h)  0.217  0.027  0.217  0.028  0.423  <0.001  0.382  <0.001 
T90 (%)  0.179  0.071  0.121  0.224  0.342  <0.001  0.331  0.001 
Sleep efficiency (%)  0.01  0.923  0.018  0.857  0.009  0.925  0.061  0.539 
Lowest SpO2 (%)  0.264  0.007  0.242  0.014  0.321  0.001  0.372  <0.001 
ODI (dessaturations/h)  0.181  0.068  0.172  0.083  0.428  <0.001  0.384  <0.001 
  Total cholesterol (mg/dL)LDL cholesterol (mg/dL)HDL cholesterol (mg/dL)Triglycerides (mg/dL)
  r  p  r  p  r  p  r  p 
RDI (events/h)  0.087  0.385  0.056  0.577  0.123  0.215  0.205  0.038 
T90 (%)  0.133  0.180  0.111  0.267  0.021  0.833  0.154  0.122 
Sleep efficiency (%)  0.115  0.246  0.126  0.206  0.012  0.908  0.002  0.986 
Lowest SpO2 (%)  0.110  0.269  0.079  0.432  0.008  0.937  0.141  0.155 
ODI (dessaturations/h)  0.094  0.343  0.081  0.421  0.119  0.229  0.175  0.076 
  Homocysteine (μmol/L)Adrenaline (μg/24h U)Noradrenaline (μg/24h U)Dopamine (μg/24h U)
  r  p  r  p  r  p  r  p 
RDI (events/h)  0.028  0.782  0.083  0.407  0.107  0.284  0.08  0.42 
T90 (%)  0.083  0.405  0.045  0.651  0.028  0.78  0.001  0.99 
Sleep efficiency (%)  0.135  0.176  0.095  0.342  0.052  0.61  0.033  0.744 
Lowest SpO2 (%)  0.001  0.992  0.029  0.773  0.044  0.659  0.013  0.899 
ODI (dessaturations/h)  0.056  0.577  0.024  0.81  0.053  0.592  0.029  0.77 

Clinical and analytical evaluation of OSAS treatment patients are shown in Tables 1 and 3. 46 OSAS patients underwent PAP (22 (48%) were mild–moderate and 24 (52%) were severe). Patients showed a mean compliance of 4.37h/night. Additionally in PAP follow up, weight and smoking habits were always asked and there were no changes in both parameters. After six months of treatment, OSAS patients showed a statistical decrease in Hcy, glycemia, total and LDL cholesterol (p<0.05) (Table 3). Instead, in severe OSAS only glycemia and LDL cholesterol showed a significant reduction (p<0.05).

Table 3.

OSAS, Mild-Moderate and severe OSAS patients: comparative analysis in terms of glycemic and lipidic profiles, homocysteine, and urinary catecholamines, before and after PAP therapy (LDL: low-density lipoprotein; HDL: high-density lipoprotein; HOMA-IR: homeostasis model assessment; OSAS: obstructive sleep apnea syndrome; PAP: positive airway pressure; U: urine).

  OSASMild-Moderate OSASSevere OSAS
  n  Pre PAP  Post PAP  p  n  Pre PAP  Post PAP  p  n  Pre PAP  Post PAP  p 
Glucose (mg/dL)  46  103.6/26.8  99.24/22.2  0.030  22  97.3/20.2  96.6/21.7  0.695  24  109.4/31.0  101.6/22.9  0.027 
Glycosylated haemoglobin (%)  46  5.9/0.9  5.9/1.0  0.914  22  5.6/0.7  5.7/0.8  0.125  24  6.2/1.0  6.1/1.1  0.584 
Insulin (mU/L)  46  16.3/9.5  20.9/23.1  0.169  22  11.3/5.0  12.1/5.9  0.316  24  20.8/10.4  28.9/29.6  0.206 
HOMA-IR  43  4.4/2.8  5.4/6.2  0.294  20  2.9/1.8  3.0/2.0  0.762  23  5.6/2.9  7.4/7.8  0.311 
Total cholesterol (mg/dL)  46  192.7/36.2  184.2/29.5  0.043  22  191.6/42.7  184.0/28.4  0.254  24  193.7/29.9  184.3/31.0  0.087 
LDL cholesterol (mg/dL)  45  122.9/30.1  108.6/32.6  0.003  22  123.8/32.6  114.6/25.3  0.066  23  122.0/28.2  102.9/37.9  0.017 
HDL cholesterol (mg/dL)  46  42.7/9.4  43.3/8.6  0.657  22  44.6/12.3  45.9/10.0  0.598  24  41.0/5.5  40.9/6.4  0.937 
Triglycerides (mg/dL)  46  141.2/77.2  137.4/76.0  0.736  22  120.0/57.1  118.3/47.1  0.861  24  160.7/88.7  154.9/92.8  0.775 
Homocysteine (μmol/L)  46  15.3/2.8  13.2/2.6  0.005  22  14.9/3.1  16.0/2.5  0.039  24  15.6/2.6  16.5/2.7  0.065 
Adrenaline (μg/24h U)  46  24.9/67.6  18.4/11.5  0.53  22  14.2/13.1  16.9/6.8  0.386  24  34.7/92.6  19.8/14.5  0.451 
Noradrenaline (μg/24h U)  46  107.8/266.4  54.3/22.0  0.182  22  62.0/35.4  51.3/17.4  0.212  24  149.7/365.9  56.9/25.6  0.229 
Dopamine (μg/24h U)  46  503.0/1130.1  311.8/132.0  0.26  22  334.7/220.4  298.8/122.0  0.453  24  657.2/1550.0  323.8/142.2  0.307 

This study showed after six months of PAP, homocysteine, glycemia, total and LDL cholesterol decrease in OSAS patients pointing to cardiovascular/metabolic protective role of this treatment.

In our study, Hcy was similar in snorers and OSAS patients, and also in different OSAS severities, although being higher than normal range. Hcy is an emerging independent risk factor for CVD, but it is not clear its association with OSAS. Both smoking and obesity may affect Hcy levels,42–47 which could be confounders in the association with CVD. In this study, smoking habits and prevalence of CVD were similar between snorers and OSAS patients, and between different levels of OSAS severity. Concerning obesity, snorers and OSAS patients were obese, still OSAS patients presented a higher BMI, which could influence the Hcy levels. The presence of obesity even in snorers is probably responsible for OSAS suspicion and referral to sleep clinic.48 Also, several diseases such as dyslipidemia13,23 are associated with elevated levels of Hcy, and this disease was more prevalent in OSAS patients.

A meta-analysis (432 subjects) showed higher Hcy levels in OSAS than in controls,49 especially when BMI30, age<50 years, and severe OSAS. Other authors50,51 also reported higher Hcy levels in severe OSAS. A recent study reported higher Hcy levels in patients with coronary artery disease, with OSAS and with both diseases,30 and the highest values for Hcy were observed in the latter group. Further, there was no correlation between Hcy levels and oxygen desaturation, as showed in the present study. Contrary to these results, some studies did not report increased levels of Hcy in OSAS patients with34,35 or without associated CVD.28,29,36 Although, Hcy was not correlated with sleep parameters, in OSAS patients it decreased for normal values after 6 months of PAP therapy, which may suggest that its levels could in part be related with OSAS. These results are similar to a study of 12 OSAS patients with CVD, which reported a reduction in Hcy levels after PAP therapy.33 This behaviour under PAP was confirmed in a recent meta-analysis.52 On the contrary, other studies29,35–37 reported that PAP therapy or mandibular advancement device37 did not influence Hcy levels in OSAS patients.

Previous studies suggest that OSAS is associated with dyslipidemia7 and type 2 diabetes.8 In fact, in this study dyslipidemia was more prevalent in OSAS patients comparing to snorers, although both groups showed similar glycemic and lipid profiles.

Indeed, some authors found that OSAS is independently associated with disorders of lipid metabolism,53 mainly due to intermittent hypoxia54 and sleep fragmentation.55 Furthermore, as in this study, triglycerides were associated with OSAS severity.53 This is an important issue once dyslipidemia is a major cause of atherosclerotic CVD.56

Moreover, severe OSAS showed a change in glycemic profile, even in absence of known diabetes, probably suggesting a pre-diabetic state, and it was correlated with sleep parameters (RDI and nocturnal desaturation). A condition characterized by insulin resistance and glucose intolerance is known as prediabetes.57 Individuals presenting this state are at risk of CVD and the majority will develop diabetes,58,59 putting our severe patients in an increased risk for both disorders. These results are in agreement with a meta-analysis which confirmed that moderate/severe OSAS increases the risk of development of type 2 diabetes,60 even following adjustment of obesity, age, co-morbidities, and medication use.61 Sleep fragmentation and intermittent hypoxia62 seem to be involved in carbohydrate dysregulation in OSAS, with impaired lipid metabolism, inflammation, oxidative stress and sympathetic nervous system activation.63

Concerning the evaluation of both profiles after PAP therapy, OSAS patients presented a statistical change in glycemic and lipid profiles, with a decrease in glucose, total and LDL cholesterol. Some trials provide evidence that PAP therapy may improve glucose metabolism64 especially in sleepy patients.65 However, other studies do not support this improvement,66 but the duration of treatment could be an explanation. A recent study has shown improvement in glucose metabolism with PAP therapy even in OSAS patients (overweight or obese) with prediabetes.67 Additionally, even in non-diabetic adults with OSAS, two meta-analyses have reported that PAP therapy modestly decreases HOMA-IR.68,69 Another study in diabetic OSAS patients has shown that one month of PAP therapy led to reduction of fasting glucose, HbA1c, and HOMA-IR, without change in BMI.70

A meta-analysis reported that PAP therapy decreases total cholesterol level, especially in OSAS patients who are younger, more obese, and who use PAP for a longer period (≥12 weeks).71 However, in this meta-analysis PAP had no effect on fasting glucose or HOMA-IR. Also in a meta-regression analysis, PAP improved total and LDL cholesterol, with an increase in HDL cholesterol.7 A more recent meta-analysis72 reported that PAP significantly lowered total cholesterol, triglyceride, and HDL, but not LDL, particularly in moderate-severe patients, good compliance and daytime somnolence. However the magnitude of lipid reduction was modest and only significant in studies where autonomic hyperactivity was also lowered by PAP. In fact, in the present study OSAS patients presented a higher prevalence of dyslipidemia and after PAP there was a decrease in total and LDL cholesterol, without changing lifestyle habits. Moreover, urinary cathecolamines decrease to normal levels, however without statistical significance, which could have conditioned lipid lowering effect of PAP.

Treatment with PAP in OSAS may improve dyslipidemia through ameliorating hypoxia, inflammation,73 and insulin resistance.74 However, dyslipidemia in OSAS patients is far from being a simple process because, besides OSAS severity, several factors can contribute for it such as obesity, diet, and exercise.34,53,75,76 This fact and probably sample size could explain that the remainder of lipidic profile (triglyceride, total and HDL cholesterol) was not affected by PAP in this study.

This study showed a similar pattern of urinary catecholamines between snorers and OSAS patients and between OSAS patients of different severities. Additionally, in severe OSAS patients urinary catecholamines were higher than normal range. Although urinary cathecolamines were not correlated with sleep parameters, after six months of PAP, they decreased to normal levels, nonetheless without statistical significance. These results may be due to sample size because previous studies reported that in OSAS there is an increase in sympathetic activity, independently of obesity.77 In fact, Pinto et al.78 reported 24-h urinary norepinephrine levels significantly higher in severe OSAS than in mild–moderate, with a significant reduction after one month of PAP. Another study79 reported that PAP withdrawal resulted in rise in urinary noradrenaline and that was positively associated with hypoxaemia severity. Reduction of sympathetic activity can be a potential mediator of metabolic benefit from PAP (with improvement of glucose levels) as shown in a study by Pamidi et al.67

There are some limitations of this study, such as small sample size, female exclusion, and BMI differences between groups. Furthermore, drugs and diseases that interfere with vitamin B metabolism are potential causes for higher Hcy concentrations,80 and these vitamins were not determined in this study.


The present study demonstrated an association between glucose metabolism parameters and triglycerides with OSAS severity, contributing to the complexity of the process leading to cardiovascular/metabolic complications in this disorder. Moreover, Hcy, glycemic, and lipid profiles changed significantly after 6 months of PAP therapy in OSAS patients, supporting its cardiovascular and metabolic protective effect.

In conclusion, our study has reinforced the importance of analytical cardiovascular/metabolic evaluation as complementary tool of diagnosis/treatment response in OSAS patients.

Ethical disclosuresProtection of human and animal subjects

The authors declare that no experiments were performed on humans or animals for this study.

Confidentiality of data

The authors declare that no patient data appear in this article.

Right to privacy and informed consent

The authors declare that no patient data appear in this article.

Conflicts of interest

The authors have no conflicts of interest to declare.

D.J. Eckert,A. Malhotra
Pathophysiology of adult obstructive sleep apnea
Proc Am Thorac Soc, 5 (2008), pp. 144-153
K. Franklin,E. Lindberg
Obstructive sleep apnea is a common disorder in the population – a review on the epidemiology of sleep apnea
D. Martinez,C. Klein,L. Rahmeier,R.P. da Silva,C.Z. Fiori,C. Cassol
Sleep apnea is a stronger predictor for coronary heart disease than traditional risk factors
Sleep Breath, 16 (2012), pp. 695-701
P.M. Macey,R. Kumar,M.A. Woo,F.L. Yan-Go,R.M. Harper
Heart rate responses to autonomic challenges in obstructive sleep apnea
J.S. Floras
Sleep apnea and cardiovascular risk
S. Ryan,S.J. Crinion,W.T. McNicholas
Obesity and sleep-disordered breathing when two ‘bad guys’ meet
R. Nadeem,M. Singh,M. Nida,I. Waheed,A. Khan,S. Ahmed
Effect of obstructive sleep apnea hypopnea syndrome on lipid profile: a meta regression analysis
J Clin Sleep Med, 10 (2014), pp. 475-489
S. Pamidi,E. Tasali
Obstructive sleep apnea and type 2 diabetes: is there a link?
J. Dempsey,S. Veasey,B. Morgan,C. O’Donnell
Pathophysiology of sleep apnea
Physiol Rev, 90 (2010), pp. 47-112
P. Lévy,S. Ryan,O. Oldenburg,G. Parati
Sleep apnoea and the heart
Eur Respir Rev, 22 (2013), pp. 333-352
J. Feng,D. Zhang,B. Chen
Endothelial mechanisms of endothelial dysfunction in patients with obstructive sleep apnea
Sleep Breat, 16 (2012), pp. 283-294
V. Veeranna,S.K. Zalawadiya,A. Niraj,J. Pradhan,B. Ference,R.C. Burack
Homocysteine and reclassification of cardiovascular disease risk
J Am Coll Cardiol, 58 (2011), pp. 1025-1033
D. Faeh,A. Chiolero,F. Paccaud
Homocysteine as a risk factor for cardiovascular disease: should we (still) worry about it?
Swiss Med Wkly, 136 (2006), pp. 745-756
J. Loscalzo,D.E. Handy
Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference Series)
Pulm Circ, 4 (2014), pp. 169-174
W.F. Bremner,E.W. Holmes,E.L. Kanabrocki,R.C. Hermida,D. Ayala,J. Garbincius
Circadian rhythm of serum total homocysteine in men
Am J Cardiol, 86 (2000), pp. 1153-1156
Y. Xiao,Y. Zhang,X. Lv,D. Su,D. Li,M. Xia
Relationship between lipid profile and plasma total homocysteine, cysteine and the risk of coronary artery disease in coronary angiographic subjects
Lipid Health Dis, 10 (2011), pp. 137
X. Pang,J. Liu,J. Zhao,J. Mao,X. Zhang,L. Feng
Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF-KB signal pathway in rat vascular smooth muscle cells
O. Stanger,W. Herrmann,K. Pietrzik,B. Fowler,J. Geisel,J. Dierkes
Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases
D. Girelli,N. Martinelli,O. Olivieri,F. Pizzolo,S. Friso,G. Faccini
Hyperhomocysteinemia and mortality after coronary artery bypass grafting
Y.H. Zhou,J.Y. Tang,M.J. Wu,J. Lu,X. Wei,Y.Y. Qin
Effect of folic acid supplementation on cardiovascular outcomes: a systematic review and meta analysis
A.H. Ford,G.J. Garrido,C. Beer,N.T. Lautenschlager,L. Arnolda,L. Flicker
Homocysteine, grey matter and cognitive function in adults with cardiovascular disease
T. Okura,K. Miyoshi,J. Irita,D. Enomoto,T. Nagao,M. Kukida
Hyperhomocysteinemia is one of the risk factors associated with cerebrovascular stiffness in hypertensive patients, especially elderly males
Naturecom Sci Rep, 4 (2014), pp. 5663
V. Shenov,V. Mehendale,K. Prabhu,R. Shetty,P. Rao
Correlation of serum homocysteine levels with the severity of coronary artery disease
Ind J Clin Biochem, 29 (2014), pp. 339-344
A. Baszczuk,Z. Kopczynski
Hyperhomocysteinemia in patients with cardiovascular disease
Postepy Hig Med Dosw, 68 (2014), pp. 579-589
S. Zhang,B. Yong-Yi,L.M. Luo,W.K. Xiao,H.M. Wu,P. Ye
Association between serum homocysteine and arterial stiffness in elderly: a community-based study
S.R. Lentz
Mechanisms of homocysteine induced atherothrombosis
J Thromb Haemost, 3 (2005), pp. 1646-1654
L. Lavie,A. Perelman,P. Lavie
Plasma homocysteine levels in obstructive sleep apnea – association with cardiovascular morbidity
Chest, 120 (2001), pp. 900-908
L. Lavie
Obstructive sleep apnoea syndrome: an oxidative stress disorder
Sleep Med Rev, 7 (2003), pp. 35-51
A. Svatikova,R. Wolk,M.J. Magera,A.S. Shamsuzzaman,B.G. Phillips,V.K. Somers
Plasma homocystein in obstructive sleep apnea
Eur Heart J, 25 (2004), pp. 1325-1329
E.O. Ersoy,H. Fırat,S. Akaydın,Y. Özkan,M. Durusu,G.D. Yüce
Association of obstructive sleep apnea with homocystein, nitric oxide and total antioxidant capacity levels in patients with or without coronary artery disease
Tuberk Toraks, 62 (2014), pp. 207-214
M. Can,S. Açikgöz,G. Mungan,T. Bayraktaroğlu,E. Koçak,B. Güven
Serum cardiovascular risk factors in obstructive sleep apnea
O. Kokturk,T.U. Ciftci,E. Mollarecep,B. Ciftci
Serum homocysteine levels and cardiovascular morbidity in obstructive sleep apnea syndrome
Resp Med, 100 (2006), pp. 536-541
W. Jordan,C. Berger,S. Cohrs,A. Rodenbeck,G. Mayer,P.D. Niedmann
CPAP-therapy effectively lowers serum homocysteine in obstructive sleep apnea syndrome
J Neural Transm, 111 (2004), pp. 683-689
G.V. Robinson,J.C.T. Pepperell,H.C. Segal,R.J.O. Davies,J.R. Stradling
Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials
A. Barceló,F. Barbé,M. de la Peña,M. Vila,G. Pérez,J. Piérola
Antioxidant status in patients with sleep apnoea and impact of continuous positive airway pressure treatment
Eur Respir J, 27 (2006), pp. 756-760
S. Ryan,G.M. Nolan,E. Hannigan,S. Cunningham,C. Taylor,W.T. McNicholas
Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity
C. Dal-Fabbro,S. Garbuio,V. D’Almeida,F. Cintra,S. Tufik,L. Bittencourt
Mandibular advancement device and CPAP upon cardiovascular parameters in OSA
Sleep Breath, 18 (2014), pp. 749-759
R.B. Berry,R. Budhiraja,D.J. Gottlieb,D. Gozal,C. Iber,V.K. Kapur
Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for Scoring of Sleep and Associated Events Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine
J Clin Sleep Med, 8 (2012), pp. 597-619
A. Qaseem,J.-E. Holty,D. Owens,P. Dallas,M. Starkey,P. Shekelle
The Clinical Guidelines Committee of the American College of Physicians Management of Obstructive Sleep Apnea in Adults: a clinical practice guideline from the American College of Physicians
T.M. Wallace,J.C. Levy,D.R. Matthews
Use and abuse of HOMA modeling
Diab Care, 27 (2004), pp. 1487-1495
T.E. Weaver,A.M. Sawyer
Adherence to continuous positive airway pressure treatment for obstructive sleep apnea: implications for future interventions
Indian J Med Res, 131 (2010), pp. 245-258
T.T. Fung,E.B. Rimm,D. Spiegelman,N. Rifai,G.H. Tofler,W.C.D. Willett
Association between dietary patterns and plasma biomarkers of obesity and cardiovascular disease risk
Am J Clin Nutr, 73 (2001), pp. 61-67
G. De Pergola,N. Pannacciulli,M. Zamboni,A. Minenna,G. Brocco,M. Sciaraffia
Homocysteine plasma levels are independently associated with insulin resistance in normal weight, overweight and obese pre-menopausal women
Diabetes Nutr Metab, 14 (2001), pp. 253-258
V. Sanchez-Margalet,M. Valle,F.J. Ruz,F. Gascon,J. Mateo,R. Goberna
Elevated plasma total homocysteine levels in hyperinsulinemic obese subjects
J Nutr Biochem, 13 (2002), pp. 75-79
D. Konukoğlu,O. Serin,M. Ercan,M.S. Turhan
Plasma homocysteine levels in obese and non-obese subjects with or without hypertension; its relationship with oxidative stress and copper
Clin Biochem, 36 (2003), pp. 405-408
L.A. Bazzano,J. He,P. Muntner,S. Vupputuri,P.K. Whelton
Relationship between cigarette smoking and novel risk factors for cardiovascular disease in the United States
Ann Intern Med, 138 (2003), pp. 891-897
A. Sobczak,W. Wardas,W. Zielinska-Danch,K. Pawlicki
The influence of smoking on plasma homocysteine and cysteine levels in passive and active smokers
Clin Chem Lab Med, 42 (2004), pp. 408-414
G. Slater,M. Pengo,C. Kosky,J. Steier
Obesity as an independent predictor of subjective excessive daytime sleepiness
Respir Med, 107 (2013), pp. 305-309
X. Niu,X. Chen,Y. Xiao,J. Dong,R. Zhang,M. Lu
The differences in homocysteine level between obstructive sleep apnea patients and controls: a meta-analysis
M. Chen,B. Wu,X. Ye,Z. Zhou,X. Yue,W. Wang
Association between plasma homocysteine levels and obstructive sleep apnoea in patients with ischaemic stroke
J Clin Neurosci, 18 (2011), pp. 1454-1457
L.V. Sales,V.M. Bruin,V. D’Almeida,S. Pompéia,O.F. Bueno,S. Tufik
Cognition and biomarkers of oxidative stress in obstructive sleep apnea
Clinics (Sao Paulo), 68 (2013), pp. 449-455
X. Chen,X. Niu,Y. Xiao,J. Dong,R. Zhang,M. Lu
Effect of continuous positive airway pressure on homocysteine levels in patients with obstructive sleep apnea: a meta-analysis
Sleep Breath, 18 (2014), pp. 687-694
Y. Toyama,K. Chin,Y. Chihara,M. Takegami,K. Takahashi,K. Sumi
Association between sleep apnea, sleep duration, and serum lipid profile in an urban, male, working population in Japan
Chest, 143 (2013), pp. 720-728
N.A. Dewan,F.J. Nieto,V.K. Somers
Intermittent hypoxemia and OSA: implications for comorbidities
Chest, 147 (2015), pp. 266-274
Y. Qian,H. Yi,J. Zou,L. Meng,X. Tang,H. Zhu
Independent association between sleep fragmentation and dyslipidemia in patients with obstructive sleep apnea
Scient Rep, 6 (2016), pp. 26089
I. Graham,M.T. Cooney,D. Bradley,A. Dudina,Z. Reiner
Dyslipidemias in the prevention of cardiovascular disease: risks and causality
Curr Cardiol Rep, 14 (2012), pp. 709-720
Centers for Disease Control and Prevention
National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011
US Department of Health and Human Services, Centers for Disease Control and Prevention, (2011)
D.M. Nathan,M.B. Davidson,R.A. De Fronzo,R.J. Heine,R.R. Henry,R. Pratley
American Diabetes Association impaired fasting glucose and impaired glucose tolerance: implications for care
Diab Care, 30 (2007), pp. 753-759
R.A. De Fronzo,M. Abdul-Ghani
Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose
Am J Cardiol, 108 (2011), pp. 3B-24B
X. Wang,Y. Bi,Q. Zhang,F. Pan
Obstructive sleep apnoea and the risk of type 2 diabetes: a meta-analysis of prospective cohort studies
B.D. Kent,L. Grote,S. Ryan,J.L. Pépin,M.R. Bonsignore,R. Tkacova
Diabetes mellitus prevalence and control in sleep-disordered breathing: the european sleep apnea cohort (ESADA) study
Chest, 146 (2014), pp. 982-990
A.L. Borel,D. Monneret,R. Tamisier,J.P. Baguet,P. Faure,P. Levy
The severity of nocturnal hypoxia but not abdominal adiposity is associated with insulin resistance in non-obese men with sleep apnea
A. Briançon-Marjollet,M. Weiszenstein,M. Henri,A. Thomas,D. Godin-Ribuot,J. Polak
The impact of sleep disorders on glucose metabolism: endocrine and molecular mechanisms
Diabetol Metabol Synd, 7 (2015), pp. 25
P. Steiropoulos,N. Papanas,E. Nena,V. Tsara,C. Fitili,A. Tzouvelekis
Markers of glycemic control and insulin resistance in non-diabetic patients with obstructive sleep apnea hypopnea syndrome: does adherence to CPAP treatment improve glycemic control?
T.G. Weinstock,X. Wang,M. Rueschman,F. Ismail-Beigi,J. Aylor,D.C. Babineau
A controlled trial of CPAP therapy on metabolic control in individuals with impaired glucose tolerance and sleep apnea
Sleep, 35 (2012), pp. 25B-617B
L. Hecht,R. Mohler,G. Meyer
Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis
Ger Med Sci, 9 (2011), pp. Doc20
S. Pamidi,K. Wroblewski,M. Stepien,K. Sharif-Sidi,J. Kilkus,H. Whitmore
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial
Am J Respir Crit Care Med, 192 (2015), pp. 96-105
I.H. Iftikhar,M.F. Khan,A. Das,U.J. Magalang
Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes
Ann Am Thorac Soc, 10 (2013), pp. 115-120
D. Yang,Z. Liu,H. Yang,Q. Luo
Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis
Sleep Breath, 17 (2013), pp. 33-38
L.X. Guo,X. Zhao,Q. Pan,X. Sun,H. Li,X.X. Wang
Effect of continuous positive airway pressure therapy on glycemic excursions and insulin sensitivity in patients with obstructive sleep apnea-hypopnea syndrome and type 2 diabetes
Chin Med J, 128 (2015), pp. 2301-2306
H. Xu,H. Yi,J. Guan,S. Yin
Effect of continuous positive airway pressure on lipid profile in patients with obstructive sleep apnea syndrome: a meta-analysis of randomized controlled trials
M.T. Lin,H.H. Lin,P.L. Lee,P.H. Weng,C.C. Lee,T.C. Lai
Beneficial effect of continuous positive airway pressure on lipid profiles in obstructive sleep apnea: a meta-analysis
Sleep Breath, 19 (2015), pp. 809-817
K.G. Cholidou,I.D. Kostakis,E.D. Manali,D. Perrea,A. Margeli,K. Vougas
Calprotectin: a protein related to cardiovascular risk in adult patients with obstructive sleep apnea
N.J. Buechner,W. Zidek,M. Eer,M. Haske,B.M. Sanner
Obstructive sleep apnea syndrome. Effects of therapy on dyslipidemia
Somnologie, 5 (2001), pp. 97-102
W. Trzepizur,M. Le Vaillant,N. Meslier,T. Pigeanne,P. Masson,M.P. Humeau
Independent association between nocturnal intermittent hypoxemia and metabolic dyslipidemia
Chest, 143 (2013), pp. 1584-1589
M.S. Ip,K.S. Lam,C. Ho,K.W. Tsang,W. Lam
Serum leptin and vascular risk factors in obstructive sleep apnea
Chest, 118 (2000), pp. 580-586
G. Grassi,A. Facchini,F.Q. Trevano,R. Dell’Oro,F. Arenare,F. Tana
Obstructive sleep apnea-dependent and -independent adrenergic activation in obesity
P. Pinto,C. Bárbara,J. Montserrat,R. Patarrão,M. Guarino,M. Carmo
Effects of CPAP on nitrate and norepinephrine levels in severe and mild–moderate sleep apnea
BMC Pulm Med, 13 (2013), pp. 13
C. Phillips,Q. Yang,A. Williams,M. Roth,B. Yee,J. Hedner
The effect of short-term withdrawal from continuous positive airway pressure therapy on sympathetic activity and markers of vascular inflammation in subjects with obstructive sleep apnoea
M. Curro,A. Gugliandolo,C. Gangemi,R. Risitano,R. Lentile,D. Caccamo
Toxic effects of mildly elevated homocysteine concentrations in neuronal-like cells
Neurochem Res, 39 (2014), pp. 1485-1495
Corresponding author. (A. Feliciano
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Rev Port Pneumol 2017;23:193-202 - Vol. 23 Num.4 DOI: 10.1016/j.rppnen.2017.02.010