Impact of Obstructive Sleep Apnea Syndrome on Metabolic Syndrome in Severe Obesity
Impact of Obstructive Sleep Apnea Syndrome on Metabolic Syndrome in Severe Obesity
The aim of this project is to study the relationship between obstructive sleep apnea (OSA)
 and metabolic syndrome (MS) in a population of obese patients who are candidates for
 bariatric surgery. The investigators will study the influence of OSA through hypoxia and
 sleep fragmentation on different proinflammatory adipokines and cytokines, on metabolic
 syndrome and on insulin resistance, as well as how these respond to treatment with continuous
 positive airway pressure (CPAP).

 In the first part of the study (part A) the investigators will perform an observational study
 of cases and controls. Based on the diagnostic polysomnography the patients will be divided
 into two groups depending on their apnea-hypopnea index (AHI): OSA (AHI >= 15/h) and non-OSA
 (AHI <15/h). The results will be analyzed depending on the presence or not of OSA.

 In the second part of the study (part B), the patients with severe OSA (AHI ≥ 30/h) will be
 randomized into two groups: one group will receive CPAP + diet treatment and the other group
 will only receive diet treatment. After 3 months of treatment (CPAP + diet vs. diet), the
 investigators will analyze the overall effect on metabolic syndrome and the effect on its
 individual components, as well as the above-mentioned inflammatory pathways and insulin
 sensitivity, between the 2 groups. This will be carried out through a randomized controlled
 study in which the investigators will compare the effect of CPAP with the effect of
 conservative treatment.
METHODOLOGY

 PARTICIPATING CENTERS: Respiratory Medicine and Endocrinology Services of the Hospital
 Universitari de Bellvitge, of the Hospital de la Santa Creu i Sant Pau and of Hospital Clínic
 de Barcelona.

 PATIENTS (recorded in eligibility criteria)

 Ethical aspects: All patients will be asked for informed consent in accordance with the
 procedures of the Ethical Committee of the hospitals. Patients will be recruited in the
 initial stage of the protocol and waiting list for bariatric surgery. Currently the waiting
 list is 2 to 3 years long and the patients are screened for OSA in the year before the
 intervention, with the aim of treating OSA patients in order to reduce the perioperative
 surgical risk. Therefore the protocol will not lead to a delay in the start of treatment,
 since treatment will be commenced earlier than usual. Once the study period is over, the
 patients in the control group will receive CPAP if necessary.

 DESIGN:

 Multi-center study (with the participation of 3 centers), with an initial part (A) that is an
 observational prospective case-control study coordinated by the Hospital Universitari de
 Bellvitge. Based on the polysomnography performed on all patients who fulfill the inclusion
 criteria, the patients will be put into two groups: CASES: patients with OSA (AHI >= 15) and
 CONTROLS: Non-OSA (AHI < 15). We will analyze whether metabolic syndrome is present or not
 and the different determinations depending on whether or not the patients have OSA. In the
 second part of the study (B) coordinated by the Hospital de la Santa Creu i Sant Pau we will
 analyze the treatment response of OSA patients with AHI >= 30 to CPAP with a prospective,
 controlled and randomized study of parallel groups, in which CPAP treatment will be compared
 with conservative treatment in the form of a diet.

 Sample Size:

 In the observational study (part A), based on previous studies and accepting an alpha risk of
 0.05 and a beta risk of 0.20 in bilateral contrast, we calculated that 39 subjects are needed
 in each group to detect a difference greater than or equal to 0.32 between them. A proportion
 of 0.55 is assumed in one of the groups. The dropout rate for the study has been estimated at
 10%. The ARCCOSINE approximation has been used.

 In the treatment response study (part B), 63 subjects are needed in each group to detect a
 difference that is greater or equal to 1 units of HOMA, assuming a standard deviation of 1.90
 based on previous studies. The dropout rate for the study has been estimated at 10%.

 STUDY VARIABLES:

 1. Anthropometric and demographic data: age, sex, weight, height, BMI, neck circumference.
 Time between when patient became obese and recruitment date (period of obesity).

 2. Measures of central obesity: waist circumference (above the superior border of the iliac
 crest). The body mass index will be determined by dividing the weight in kilograms by
 the height in meters squared. The waist/hip ratio will be measured.

 3. Body fat composition will be measured with electrical bioimpedance using the
 Bioimpedance Meter BIA 101 (Akern Bioresearch, Florence, Italy), with an analyzer for
 bioimpedance of the vectors R (resistance) and Xc (reactance) with reference values for
 obese subjects (Piccoli A. et al. Int. Journ. Of Obesity 1998; 22:97-104).

 4. General clinical questionnaire: cardiovascular risk factors and co-morbidity.

 5. Self-assessment of daytime sleepiness. This will be analyzed using the Epworth scale (MW
 Johns, Sleep 1991, 14;540).

 6. Degree of sleepiness according to the definition of the American Thoracic Society:
 classification into three categories: light, moderate and severe somnolence.

 7. Hours of sleep: this will be analyzed using a sleep diary that will be kept during a
 period of 15 consecutive days. In addition, basic questions will be asked of each
 patient while obtaining the medical history about the usual hours of sleep on working
 days and weekends and holidays.

 8. Physical activity questionnaire: international self-administered questionnaire of
 physical activity, short version. International physical activity questionnaire (IPAQ)
 www.ipaq.ki.se.

 9. Questionnaire on quality of life in patients with sleep apnea Quebec Sleep Questionnaire
 (QSQ), self-administered, version translated into Spanish. (Y Lacasse, Thorax 2004).

 10. Respiratory Function Study: maximum F/V loop performed with Datospir 500 spirometer
 (SIBEL, Barcelona), in accordance with the norms and reference values of the SEPAR (Roca
 et al. Bull Eur Physiopathol Respir, 1986, 22: 217-24). In addition to the spirometric
 variables (FVC; FEV1, FEV1/FVC,PEF), MIF50, MEF50/MIF50, PEF/FEV1 FEV0,5/FEV1, VVM/FEV1
 will also be assessed. Static lung volumes. Helium dilution technique in accordance with
 the norms and reference values of the SEPAR (Roca el al. Bull Eur Physiopathology
 Respir, 1986, 22: 217-224). Arterial gases will be taken at rest while the subject is
 seated and breathing room air and they will be evaluated using the established
 recommendations (SEPAR working group for the practice of arterial gasometry (Arch.
 Bronconeumol 1998: 34: 142-151).

 11. Conventional Polysomnography (PSG). This will be performed over an entire night using a
 Compumedics Siesta Polysomnograph (Compumedics, Melbourne, Australia). It will include 2
 electroencephalogram channels, 2 electro-oculography channels, chin electromyography,
 oronasal flow measured by a thermistor and nasal canula, thoracic and abdominal
 excursion bands, oxyhaemoglobin saturation (SpO2) measured with a finger probe,
 electrocardiogram, anterior tibial electromyogram, sound recording for snores, and a
 body position sensor. The criteria of Rechtstaffen and Kales will be used for visual
 scoring of sleep stages. The minimum recording time is 6 hours and the minimum sleep
 time is 3 hours. Definition of apnea: absence of flow for at least 10 seconds.
 Definition of hypopnea: any reduction of flow with a minimum duration of at least 10
 seconds that is accompanied by a desaturation (greater or equal to 3%) and/or a
 transitory awakening or arousal (with arousal defined according to ASDA criteria: Sleep,
 1992; 15: 173-184). Definition of hypoventilation: prolonged periods of arterial
 desaturation not preceded by episodes of respiratory events. The following data will be
 recorded: number of apnea/hypopnea episodes per hour (AHI), percentage of time in apnea
 and/or hypopnea, number of arousals/hour, sleep efficiency (total sleep time/length of
 recording), percentage of time in phases 1, 2, 3-4 and REM, initial oxyhemoglobin
 saturation, average of oxyhemoglobin saturation, minimum saturation, time with
 saturation of oxyhemoblobin under 90 % (CT90) and 85 % (CT85).

 12. Blood tests: a blood sample will be taken from all patients to determine their
 biochemical profile and full general blood count, lipid profile (Triglycerides,
 cholesterol (total cholesterol, HDL, VDL, LDL), glycosylated hemoglobin, insulin,
 leptin, TNF alpha, TNF alpha soluble receptors 1 and 2, IL-6, IL-8 and adiponectin.

 13. Measurement of blood pressure: The morning after the PSG is carried out 2 blood pressure
 measurements will be taken at rest in a supine position, separated by 5 minutes, and
 additional measurements will be made if there is a difference of more than 5 mmHg
 between them. In accordance with the rules of the Sociedad Española de Hipertensión.
 (Hipertension 2005; 22 supl 2: 16-20)

 14. Calculation of insulin resistance: This will be performed using the HOMA calculation
 (Homeostasis Model Assessment) modeled by Matthews et al (Diabetologia 1985; 28:
 412-419.).

 15. Glucose tolerance measurements: In those patients without recognized diabetes mellitus,
 a glucose load will be given after 12 hours of fasting, by administering 75 g of glucose
 and determining glucose levels at 0 and 120 minutes.

 16. Metabolic Syndrome: The percentage of Metabolic Syndrome will be defined for each of the
 groups, with Metabolic Syndrome defined in accordance with international criteria (Adult
 Treatment Panel III. JAMA 2001; 2486-2497) as the existence of the following three
 conditions: 1) Central obesity: waist > 88 cm in women, > 102 cm in men, 2) Arterial
 hypertension: AHT greater than or equal to 130/85 mmHg or treatment, 3) Hyperglycemia:
 plasma glucose > 6.1 mmol/L, 4) Hypertriglyceridemia: TG greater than 1.7 mmol/L, 5)
 Hypo-HDL: HDL less than 1.3 mmol/L in men and 1 mmol/L in women. A metabolic index will
 be established for each subject that will define the number of individual components of
 Metabolic Syndrome they present.

 PROCEDURE:

 Part A: All patients from the obesity surgery program of the Endocrinology service that
 fulfill the inclusion criteria will be recruited. Patients will be assigned to groups
 according to the result of the polysomnography. Patients with AHI >= 15 will be considered
 OSA and all other patients non-OSA until there are 39 patients in each group, in accordance
 with the sample calculation. Thus all patients will be evaluated at baseline according to
 their condition of OSA/non-OSA.

 Part B: Subsequently, the patients with severe OSA (AHI>=30) who do not fulfill the specific
 exclusion criteria for part B will randomized into the group for treatment with CPAP and diet
 or the group for conservative treatment (diet). The patients will be evaluated after 6 and 12
 weeks from the start of treatment (CPAP and diet vs. diet). The variables will be determined
 at baseline and after 12 weeks.

 STATISTICAL ANALYSIS:

 A descriptive analysis of the sample will be carried out in accordance with central tendency
 measures (mean, median) and dispersion measures (standard deviation and interquartile range)
 in accordance with normality criteria (Kolmogorov-Smirnov test). Then a comparative study
 will be performed between the groups using chi-square test or Fisher's exact test as
 appropriate to the qualitative variables; and Student's t test or the Mann-Whitney U test
 will be used for the quantitative variables according to normality criteria.

 The percentages of metabolic syndrome in the OSA and non-OSA patients, as well as the
 percentages of OSA in the groups with and without metabolic syndrome will be compared. The
 differences in metabolic syndrome and the metabolic index will be analyzed according to the
 severity of the OSA. This will initially be carried out through the univariate analysis of
 the variables gathered in the group of patients and the control groups, and those variables
 that have an association with p-value < 0.10, and that do not interact among themselves will
 be considered in a binary logistic regression model.

 In the second part of the study, after 12 weeks of CPAP treatment, the variables from the
 baseline and final situation will be compared with the parametric or non-parametric tests as
 appropriate depending on their normality.

 The analysis will be carried out using the statistical package SPSS 15.0 (Illinois, Chicago),
 and a p-value < 0.05 will be considered statistically significant in all cases.
Inclusion Criteria for part A:

 Patients who are included in the obesity surgery program will be recruited if they fulfill
 the following criteria:

 -  Age between 18 and 65 years.

 -  Body mass index (BMI) >40 kg/m2 or BMI > 35 kg/m2 with co-morbidity related to
 obesity.

 Inclusion Criteria for part B:

 In the treatment response study we will include patients diagnosed at the baseline
 polysomnography with severe OSA (AHI >= 30) who fulfill the inclusion criteria for part A
 and who do not present specific exclusion criteria for part B.

 General Exclusion Criteria (for part A):

 -  Prior treatment with CPAP.

 -  Severe or unstable cardiovascular disease (severe or surgically treated valvulopathy,
 myocardial infarction, unstable angina, cardiac surgery) during the 6 months prior to
 inclusion in the study.

 -  Evidence of acute or chronic inflammatory illness different to obesity itself
 (connective tissue disease, active neoplasia) or associated infectious process during
 the 6 weeks prior to inclusion in the study.

 -  Severe cognitive or psychiatric disorder that would make it difficult to complete the
 clinical questionnaires.

 -  Severe chronic diseases that may interfere in a significant way with the results of
 the study.

 -  Chronic obstructive pulmonary disease defined by FEV1/FVC < 0.7.

 -  Pregnancy.

 -  Alcohol abuse (daily alcohol consumption >80 g).

 -  Express decision of the patient to not participate in the study.

 Exclusion Criteria for part B:

 -  Severe or incapacitating somnolence.

 -  Professional drivers or users of dangerous machinery.

 -  Congestive cardiac insufficiency or significant valvulopathy or chronic cor pulmonale.

 -  Use of oral anti-diabetic drugs or insulin.