The Effects of Treating Obese and Lean Patients With Sleep Apnea (PISA)

Responses to CPAP Treatment in Obese and Lean Sleep Apnea Patients

The investigators' overall goal is to compare the effect of CPAP treatment on intermediate cardiovascular risk measures in obese versus lean patients with obstructive sleep apnea (OSA). The overall hypothesis is that, adjusting for OSA severity and obtaining normative data from non-OSA subjects with comparable amounts of visceral adiposity, the two OSA groups will have comparable improvements in daytime sleepiness, but that the cardiovascular and metabolic improvements following CPAP therapy will be decreased in OSA patients with increased visceral adipose tissue. The investigators anticipate that, although there will be a greater absolute change in markers of sympathetic activity, inflammation and oxidative stress in obese compared to lean OSA patients following CPAP treatment, the levels will still be abnormally high in the obese patients resulting in the decreased improvements in insulin resistance, arterial blood pressure, and vascular health in obese versus lean OSA patients.

Study Overview

• Status: Completed
• Conditions: Obesity; Sleep Apnea
• Intervention / Treatment: Other: Usual Care; Device: Positive Airway Pressure During Sleep (ResMed S9 Elite)

Detailed Description

Obesity and obstructive sleep apnea (OSA) are independent risk factors for insulin resistance, systemic hypertension and cardiovascular disease. Both obesity and OSA are associated with increased sympathetic activity, inflammatory activity, and oxidative stress, the presumed mediators of their shared clinical consequences. Due to the conflicting results of previous intervention studies treating OSA patients with CPAP, the investigators still do not know if treatment of obese OSA patients has a substantial benefit on these risk factors. In Aim 1, to determine the effects of obesity on the response to CPAP treatment in OSA patients, the investigators will compare responses in daytime sleepiness, insulin resistance, and arterial blood pressure following CPAP treatment in obese and lean OSA patients, stratified by the amount of abdominal visceral adipose tissue, a fat depot associated with increased sympathetic activity, inflammation, and oxidative stress, and a more powerful predictor than BMI of adverse cardiovascular and metabolic outcomes. Aim 2 will determine the effect of CPAP treatment in these two patients groups on sympathetic activity, and inflammatory and oxidative stress biomarkers. The overall hypothesis is that, adjusting for OSA severity and obtaining normative data from non-OSA subjects with comparable amounts of visceral adiposity (Aim 3), the two OSA groups will have comparable improvements in daytime sleepiness, but that the cardiovascular and metabolic improvements following CPAP therapy will be decreased in OSA patients with increased visceral adipose tissue. The investigators anticipate that, although there will be a greater absolute change in markers of sympathetic activity, inflammation and oxidative stress in obese compared to lean OSA patients following CPAP treatment, the levels will still be abnormally high in the obese patients resulting in the decreased improvements in insulin resistance, arterial blood pressure, and vascular health in obese versus lean OSA patients. Relevance: Obese patients are at increased risk of developing sleep apnea. Both obesity and sleep apnea are felt to increase the risk of diabetes, hypertension, and cardiovascular disease. The proposed research will begin to determine if treating obese patients with sleep apnea helps to reduce these risks. If the beneficial effects of CPAP treatment are reduced in obese compared to lean patients with sleep apnea, then treatment of sleep apnea in obese patients needs to be combined with effective management of their obesity.

• Study Type: Interventional
• Enrollment (Actual): 450
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 40-65 years; Will only recruit post-menopausal women not on hormone replacement therapy to avoid the potential confounding effects of female hormones on OSA prevalence and severity, fat distribution as well as the end-points (50-60)
• Lean subjects need to have a waist circumference score <= 107 cm in men and <= 96 cm in women.
• Obese subjects need to have a waist circumference score > 107 cm in men and > 96 cm in women
• For OSA volunteers, 15 ≤ AHI ≤ 75 (see Preliminary Results for justification of upper limit) on full-night in-laboratory polysomnogram within the last 6 months.
• Stable medical history and no change in medications, including anti-hypertensive and lipid-lowering medications, in the previous 2 months
• No regular daytime use (> 3 times/week) of sedative or hypnotic medications in the last 2 months
• Arm circumference ≤ 50 cm (manufacturer limit for performing ambulatory BP recording)

Exclusion Criteria:

• Unable or unwilling to provide informed consent.
• Not satisfied with reimbursement
• Time constraints
• No telephone access or inability to return for follow up testing.
• BMI > 40 kg/m2.
• Diagnosis of another sleep disorder in addition to OSA based on PSG (e.g., periodic limb movement disorder [≥ 15 limb movements/hour of sleep with arousal], central sleep apnea [≥ 50% of apneas on diagnostic PSG are central apneas], insomnia, restless legs syndrome obesity hypoventilation syndrome, or narcolepsy).
• Previous treatment with positive airway pressure, home oxygen therapy, tracheotomy, uvulopalatopharyngoplasty, or other surgery for OSA
• Requiring oxygen or bi-level positive airway pressure for treatment of OSA.
• A clinically unstable medical condition as defined by a new diagnosis or change in medical management in the previous 2 months (e.g., myocardial infarction, congestive heart failure, Cheyne-Stokes breathing, unstable angina, thyroid disease, depression or psychosis, ventricular arrhythmias, cirrhosis, surgery, or recently diagnosed cancer)
• Positive urine toxicology screen
• Rotating Night shift workers in situations or occupations where they regularly experience jet lag, or have irregular work schedules by history over the last 6 months.
• Routine consumption of more than 2 alcoholic beverages per day as determined by the CAGE questionnaire (63-65).
• Unable to perform tests due to inability to communicate verbally, inability to write and read in English; less than a 5th grade reading level; visual, hearing or cognitive impairment (e.g. previous head injury); or upper extremity motor deficit (e.g., previous stroke that prevents patient from using CPAP treatment).
• Current illicit drug use
• Excessive caffeine use (More than 10 caffeinated beverages per day)
• Recent or recurring history of recreational drug use leading to tolerance or dependance.
• Subjects with known moderate to severe renal disease will not undergo the enhanced or dynamic portion of the study.
• Women with a positive pregnancy test will be excluded from the study.
• Subjects who are found to have mild sleep apnea will be ineligible to participate further in the study and will paid up until that time.
• Active infection, malignancy or chronic inflammatory disorders such as autoimmune diseases since these conditions can alter inflammatory biomarker levels.
• No metal parts in the body as participants would not be allowed to enter the magnet during their MRI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Obese Patients with Obstructive Sleep Apnea; Obese adults between the 40 and 65 years of age with a new diagnosis of OSA as evidenced by an apnea/hypopnea index ≥ 15, ≤ 75 episodes per hour, who are naïve to CPAP use will be started on CPAP treatment.	Device: Positive Airway Pressure During Sleep (ResMed S9 Elite); Positive airway pressure during sleep (ResMed S9 Elite).
Active Comparator: Non-obese Patients with Obstructive Sleep Apnea; Non-obese adults between the 40 and 65 years of age with a new diagnosis of OSA as evidenced by an apnea/hypopnea index ≥ 15, ≤ 75 episodes per hour, who are naïve to CPAP use will be started on CPAP treatment.	Device: Positive Airway Pressure During Sleep (ResMed S9 Elite); Positive airway pressure during sleep (ResMed S9 Elite).
Other: Obese subjects without OSA; Control.	Other: Usual Care; Usual care.
Other: Non-obese subjects without OSA; Control.	Other: Usual Care; Usual care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Arterial Blood Pressure	Change in mean 24-hour ambulatory blood pressure from baseline following 4-months of PAP treatment	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Psychomotor Vigilance Task	Change from Baseline in Psychomotor Vigilance Task as measured by number of lapses during 10-minute Reaction time test.	4 months
Change From Baseline in Sympathetic Nervous System Activity	Change from Baseline in Sympathetic Nervous System Activity as measured by 24-hour urine collection for norepinephrine levels.	4 months
Change From Baseline in Circulating Inflammatory Biomarker	Change from Baseline in Circulating Inflammatory Biomarker: IL-6.	4 months
Change From Baseline in Oxidative Stress	Overnight urinary excretion of 8-isoprostane.	4 months

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: University of Iceland
• Investigators: Principal Investigator: Samuel Kuna, MD, University of Pennsylvania

Publications and helpful links

General Publications

• Imayama I, Gupta A, Yen PS, Chen YF, Keenan B, Townsend RR, Chirinos JA, Weaver FM, Carley DW, Kuna ST, Prasad B. Socioeconomic status impacts blood pressure response to positive airway pressure treatment. J Clin Sleep Med. 2022 May 1;18(5):1287-1295. doi: 10.5664/jcsm.9844.
• Xu L, Keenan BT, Maislin D, Gislason T, Benediktsdottir B, Gudmundsdottir S, Gardarsdottir M, Staley B, Pack FM, Guo X, Feng Y, Chahwala J, Manaktala P, Hussein A, Reddy-Koppula M, Hashmath Z, Lee J, Townsend RR, Schwab RJ, Pack AI, Kuna ST, Chirinos JA. Effect of Obstructive Sleep Apnea and Positive Airway Pressure Therapy on Cardiac Remodeling as Assessed by Cardiac Biomarker and Magnetic Resonance Imaging in Nonobese and Obese Adults. Hypertension. 2021 Mar 3;77(3):980-992. doi: 10.1161/HYPERTENSIONAHA.120.15882. Epub 2021 Jan 19.
• Feng Y, Maislin D, Keenan BT, Gislason T, Arnardottir ES, Benediktsdottir B, Chirinos JA, Townsend RR, Staley B, Pack FM, Sifferman A, Pack AI, Kuna ST. Physical Activity Following Positive Airway Pressure Treatment in Adults With and Without Obesity and With Moderate-Severe Obstructive Sleep Apnea. J Clin Sleep Med. 2018 Oct 15;14(10):1705-1715. doi: 10.5664/jcsm.7378.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: April 11, 2012
• First Submitted That Met QC Criteria: April 12, 2012
• First Posted (Estimate): April 16, 2012

Study Record Updates

• Last Update Posted (Actual): July 5, 2019
• Last Update Submitted That Met QC Criteria: June 28, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Obesity; Sleep Apnea
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Apnea
• Other Study ID Numbers: NIH P02 HL094307-01