Effective Treatment of Sleep Apnea in Prediabetes to Reduce Cardiometabolic Risk

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of Chicago
ClinicalTrials.gov Identifier:
NCT01156116
First received: June 23, 2010
Last updated: December 11, 2013
Last verified: December 2013
  Purpose

The investigators overall goal is therefore to conduct over the next 2 years a "proof of concept" study to fill this major gap of knowledge and to rigorously test the hypothesis that effective continuous positive airway pressure (CPAP) treatment of Obstructive Sleep Apnea (OPA) with all night optimum compliance can improve glucose metabolism in prediabetes and reduce cardiometabolic risk. The investigators propose to study overweight or obese adults who have prediabetes and OSA at baseline and after randomization to either: (i) 2 weeks of effective CPAP treatment ("CPAP group") or (ii) 2 weeks of oral administration of a placebo tablet 30min before bedtime ("placebo group"). Both groups will spend each of the 14 nights in the laboratory with 8-hour bedtimes. In the CPAP group, optimum CPAP compliance during the entire night will be ensured by continuous supervision by a registered PSG technician. In all participants, the investigators will perform at baseline and at the end of the intervention, an intravenous glucose tolerance test (ivGTT) to assess insulin sensitivity (SI), insulin secretion (i.e. acute insulin response to glucose,AIRg) and the disposition index (DI; a validated marker of diabetes risk) as well as an oral glucose tolerance test (OGTT) to translate ivGTT findings into end points commonly used in clinical practice. The findings from the ivGTT will allow for the dissection of the respective roles of improvements in SI and AIRg on diabetes risk. Blood pressure (BP) will be recorded continuously over 24 hours and cardiac sympathetic activity will be assessed by heart rate variability of ambulatory EKG recordings. For all cardiometabolic measures, post-intervention changes from baseline will be compared between the CPAP and placebo groups. The investigators specific aims are: 1) to test the hypothesis that effective CPAP treatment of OSA in prediabetics reduces diabetes risk, as assessed by the DI; 2) to test the hypothesis that CPAP treatment of OSA in prediabetics enhances the nocturnal dipping of BP and reduces daytime BP. The investigators will also use state-of-the-art quantitative PSG analysis to identify potential biomarkers that may predict the cardiometabolic response to CPAP. Secondary outcomes will be plasma levels of catecholamines, free fatty acids, leptin and C-reactive protein, and GLP-1. The investigators will also collect daily data on weight, caloric intake, and energy expenditure.


Condition Intervention
Diabetes
Sleep Apnea
Device: CPAP mask
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Effective Treatment of Sleep Apnea in Prediabetes to Reduce Cardiometabolic Risk

Resource links provided by NLM:


Further study details as provided by University of Chicago:

Primary Outcome Measures:
  • Glucose levels (mg/dl) [ Time Frame: end of 2 weeks intervention ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Blood pressure (mmHg) [ Time Frame: end of 2 weeks intervention ] [ Designated as safety issue: No ]

Enrollment: 39
Study Start Date: October 2009
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Continuous positive airway pressure Device: CPAP mask

The subjects who are randomized to CPAP treatment will undergo an overnight CPAP titration in the laboratory, which will be performed manually by a registered technician according to American Academy of Sleep Medicine (AASM) guidelines .Subjects will be admitted in the early evening and will receive positive airway pressure education, hands on demonstration, careful mask fitting and acclimatization prior to titration. The goal during the titration will be to determine the optimal CPAP pressure setting that eliminates obstructive respiratory events, restore oxygen saturations and sleep continuity.

________________________________________

Other Name: continuous positive airway pressure therapy
Drug: Placebo
2 weeks of oral administration of a placebo tablet 30min before bedtime ("oral tablet group").
Other Name: oral placebo tablet
Active Comparator: Oral tablet Device: CPAP mask

The subjects who are randomized to CPAP treatment will undergo an overnight CPAP titration in the laboratory, which will be performed manually by a registered technician according to American Academy of Sleep Medicine (AASM) guidelines .Subjects will be admitted in the early evening and will receive positive airway pressure education, hands on demonstration, careful mask fitting and acclimatization prior to titration. The goal during the titration will be to determine the optimal CPAP pressure setting that eliminates obstructive respiratory events, restore oxygen saturations and sleep continuity.

________________________________________

Other Name: continuous positive airway pressure therapy
Drug: Placebo
2 weeks of oral administration of a placebo tablet 30min before bedtime ("oral tablet group").
Other Name: oral placebo tablet

  Hide Detailed Description

Detailed Description:

EFFECTIVE TREATMENT OF SLEEP APNEA IN PREDIABETES TO REDUCE CARDIOMETABOLIC RISK Diabetes is increasing in epidemic proportions in the United States of America.Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Despite the demonstrated efficacy of lifestyle interventions and the availability of multiple pharmacological treatment options, the economic and public health burden of diabetes remains enormous. Thus, the development of additional strategies to prevent or delay the onset of diabetes and its cardiovascular complications remains a critical public heath challenge. Recent estimates reveal that about 57 million of Americans have prediabetes, an intermediate state between normal glucose tolerance and overt diabetes, characterized by elevated glucose levels, insulin resistance and abnormalities in insulin secretion. Prediabetic state is a major risk factor for cardiovascular disease and progression to overt diabetes.

Obstructive sleep apnea (OSA) is a treatable sleep disorder that is pervasive among overweight and obese individuals. OSA is well recognized as an important mediator of adverse cardiovascular outcomes. Numerous studies have also shown a robust association between OSA and insulin resistance, glucose intolerance and the risk of diabetes, independently of body mass index. In an analysis of over 2500 non-diabetic individuals, the presence of OSA was associated with a significantly higher prevalence of prediabetes and incident diabetes, independently of obesity. Four recent studies including a total number of nearly 900 patients have reported an OSA prevalence in diabetes averaging a staggering 73%. Findings from our group indicate that in diabetics, the presence of OSA is associated with poorer glucose control with effect sizes ranging from 1% to 2% increases in hemoglobin A1c depending on OSA severity. These effect sizes are comparable to and sometimes larger than those of widely used hypoglycemic drugs. Despite the overwhelming evidence to support a strong association between OSA and diabetes, it remains unclear today whether continuous positive airway pressure (CPAP) treatment of OSA can significantly improve glucose control. In diabetics, only four studies including a total of a mere 86 patients, have addressed this important question. A major limitation of these studies is the insufficient CPAP use (roughly averaging 4.4 hours) or the lack of objective data on CPAP compliance. So far, not a single study has examined the effects of CPAP on glucose metabolism specifically in prediabetes, a potentially reversible state in which the development of overt diabetes and its cardiovascular complications could be prevented or delayed. Our overall goal is therefore to conduct over the next 2 years a "proof of concept" study to fill this major gap of knowledge and to rigorously test the hypothesis that effective CPAP treatment of OSA with all night optimum compliance can improve glucose metabolism in prediabetes and reduce cardiometabolic risk. We propose to study overweight or obese adults who have prediabetes and OSA at baseline and after randomization to either: (i) 2 weeks of effective CPAP treatment ("CPAP group") or (ii) 2 weeks of oral administration of a placebo tablet 30min before bedtime ("placebo group"). Both groups will spend each of the 14 nights in the laboratory with 8-hour bedtimes. In the CPAP group, optimum CPAP compliance during the entire night will be ensured by continuous supervision by a registered PSG technician. In all participants, we will perform at baseline and at the end of the intervention, an intravenous glucose tolerance test (ivGTT) to assess insulin sensitivity (SI), insulin secretion (i.e. acute insulin response to glucose; AIRg) and the disposition index (DI; a validated marker of diabetes risk) as well as an oral glucose tolerance test (OGTT) to translate ivGTT findings into end points commonly used in clinical practice. The findings from the ivGTT will allow for the dissection of the respective roles of improvements in SI and AIRg on diabetes risk. Blood pressure (BP) will be recorded continuously over 24 hours and cardiac sympathetic activity will be assessed by heart rate variability of ambulatory EKG recordings. For all cardiometabolic measures, post-intervention changes from baseline will be compared between the CPAP and placebo groups. Our specific aims are: 1) to test the hypothesis that effective CPAP treatment of OSA in prediabetics reduces diabetes risk, as assessed by the DI; 2) to test the hypothesis that CPAP treatment of OSA in prediabetics enhances the nocturnal dipping of BP and reduces daytime BP. We will also use state-of-the-art quantitative PSG analysis to identify potential biomarkers that may predict the cardiometabolic response to CPAP. Secondary outcomes will be plasma levels of catecholamines, free fatty acids, leptin and C-reactive protein, and GLP-1. We will also collect daily data on weight, caloric intake, and energy expenditure.

Today, nearly 50 million American adults have prediabetes or diabetes and have untreated OSA. The proposed research involves a focused "proof of concept" study that can be realistically completed within 2 years and that builds on our experience in clinical research on the cardiometabolic implications of sleep and its disorders. The results are expected to provide essential information for the design of future large clinical trials that will determine whether treatment of OSA, in addition to lifestyle modifications, could be a first line non-pharmacological intervention to prevent or delay the development of overt diabetes, or to improve glycemic control in overt diabetes. The findings thus have the potential to initiate a major reassessment of the clinical recommendations for the prevention, delay and management of diabetes and its cardiovascular complications for millions of Americans.

  Eligibility

Ages Eligible for Study:   45 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Overweight or obese adults (age ≥45 yrs and BMI ≥25 kg/m2)
  • prediabetes and OSA (AHI ≥ 5)
  • regular life styles and schedules (no shift work in the past 6 months, no travel across time zones during the past 4 weeks)
  • habitual bedtimes of at least 6 hours but not exceeding 9 hours will be eligible.
  • not to take any medications during the study period with the exception of antihypertensives and lipid lowering agents
  • not on hormone replacement therapy.
  • have sedentary activities and no competitive athletes or subjects with high exercise levels.

Exclusion Criteria:

  • previous or current treatment with supplemental oxygen
  • requirement of supplemental oxygen or bi-level positive airway pressure for OSA treatment during titration
  • presence of active infection, psychiatric disease or history of other significant illness (e.g., myocardial infarction, congestive heart failure, stroke, arrhythmia, chronic kidney or liver disease0
  • clinical depression as evidenced by a score >16 in CES-D scale
  • smoking, or routine alcohol use (more than 2 drinks per day), or excessive caffeine intake (>300mg per day)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01156116

Locations
United States, Illinois
The University of Chicago
Chicago, Illinois, United States, 60637
Sponsors and Collaborators
University of Chicago
Investigators
Principal Investigator: Esra Tasali, MD University of Chicago
  More Information

No publications provided

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT01156116     History of Changes
Other Study ID Numbers: 09-249-A
Study First Received: June 23, 2010
Last Updated: December 11, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Chicago:
CPAP
diabetes
sleep apnea

Additional relevant MeSH terms:
Apnea
Sleep Apnea Syndromes
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Disorders
Nervous System Diseases

ClinicalTrials.gov processed this record on September 18, 2014