Obstructive Sleep Apnea, Sleep Apnea, Sleep-disordered Breathing
Conditions
Keywords
Obstructive sleep apnea, Sleep Apnea, Sleep-disordered breathing, Insulin sensitivity, Glucose tolerance, Type 2 diabetes
Brief summary
Obstructive sleep apnea affects approximately 2-4% of middle-aged adults in the general population and is associated with several medical conditions including hypertension and coronary artery. Research over the last decade has shown that obstructive sleep apnea may also increase the propensity for insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Positive airway pressure (PAP) is the first line therapy for the treatment of obstructive sleep apnea. While PAP therapy has several favorable effects such as improvements in daytime sleepiness and quality of life, it is not clear whether using PAP therapy can alter metabolic risk. The overall objective of this study is to examine whether treatment of obstructive sleep apnea with positive airway pressure therapy improves glucose tolerance and insulin sensitivity. The primary hypothesis of this study is that PAP therapy of obstructive sleep apnea will improve in insulin sensitivity and glucose metabolism.
Detailed description
Type 2 diabetes mellitus is one of the most prevalent medical conditions, affecting a staggering 246 million people worldwide. Obstructive sleep apnea is a relatively common and often undiagnosed condition in the general population. Cross-sectional studies of clinic and population-based samples suggest that up to 40% of patients with obstructive sleep apnea have type 2 diabetes and up to 75% of patients with type 2 diabetes have obstructive sleep apnea. There is increasing evidence that the pathophysiological features of intermittent hypoxia and sleep fragmentation may be responsible for altering glucose homeostasis and worsening insulin sensitivity. The mechanisms through which obstructive sleep apnea impairs glucose metabolism are largely unknown. While intermittent hypoxemia and sleep fragmentation are likely to play an essential role, the relative contribution of each in the causal pathway remains to be determined. Moreover, whether the adverse effects of intermittent hypoxia and sleep fragmentation are mediated through an increase in sympathetic nervous system activity, alterations in corticotropic function, and/or systemic inflammation is not known. Furthermore, it remains to be determined whether positive pressure therapy for obstructive sleep apnea has salutary effects on glucose metabolism. Many of the available studies examining the effects of PAP on glucose tolerance and insulin sensitivity are plagued by small sample sizes, lack of a control group, and limited data on compliance with positive pressure therapy. The current study will assess, using a community-based sample, whether treatment of obstructive sleep apnea with positive pressure therapy will improve insulin sensitivity, as assessed by the frequently sample intravenous glucose tolerance test (primary outcome measure).
Interventions
DEVICEPositive Pressure Therapy (PAP)
Positive pressure therapy is the standard of care for managing obstructive sleep apnea. It entails wearing a mask that is connected to the PAP device which deliver pressure to the upper airway during sleep.
BEHAVIORALLifeStyle Counseling
Subjects randomized to the lifestyle (and nutritional) counseling arm will be given advice on a balanced dietary and exercise plan.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Ability to give informed consent * Obstructive sleep apnea (untreated) * Ability to comply with study-related assessments
Exclusion criteria
* Inability to consent or commit to the required visits * Diabetes mellitus (fasting glucose \> 126 mg/dl) * Use of insulin or oral hypoglycemic agent * Weight change of 10% in last six months * Use of oral steroids in the last six months * Severe pulmonary disease (i.e., COPD) * Renal or hepatic insufficiency * Recent Myocardial Infarction (MI) or stroke (\< 3 months) * Occupation as a commercial driver * Active substance use * Untreated thyroid disease * Pregnancy * Anemia (Hematocrit \< 30%) * Any history of seizures or other neurologic disease * Poor sleep hygiene or sleep disorder other than sleep apnea * Excessive subjective sleepiness (Epworth score \> 18)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Sensitivity (SI) | Baseline | Insulin sensitivity will be determined with the insulin-modified frequently sampled intravenous glucose tolerance test (IVGTT) before and 2-months after study intervention. This test requires administration of a weight-adjusted dose of D50W as an IV bolus at time zero. After the glucose bolus, blood samples are drawn at the scheduled times for 3-hours. At the 20-minute mark, a weight-adjusted dose of regular insulin is administered. The resulting serum is analyzed for glucose and insulin and the minimal model (MINMOD) will be used to derive insulin sensitivity. A low SI signifies low insulin sensitivity and high SI represents high insulin sensitivity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disposition Index (DI) | Baseline | The disposition index is the mathematical product of insulin sensitivity (SI) and acute insulin response to glucose (AIRG) both of which are derived from the MINMOD analysis of the frequently sampled intravenous glucose tolerance test data. A low DI is indicative of a higher risk of developing diabetes. |
| Acute Insulin Response to Glucose (AIRG) | Baseline | The acute insulin response to glucose (AIRG) value is derived from the MINMOD analysis of the glucose and insulin levels obtained during the frequently sampled intravenous glucose tolerance test. A low AIRG indicates decreased ability of the pancreas to secrete insulin. |
| Glucose Effectiveness (SG) | Baseline | Glucose effectiveness is the ability for glucose to move intracellularly in the absence of insulin. It is a parameter that results from the MINMOD analysis of the serum glucose and insulin levels derived from the frequently sampled intravenous glucose tolerance test. Low SG indicates a lower predisposition for glucose disposal independent of any effects of insulin. |
| Area Under the Curve Assessed by Oral Glucose Tolerance Test | Baseline | Results of the oral glucose tolerance test will be analyzed using indices derived from the serial glucose and insulin levels over the 2 hour period. This will be the area under the glucose/ insulin curves |
| Area Under the Curve Assessed by Oral Glucose Tolerance Test (OGTT) | 2 month after intervention | Results of the oral glucose tolerance test will be analyzed using indices derived from the serial glucose and insulin levels over a 2 hour period 2 months post intervention. This will be the area under the glucose/ insulin curves |
| Endothelial Function | Baseline | Endothelial function will be assessed using peripheral arterial tonometry using the Endo-PAT device. Using the EndoPat device, the relative vasoconstriction of occluded versus non-occluded arms was derived and provided the relative hyperemic index. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Positive Pressure Therapy (PAP) Positive airway pressure(PAP) therapy is the standard of care for patients with obstructive sleep apnea. During sleep, a mask is worn over the nose and connected to the PAP machine.
Positive Pressure Therapy (PAP): Positive pressure therapy is the standard of care for managing obstructive sleep apnea. It entails wearing a mask that is connected to the PAP device which deliver pressure to the upper airway during sleep. | 53 |
| Lifestyle Counseling Positive Pressure Therapy (PAP): Positive pressure therapy is the standard of care for managing obstructive sleep apnea. It entails wearing a mask that is connected to the PAP device which deliver pressure to the upper airway during sleep.
LifeStyle Counseling: Subjects randomized to the lifestyle (and nutritional) counseling arm will be given advice on a balanced dietary and exercise plan. | 55 |
| Total | 108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Lifestyle Counseling | Positive Pressure Therapy (PAP) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 8 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 44 Participants | 45 Participants | 89 Participants |
| Age, Continuous | 57.2 years STANDARD_DEVIATION 8.2 | 54.8 years STANDARD_DEVIATION 9.2 | 56.0 years STANDARD_DEVIATION 8.8 |
| Region of Enrollment United States | 55 Participants | 53 Participants | 108 Participants |
| Sex: Female, Male Female | 16 Participants | 12 Participants | 28 Participants |
| Sex: Female, Male Male | 39 Participants | 41 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 55 | 0 / 56 |
| other Total, other adverse events | 0 / 55 | 0 / 56 |
| serious Total, serious adverse events | 0 / 55 | 0 / 56 |
Outcome results
Primary
Insulin Sensitivity (SI)
Insulin sensitivity will be determined with the insulin-modified frequently sampled intravenous glucose tolerance test (IVGTT) before and 2-months after study intervention. This test requires administration of a weight-adjusted dose of D50W as an IV bolus at time zero. After the glucose bolus, blood samples are drawn at the scheduled times for 3-hours. At the 20-minute mark, a weight-adjusted dose of regular insulin is administered. The resulting serum is analyzed for glucose and insulin and the minimal model (MINMOD) will be used to derive insulin sensitivity. A low SI signifies low insulin sensitivity and high SI represents high insulin sensitivity.
Time frame: Baseline
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Insulin Sensitivity (SI) | 1.95 [mU/L]^-1 x [min]^-1 | Standard Deviation 1.21 |
| Lifestyle Counseling | Insulin Sensitivity (SI) | 2.22 [mU/L]^-1 x [min]^-1 | Standard Deviation 1.45 |
Primary
Insulin Sensitivity (SI)
Insulin sensitivity will be determined with the insulin-modified frequently sampled intravenous glucose tolerance test (IVGTT) before and 2-months after study intervention. This test requires administration of a weight-adjusted dose of D50W as an IV bolus at time zero. After the glucose bolus, blood samples are drawn at the scheduled times for 3-hours. At the 20-minute mark, a weight-adjusted dose of regular insulin is administered. The resulting serum is analyzed for glucose and insulin and the minimal model (MINMOD) will be used to derive insulin sensitivity. A low SI signifies low insulin sensitivity and high SI represents high insulin sensitivity.
Time frame: 2 months after intervention
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Insulin Sensitivity (SI) | 3.01 [mU/L]^-1 x [min]^-1 | Standard Deviation 2.77 |
| Lifestyle Counseling | Insulin Sensitivity (SI) | 1.83 [mU/L]^-1 x [min]^-1 | Standard Deviation 1.03 |
Secondary
Acute Insulin Response to Glucose (AIRG)
The acute insulin response to glucose (AIRG) value is derived from the MINMOD analysis of the glucose and insulin levels obtained during the frequently sampled intravenous glucose tolerance test. A low AIRG indicates decreased ability of the pancreas to secrete insulin.
Time frame: Baseline
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Acute Insulin Response to Glucose (AIRG) | 537.48 [mU/L-min] | Standard Deviation 394.88 |
| Lifestyle Counseling | Acute Insulin Response to Glucose (AIRG) | 632.38 [mU/L-min] | Standard Deviation 728.65 |
Secondary
Acute Insulin Response to Glucose (AIRG)
The acute insulin response to glucose (AIRG) value is derived from the MINMOD analysis of the glucose and insulin levels obtained during the frequently sampled intravenous glucose tolerance test. A low AIRG indicates decreased ability of the pancreas to secrete insulin.
Time frame: 2 months after intervention
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Acute Insulin Response to Glucose (AIRG) | 513.06 [mU/L-min] | Standard Deviation 338.41 |
| Lifestyle Counseling | Acute Insulin Response to Glucose (AIRG) | 563.64 [mU/L-min] | Standard Deviation 546.2 |
Secondary
Area Under the Curve Assessed by Oral Glucose Tolerance Test
Results of the oral glucose tolerance test will be analyzed using indices derived from the serial glucose and insulin levels over the 2 hour period. This will be the area under the glucose/ insulin curves
Time frame: Baseline
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Area Under the Curve Assessed by Oral Glucose Tolerance Test | 7939.9 mg/dL per 120 min | Standard Deviation 3327.8 |
| Lifestyle Counseling | Area Under the Curve Assessed by Oral Glucose Tolerance Test | 7245.31 mg/dL per 120 min | Standard Deviation 2988.4 |
Secondary
Area Under the Curve Assessed by Oral Glucose Tolerance Test (OGTT)
Results of the oral glucose tolerance test will be analyzed using indices derived from the serial glucose and insulin levels over a 2 hour period 2 months post intervention. This will be the area under the glucose/ insulin curves
Time frame: 2 month after intervention
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Area Under the Curve Assessed by Oral Glucose Tolerance Test (OGTT) | 7531.8 mg/dL per 120 min | Standard Deviation 3179.2 |
| Lifestyle Counseling | Area Under the Curve Assessed by Oral Glucose Tolerance Test (OGTT) | 7655.1 mg/dL per 120 min | Standard Deviation 3057.6 |
Secondary
Disposition Index (DI)
The disposition index is the mathematical product of insulin sensitivity (SI) and acute insulin response to glucose (AIRG) both of which are derived from the MINMOD analysis of the frequently sampled intravenous glucose tolerance test data.
Time frame: 2 months after intervention
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Disposition Index (DI) | 1385.9 [mU/L]^-1 x [min]^-1] x [mU/L-min] | Standard Deviation 1670.1 |
| Lifestyle Counseling | Disposition Index (DI) | 815.4 [mU/L]^-1 x [min]^-1] x [mU/L-min] | Standard Deviation 579.5 |
Secondary
Disposition Index (DI)
The disposition index is the mathematical product of insulin sensitivity (SI) and acute insulin response to glucose (AIRG) both of which are derived from the MINMOD analysis of the frequently sampled intravenous glucose tolerance test data. A low DI is indicative of a higher risk of developing diabetes.
Time frame: Baseline
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Disposition Index (DI) | 931.4 [mU/L]^-1 x [min]^-1] x [mU/L-min] | Standard Deviation 957.1 |
| Lifestyle Counseling | Disposition Index (DI) | 1093.1 [mU/L]^-1 x [min]^-1] x [mU/L-min] | Standard Deviation 1037.9 |
Secondary
Endothelial Function
Endothelial function will be assessed using peripheral arterial tonometry using the Endo-PAT device. Using the EndoPat device, the relative vasoconstriction of occluded versus non-occluded arms was derived and provided the relative hyperemic index.
Time frame: Baseline
Population: Data was unable to be collected for all participants in this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Endothelial Function | 1.91 ratio of occluded versus non-occluded | Standard Deviation 0.46 |
| Lifestyle Counseling | Endothelial Function | 1.92 ratio of occluded versus non-occluded | Standard Deviation 0.49 |
Secondary
Endothelial Function
Endothelial function will be assessed using peripheral arterial tonometry using the Endo-PAT device. Using the EndoPat device, the relative vasoconstriction of occluded versus non-occluded arms was derived and provided the relative hyperemic index.
Time frame: 2 month after intervention
Population: Data was not collected for all participants for this outcome measure. Participants for whom data was available are included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Endothelial Function | 1.90 ratio | Standard Deviation 0.53 |
| Lifestyle Counseling | Endothelial Function | 1.91 ratio | Standard Deviation 0.46 |
Secondary
Glucose Effectiveness (SG)
Glucose effectiveness is the ability for glucose to move intracellularly in the absence of insulin. It is a parameter that results from the MINMOD analysis of the serum glucose and insulin levels derived from the frequently sampled intravenous glucose tolerance test. Low SG indicates a lower predisposition for glucose disposal independent of any effects of insulin.
Time frame: 2 months after intervention
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Glucose Effectiveness (SG) | 0.01720 [min]^-1 | Standard Deviation 0.01094 |
| Lifestyle Counseling | Glucose Effectiveness (SG) | 0.01385 [min]^-1 | Standard Deviation 0.00636 |
Secondary
Glucose Effectiveness (SG)
Glucose effectiveness is the ability for glucose to move intracellularly in the absence of insulin. It is a parameter that results from the MINMOD analysis of the serum glucose and insulin levels derived from the frequently sampled intravenous glucose tolerance test. Low SG indicates a lower predisposition for glucose disposal independent of any effects of insulin.
Time frame: Baseline
Population: 55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | Glucose Effectiveness (SG) | 0.01498 [min]^-1 | Standard Deviation 0.006408 |
| Lifestyle Counseling | Glucose Effectiveness (SG) | 0.01537 [min]^-1 | Standard Deviation 0.00636 |