An interventional study of Positive Pressure Therapy (PAP) and LifeStyle Counseling in Obstructive Sleep Apnea, Sleep Apnea and Sleep-disordered Breathing, sponsored by Johns Hopkins University. Completed at 1 site in United States. Open to participants aged 21 Years to 75 Years. Per ClinicalTrials.gov, last updated 2017-10-19.
Sponsored by Johns Hopkins University · Not applicable, Interventional, and Treatment
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.
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).
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Exclusion Criteria:
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.
Device: Positive Pressure Therapy (PAP)
Behavioral: LifeStyle Counseling
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.
Also known as: CPAP
Subjects randomized to the lifestyle (and nutritional) counseling arm will be given advice on a balanced dietary and exercise plan.
Also known as: Dietary and Lifestyle Counseling
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
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
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
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
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
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
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
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
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
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
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
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
| Milestone | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Started | 55 | 56 |
| Completed | 53 | 55 |
| Not completed | 2 | 1 |
| Withdrew: Withdrawal by subject | 2 | 1 |
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.
| [mU/L]^-1 x [min]^-1 | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Insulin Sensitivity (SI) | 1.95 ± 1.21 | 2.22 ± 1.45 |
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.
| [mU/L]^-1 x [min]^-1 | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Insulin Sensitivity (SI) | 3.01 ± 2.77 | 1.83 ± 1.03 |
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.
| [min]^-1 | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Glucose Effectiveness (SG) | 0.01498 ± 0.006408 | 0.01537 ± 0.00636 |
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.
| [min]^-1 | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Glucose Effectiveness (SG) | 0.01720 ± 0.01094 | 0.01385 ± 0.00636 |
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.
| [mU/L]^-1 x [min]^-1] x [mU/L-min] | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Disposition Index (DI) | 931.4 ± 957.1 | 1093.1 ± 1037.9 |
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.
| [mU/L]^-1 x [min]^-1] x [mU/L-min] | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Disposition Index (DI) | 1385.9 ± 1670.1 | 815.4 ± 579.5 |
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.
| [mU/L-min] | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Acute Insulin Response to Glucose (AIRG) | 537.48 ± 394.88 | 632.38 ± 728.65 |
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.
| [mU/L-min] | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Acute Insulin Response to Glucose (AIRG) | 513.06 ± 338.41 | 563.64 ± 546.20 |
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.
| ratio of occluded versus non-occluded | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Endothelial Function | 1.91 ± 0.46 | 1.92 ± 0.49 |
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.
| ratio | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Endothelial Function | 1.90 ± 0.53 | 1.91 ± 0.46 |
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
| mg/dL per 120 min | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Area Under the Curve Assessed by Oral Glucose Tolerance Test | 7939.9 ± 3327.8 | 7245.31 ± 2988.4 |
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
| mg/dL per 120 min | Positive Pressure Therapy (PAP) | Lifestyle Counseling |
|---|---|---|
| Area Under the Curve Assessed by Oral Glucose Tolerance Test (OGTT) | 7531.8 ± 3179.2 | 7655.1 ± 3057.6 |
Collected over up to 4 months after enrollment in study. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Positive Pressure Therapy (PAP) | 0/55 (0%) | 0/55 (0%) | 0/55 (0%) |
| Lifestyle Counseling | 0/56 (0%) | 0/56 (0%) | 0/56 (0%) |
55 randomized to PAP (2 dropout); 56 randomized to lifestyle (1 dropout)
| Age, Categorical(Participants) | Positive Pressure Therapy (PAP) | Lifestyle Counseling | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 45 | 44 | 89 |
| >=65 years | 8 | 11 | 19 |
| Age, Continuous(years) | Positive Pressure Therapy (PAP) | Lifestyle Counseling | Total |
|---|---|---|---|
| Mean | 54.8 ± 9.2 | 57.2 ± 8.2 | 56.0 ± 8.8 |
| Sex: Female, Male(Participants) | Positive Pressure Therapy (PAP) | Lifestyle Counseling | Total |
|---|---|---|---|
| Female | 12 | 16 | 28 |
| Male | 41 | 39 | 80 |
| Region of Enrollment(Participants) | Positive Pressure Therapy (PAP) | Lifestyle Counseling | Total |
|---|---|---|---|
| United States | 53 | 55 | 108 |
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