Eight Hours of Nightly CPAP Treatment of Obstructive Sleep Apnea Improves. Glucose Metabolism in Prediabetes: A Randomized Controlled Trial

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1 Eight Hours of Nightly CPAP Treatment of Obstructive Sleep Apnea Improves Glucose Metabolism in Prediabetes: A Randomized Controlled Trial Sushmita Pamidi, MD 1, Kristen Wroblewski, MSc 2, Magdalena Stepien BSc 3, Khalid Sharif-Sidi, BSc 3, Jennifer Kilkus RD 3, Harry Whitmore RPSGT 3, Esra Tasali, MD 3 ONLINE DATA SUPPLEMENT

2 METHODS Inclusion and Exclusion Criteria Overweight or obese (body mass index [BMI] 25 kg/m 2 ) adults aged 45 years, who had OSA (apnea-hypopnea index [AHI] 5) and prediabetes (1) were recruited from the local community through advertisements. Participants were eligible if they had habitual bedtimes between 6 to 8 hours and regular lifestyles and schedules (no shift work in the past 6 months, no travel across time zones during the past 4 weeks). Individuals taking medications other than antihypertensives and lipid-lowering agents were excluded. Those prescribed lipid-lowering agents and/or antihypertensives other than beta-blockers and thiazide diuretics were included as long as the dose was stable for the preceding 3 months prior to enrolment. Women were excluded if they were on hormone replacement therapy or menstruating. Additional exclusion criteria were: 1) previous or current treatment with supplemental oxygen, 2) requirement of supplemental oxygen or bi-level positive airway pressure for OSA treatment during laboratory titration, 3) 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 disease), 4) clinical depression as evidenced by a score >16 on CES-D scale, 5) active smoking, or routine alcohol use (more than 2 drinks per day), or excessive caffeine intake (>300mg per day). Study protocol This was a randomized, placebo-controlled, parallel-group study. Participants were randomized in a 2:1 ratio to receive either 2-weeks of optimal CPAP treatment or E2

3 2-weeks of oral placebo tablet. During the week preceding the study, participants were asked to maintain their habitual sleep-wake and meal schedules, and home sleep duration was continuously monitored by wrist actigraphy (Actiwatch, Philips/Respironics). A schema of the study protocol is provided in Figure 1. During the entire protocol, both groups spent each night in the laboratory with enforced 8-hour bedtimes (from 11:00 pm to 7:00 am), while sleep was recorded by attended polysomnography. Participants were discharged after breakfast (or after lunch on the days of metabolic testing) and were able to engage in routine daily activities until the evening when they returned to the laboratory. At baseline and after the 2-week treatment period, metabolic testing including a morning standard OGTT, a morning frequently sampled intravenous glucose tolerance test (ivgtt), and ambulatory 24- hour blood pressure (BP) monitoring were performed in both groups on consecutive days. Participants continued their assigned treatment during the post-treatment testing period. Participants in the CPAP group underwent an overnight laboratory CPAP titration according to guidelines in order to identify optimal CPAP pressure needs (2). During the 2-week treatment period, CPAP was applied at the optimal therapeutic pressure and allnight adherence was ensured by continuous supervision by a registered polysomnography technician. As necessary, the following strategies were also used on an individual basis to optimize CPAP treatment: change or adjustment of mask to optimize patient comfort and prevent pressure leak, use of expiratory pressure relief, and adjustment of CPAP pressure setting if persistent obstructive respiratory events occurred during the night. In a few subjects, the pressure settings were adjusted (only E3

4 by 1-2 cm of water pressure) during the first few nights of the treatment period, as needed. Participants were only allowed to take the CPAP off during occasional bathroom use. Participants assigned to the oral placebo group were administered a sugar tablet 30 minutes before bedtime and were told that it is intended to improve upper airway function and OSA. After the completion of the study, participants were fully debriefed about the study treatment arms, offered a referral to a sleep specialist and strongly encouraged to pursue effective OSA therapy. Polysomnography Attended laboratory polysomnography (Neurofax EEG 1100, Nihon Kohden, CA) was performed with bedtimes between 11:00 pm and 07:00 am. Polysomnographic recordings included electroencephalogram (EEG) with two frontal, two central, and two occipital EEG, electrooculogram (left and right), chin and leg electromyography, electrocardiography, airflow by nasal pressure transducer and oronasal thermistor, thoracic and abdominal respiratory efforts, and arterial oxygen saturation by pulse oximetry. Sleep recordings were initially scored by two registered polysomnographic technicians and then reviewed by a board-certified sleep physician. Sleep stages were visually scored in 30-second epochs as rapid eye movement (REM) sleep, non-rem sleep i.e. stages N1, N2, and N3 and wake according to standard criteria (3). Respiratory events and microarousals were scored according to established criteria (3). The AHI was calculated as the total number of obstructive apneas and hypopneas per hour of sleep. Hypopneas were defined as a decrease in nasal pressure signal of 30% of baseline, which was associated with either a 3% desaturation or an arousal. OSA E4

5 was defined as AHI 5 events per hour. The 3% oxygen desaturation index (ODI) was calculated as the total number of 3% desaturations per hour of sleep. Arousal index was calculated as the total number of microarousals per hour of sleep. Post-treatment polysomnographic data were missing in a total of 5 participants in the CPAP group (3 withdrew for personal reasons and 2 had CPAP intolerance). Oral glucose tolerance test (OGTT) Prediabetes was defined as having impaired fasting glucose (fasting glucose level between 100 and 125 mg/dl) and/or impaired glucose tolerance (the 2-hour glucose level between 140 and 199 mg/dl) according to standard guidelines (4). After an overnight fast, an antecubital intravenous catheter was inserted in the morning. Baseline samples were obtained at -15 and 0 min for measurement of glucose, insulin and c-peptide concentrations. At time 0 min, a 75 g oral glucose load was administered, and blood samples were subsequently collected at 30, 60, 90 and 120 min. Additionally, plasma norepinephrine levels were measured at each time point during the OGTT. Area under the curves for glucose (AUC glu ), insulin (AUC ins ), and insulin secretion rate (AUC insulin secretion ) were calculated according to the trapezoidal rule between the 0 and 120min during the OGTT. Insulin secretory rates were estimated by deconvolution method using c-peptide profiles measured during the OGTT (5). Posttreatment OGTT data were missing in a total of 6 participants: 3 in the CPAP group withdrew due to personal reasons during the treatment period; 2 had CPAP intolerance; and the testing could not be performed in 1 participant in the oral placebo group who did not follow the fasting instructions. E5

6 Frequently sampled intravenous glucose tolerance test (ivgtt) After an overnight fast, 1 ml blood samples were drawn every 5 min for 15 min (3 baseline samples), at which time glucose was administered as an intravenous bolus (0.3 g/kg body weight). Blood samples were then taken at 2, 3, 4, 5, 6, 8, 10, 12, 15, 19, 21, 22, 24, 26, 28, 30, 40, 50, 60, 70, 90, 100, 120, 140, 180, 210 and 240 min to measure glucose, insulin and c-peptide levels. At time 20 min, intravenous insulin (0.03 U/kg body weight) was administered. Each sample was assayed for glucose, insulin and c-peptide. The insulin sensitivity and the acute insulin response to glucose (i.e. a marker of pancreatic beta-cell function) were estimated using Bergmann's minimal model approach (6). Baseline ivgtt data were missing in a total of 3 participants (2 in the CPAP group and 1 in the oral placebo group) because technical difficulties during the procedure invalidated the estimation of insulin sensitivity and secretion. Post-treatment ivgtt data were missing in a total of 11 participants: 3 in the CPAP group withdrew due to personal reasons during the treatment period; 2 had CPAP intolerance; and the testing could not be performed in a total of 6 participants (one in the oral placebo group did not follow the fasting instructions, another in the oral placebo group had fasting glucose levels in the diabetic range, two in the CPAP group had glucose levels in diabetic range after protocol violations [high fat diet, personal life stress]); and in two participants in the CPAP group, technical difficulties during the procedure invalidated the estimation of insulin sensitivity and secretion. 24-hour Ambulatory Blood Pressure (BP) E6

7 24-hour ambulatory BP was monitored (Oscar 2, Sun Tech Medical) using a cuff applied to the participants non-dominant arm. Measurements were taken every 15 minutes during the daytime period (07:00 am to 11:00 pm) and every 20 minutes during the bedtime period (11:00 pm to 07:00 am). During the 24-hour BP monitoring, participants were instructed to do their usual activities with minimal restrictions. Each individual BP profile was edited using conventional criteria as follows (7): BP readings at each time point were automatically discarded if systolic BP was >250 or <70 mm Hg, diastolic BP was >150 or <40 mm Hg, and pulse pressure (difference between systolic BP and diastolic BP) was >150 or <20 mm Hg. According to pre-set quality criteria, any 24-hour BP profile was considered invalid if more than one third of BP measurements were missing over the 24-hour period. The 24-hour BP value was calculated by averaging all BP readings over the 24-hour period. Average data was also calculated separately for the daytime (07:00 am to 11:00 pm) and the nighttime (11:00pm to 07:00 am) periods. Baseline 24-hour BP data were missing in a total of 8 participants: 2 in the CPAP group and 3 in the oral placebo group had invalid data according to pre-set quality criteria; the BP measurements could not be performed in 2 participants in the CPAP group who were morbidly obese; and the data could not be downloaded due to technical difficulties in another participant in the CPAP group. Post-treatment 24-hour BP data were missing in a total of 14 participants: 3 in the CPAP group withdrew due to personal reasons during the treatment period; 2 had CPAP intolerance; 4 in the CPAP group and 3 in the oral placebo group had invalid data according to pre-set quality criteria; the BP measurements could not be performed in 2 participants in the CPAP group who were E7

8 morbidly obese. Assays Blood samples were centrifuged immediately at 4ºC and plasma was frozen and stored at -80ºC until assay. Plasma glucose was assayed in duplicate by the glucose oxidase method with a coefficient of variation of less than 2%, using a STAT-2300 analyzer (Yellow Springs). Serum insulin and c-peptide measured by chemiluminescence assays using the Immulite Immunochemistry System (Diagnostic Products Corporation). Fasting glucose and insulin concentrations were calculated as the average of the 15 min and 0 min readings. Plasma norepinephrine was measured using an HPLC system (Coulochem MD5001, ESA, Inc., Chelmsford, MA) with a lower limit of sensitivity of 10 pg/ml and an intra-assay coefficient of variation of 6 to 7.8%. References: 1. Executive summary: Standards of medical care in diabetes Diabetes care 2014;37 Suppl 1:S Kushida CA, Chediak A, Berry RB, Brown LK, Gozal D, Iber C, Parthasarathy S, Quan SF, Rowley JA. Clinical guidelines for the manual titration of positive airway pressure in patients with obstructive sleep apnea. J Clin Sleep Med 2008;4: Berry RB, Brooks R, Gamaldo CE, Hardling SM, Marcus CL, Vaughn BV. The aasm manual for the scoring of sleep and associated events: Rules, terminology and technical specifications, version darien, illinois. American Academy of Sleep Medicine, E8

9 4. Standards of medical care in diabetes Diabetes care 2014;37, Supplement Polonsky KS, Licinio-Paixao J, Given BD, Pugh W, Rue P, Galloway J, Karrison T, Frank B. Use of biosynthetic human c-peptide in the measurement of insulin secretion rates in normal volunteers and type i diabetic patients. The Journal of clinical investigation 1986;77: Bergman RN. Toward physiological understanding of glucose tolerance. Minimalmodel approach. Diabetes 1989;38: Hermida RC, Ayala DE, Mojon A, Fernandez JR. Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk. Journal of the American College of Cardiology 2011;58: E9

10 Table S1: Effect of treatment on all outcomes for CPAP versus Oral placebo groups in unadjusted analyses* CPAP group Oral placebo group OGTT variable Baseline Change after 2-weeks Baseline Change after 2-weeks Treatment difference Unadjusted P value Fasting glucose (mg/dl) (100.6 to 107.4) -4.0 (-7.1 to -0.9) (95.4 to 106.5) -1.3 (-5.6 to 3.0) -2.7 (-8.0 to 2.6) 0.32 Fasting insulin (pmol/l) 74.7 (60.3 to 89.1) -5.9 (-16.8 to 5.0) 68.4 (46.0 to 90.9) 12.9 (-2.3 to 28.0) (-37.5 to -0.2) hour glucose (mg/dl) (144.1 to 163.1) -3.9 (-12.4 to 4.7) (127.0 to 169.3) 10.1 (-1.8 to 22.0) (-28.7 to 0.6) hour insulin (pmol/l) (564.7 to 905.9) ( to 48.4) (470.0 to ) ( to 46.2) 48.8 ( to 253.2) 0.64 AUC glucose ([μu.ml] -1. min) ( to ) ( to ) ( to ) ( to ) ( to ) 0.03 AUC insulin ([mg.dl] -1. min) ( to ) ( to 398.0) ( to ) ( to ) ( to ) 0.41 AUC insulin secretion (pmol/min) ( to ) ( to 260.5) ( to ) ( to 619.5) ( to ) 0.80 Norepinephrine (pg/ml) (281.7 to 381.8) ( to -53.3) (286.2 to 433.8) 20.3 (-33.1 to 73.7) ( to -45.2) ivgtt variable S I ([mu/l] -1. [min] -1 ) 2.3 (2.0 to 2.7) 0.28 (-0.15 to 0.70) 2.9 (2.1 to 3.8) (-1.07 to 0.17) 0.73 (-0.02 to 1.48) 0.06 AIRg ([mu/l] -1. [min] -1 ) (299.1 to 539.7) 28.7 (-32.5 to 89.8) (181.2 to 360.6) 98.7 (9.8 to 187.7) ( to 37.9) hour BP variable 24-hour SBP (mm Hg) (130.5 to 143.7) -2.2 (-6.4 to 2.1) (121.5 to 134.4) 7.5 (1.8 to 13.1) -9.6 (-16.7 to -2.5) Daytime SBP (mm Hg) (136.0 to 149.9) -4.0 (-8.2 to 0.3) (128.1 to 138.8) 5.9 (0.2 to 11.6) -9.9 (-17.0 to -2.7) Nighttime SBP (mm Hg) (116.6 to 132.5) 1.3 (-4.7 to 7.2) (103.3 to 124.5) 12.0 (4.0 to 20.0) (-20.7 to -0.7) hour DBP (mm Hg) 79.7 (76.5 to 83.0) -2.5 (-4.8 to -0.2) 74.6 (68.4 to 80.7) 4.6 (1.6 to 7.7) -7.1 (-10.9 to -3.3) <0.001

11 Daytime DBP (mm Hg) Nighttime DBP (mm Hg) 84.9 (81.1 to 88.8) 68.9 (65.1 to 72.6) -4.5 (-7.1 to -1.9) 1.5 (-1.6 to 4.6) 78.5 (71.8 to 85.1) 64.7 (58.8 to 70.5) 3.7 (0.2 to 7.2) 7.7 (3.5 to 11.9) -8.2 (-12.5 to -3.9) -6.2 (-11.5 to -1.0) < Data are mean (95% confidence interval). Change after 2-weeks (i.e. treatment effect) was calculated from the regression models as the post-treatment baseline effect for each treatment group. Treatment difference between the 2 groups was also calculated from the regression models as the CPAP oral placebo 2-week changes (i.e. the interaction effect from the model). Unadjusted p values for the treatment difference are from the test of the treatment group by time interaction using linear mixed model approach. * All available data was used in the primary analysis (see online supplement for further details). Area under the curve was calculated according to the trapezoidal rule between the 0 and 120min during the OGTT. OGTT = oral glucose tolerance test; AUC glucose = area under the glucose curve during OGTT; AUC insulin = area under the insulin curve during OGTT; AUC insulin secretion = area under the curve of the insulin secretion rate; ivgtt= frequently sampled intravenous glucose tolerance test; S I = insulin sensitivity; AIRg = acute insulin response to glucose; BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure.

12 Table S2. Effect of treatment on all outcomes for CPAP versus oral placebo groups using only participants who had complete data* Treatment effect OGTT variable Fasting glucose (mg/dl) Fasting insulin (pmol/l) 2-hour glucose (mg/dl) 2-hour insulin (pmol/l) AUC glucose ([μu.ml] -1. min) AUC insulin ([mg.dl] -1. min) AUC insulin secretion (pmol/min) Norepinephrine (pg/ml) ivgtt variable S I ([mu/l] -1. [min] -1 ) AIRg ([mu/l] -1. [min] -1 ) 24-hour BP variable 24-hour SBP (mm Hg) Daytime SBP (mm Hg) Nighttime SBP (mm Hg) 24-hour DBP (mm Hg) CPAP group Oral tablet group Treatment difference P value (-7.76 to -0.95) ( to 5.20) ( to 5.07) ( to 58.3) ( to ) ( to ) ( to 397.1) ( to -43.8) 0.36 (-0.14 to 0.86) 21.5 (-48.8 to 91.9) (-6.46 to 3.61) (-8.08 to 1.57) 2.47 (-4.66 to 9.60) (-4.65 to -0.19) (-4.98 to 3.84) (-5.51 to 32.87) (-1.97 to 23.69) ( to 65.1) ( to ) ( to ) ( to 828.3) 35.3 (-8.0 to 78.7) (-1.14 to 0.18) 92.2 (-2.3 to 186.7) 7.05 (1.02 to 13.07) 5.44 (-1.26 to 12.14) (2.87 to 20.30) 4.13 (-0.25 to 8.50) (-9.09 to 1.52) ( to 1.75) ( to -0.09) 35.4 ( to 245.0) ( to ) ( to ) ( to ) ( to -64.1) 0.84 (0.06 to 1.61) ( to 39.2) ( to -1.19) ( to -1.02) ( to 1.33) ( to -1.90) <

13 Daytime DBP (mm Hg) Nighttime DBP (mm Hg) (-6.96 to -1.88) 1.68 (-1.62 to 4.98) 3.12 (-1.76 to 7.99) 7.25 (1.43 to 13.07) ( to -2.35) ( to 0.71) Polysomnographic variable Total sleep time, hours Sleep efficiency, % AHI, events/hour ODI (3%), events/hour Oxygen saturation < 90%, min Microarousal index, events/hour (-0.36 to 0.02) -1.8 (-3.7 to 0.2) (-42.4 to -20.1) (-30.0 to -11.8) (-75.1 to -18.4) (-29.1 to -10.0) (-0.40 to 0.06) -2.2 (-5.0 to 0.6) 2.3 (-1.7 to 6.4) 1.6 (-1.2 to 4.5) 9.9 (-11.4 to 31.2) 1.3 (-1.9 to 4.6) (-0.28 to 0.28) 0.4 (-2.9 to 3.7) (-45.3 to -21.9) (-32.0 to -13.1) (-90.7 to -22.7) (-30.8 to -10.9) <0.001 < <0.001 Data are mean (95% confidence interval). Treatment effect (i.e. change after 2-weeks) was calculated for all variables by subtracting the baseline value from the value after 2-weeks of treatment (i.e. post-treatment). Treatment difference between the 2 groups was calculated for all variables by subtracting the 2-week change for oral placebo group from the 2-week change for CPAP group. P values for the treatment difference are from the two-sample t test. *Analyses are performed using only the participants who had available data both at baseline and post-treatment with sample sizes n=32 for OGTT glucose and insulin variables (n=21 CPAP and n=11 oral tablet), n=29 for OGTT norepinephrine (n=20 CPAP and n=9 oral tablet), n=25 for ivgtt variables (n=17 CPAP and n=8 oral tablet), n=22 for 24-hour BP variables (n=14 CPAP and n=8 oral tablet), and n=33 for polysomnographic variables (n=21 CPAP and n=12 oral tablet). Area under the curve was calculated according to the trapezoidal rule between the 0 and 120min during the OGTT. OGTT = oral glucose tolerance test; AUC glucose = area under the glucose curve during OGTT; AUC insulin = area under the insulin curve during OGTT; AUC insulin secretion = area under the curve of the insulin secretion rate; ivgtt= frequently sampled intravenous glucose tolerance test; S I = insulin sensitivity; AIRg = acute insulin response to glucose; BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure. AHI=Apnea-hypopnea index, ODI= Oxygen desaturation index