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Corresponding author at: The First Division in the Department of Endocrinology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106th of Zhongshan Er Road, Guangzhou 510080, China.
The improvement of CPAP in glucose control is a conflict in prior studies.
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CPAP was associated with a decrease in HOMA-IR following CPAP intervention.
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CPAP may reduce the risk of developing type 2 diabetes in patients with OSA.
Abstract
Background
The study assessed the effect of continuous positive airway pressure (CPAP) therapy on the risk of developing type 2 diabetes by evaluating change in the homeostasis model assessment of insulin resistance (HOMA-IR) fasting blood glucose (FBG) and fasting insulin following CPAP treatment in non-diabetic patients and pre-diabetic with obstructive sleep apnea (OSA).
Methods
Medline, PubMed, Cochrane, and EMBASE databases were searched until August 24, 2015. The analysis included randomized controlled trials (RCTs), two arm prospective studies, cohort studies, and retrospective studies. The primary outcome measure was change of HOMA-IR in pre-diabetic patients receiving CPAP treatment.
Results
Twenty-three studies were included with 965 patients who had OSA. Nineteen studies were prospective studies and four were RCTs. CPAP therapy resulted in a significant reduction in the pooled standard difference in means of HOMA-IR (−0.442, P = 0.001) from baseline levels compared with the control group. Change in FBG and fasting insulin from baseline levels was similar for the CPAP and control groups. For RCT studies (n = 4), there was no difference in change in HOMA-IR or FBG levels from baseline between CPAP and control groups. The combined effect of RCTs showed that CPAP was associated with a significant reduction in change from baseline in fasting insulin than the control group (standardized diff. in means between groups = −0.479, P value = 0.003).
Conclusion
These findings support the use of CPAP in non-diabetic and pre-diabetic patients with OSA to reduce change of HOMA-IR and possibly reduce the risk of developing type 2 diabetes in this patient population.
Obstructive sleep apnea (OSA) is a prevalent disorder characterized by repetitive upper-airway obstruction during sleep resulting in intermittent hypoxia and fragmentation of sleep. Approximately 9% of women and 24% of men are affected by OSA [
]. Cross-sectional epidemiologic studies and cohort and clinical studies found an association between OSA and deterioration in glycemic control, insulin resistance, and metabolic syndrome [
]. Intermittent hypoxia and sleep fragmentation induced by OSA may cause disorders in various systems, such as the sympathetic nervous system, oxidative stress reactions, systemic inflammation, hormone system that regulate appetite, and the hypothalamic–pituitary–adrenal axis, which in turn contribute to the development of insulin resistance, poor blood glucose control, and increase the risk of type 2 diabetes [
]. However, prior studies investigating whether CPAP can improve insulin resistance of glucose control in OSA patients have resulted in conflicting findings. Some work found CPAP treatment resulted in a significant reduction in HbA1c and improvement in glycemic control [
The impact of effective continuous positive airway pressure on homeostasis model assessment insulin resistance in non-diabetic patients with moderate to severe obstructive sleep apnea.
The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes.
The impact of effective continuous positive airway pressure on homeostasis model assessment insulin resistance in non-diabetic patients with moderate to severe obstructive sleep apnea.
The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes.
Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
]. Three previous meta-analyses have investigated the effect of CPAP on measures of glycemic control and insulin resistance in patients who did not have type 2 diabetes [
Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
]. Consequently, it is currently unclear if CPAP-therapy can have therapeutic benefit for preventing type 2 diabetes in patients with OSA. In this meta-analysis, we included both prospective and retrospective studies to evaluate whether CPAP treatment improved insulin resistance and sensitivity in non- or pre-diabetic patients with OSA treated with CPAP.
2. Material and methods
2.1 Search strategy
The study was performed in accordance with the PRISMA guidelines. Medline, PubMed, Cochrane, and EMBASE databases were searched until August 24, 2015 using the following terms: sleep apnea AND obstructive AND (continuous Positive Airway Pressure OR CPAP) AND (Diabetes Mellitus OR Insulin Resistance OR insulin sensitivity). Randomized controlled trials (RCTs) and prospective studies were included. Eligible studies had to include patients without diabetes or who were pre-diabetic. Based on the American Diabetes Association criteria, patients who met the impaired fasting glucose (IFG) (fasting plasma glucose of 100–125 mg/dL), impaired glucose tolerance (2-hour plasma glucose of 140–199 mg/dL), and/or HbA1c value ranged from 5.7 to 6.4% were diagnosed as pre-diabetes [
]. In included studies, data for body mass index (BMI), waist circumference, adiposity evaluation were reported. Patients had to have a diagnosis of OSA by polysomnographic analysis and evaluation of apnea-hypopnea index (AHI). Studies also had to use CPAP for treatment intervention, and specify duration and patient compliance with treatment. Treatment efficacy needed to be evaluated by measurement of SpO2, and biomarkers for type 2 diabetes and metabolic syndrome had to be quantitatively reported before and after CPAP intervention. Studies were excluded if they included patients with type 1 or type 2 diabetes, who had central sleep apnea, or who were already receiving CPAP treatment (therapeutic or sub-therapeutic) prior to start of the specific study. Studies were also excluded if they did not report outcomes of interest quantitatively, or were letters, comments, editorials, case report, proceeding, or personal communications. Two independent reviewers identified studies for inclusion, data extraction, and quality assessment. In cases of uncertainty, a third reviewer was consulted.
2.2 Data extraction and quality assessment
The following information/data were extracted from studies that met the inclusion criteria: the name of the first author, year of publication, study design, number of participants in each group, participants' age and gender, and the major outcomes including the HOMA-IR, fasting blood glucose (FBG), insulin sensitivity index (ISI), and fasting insulin.
The quality of the included studies was evaluated using Cochrane Collaboration's tool for prospective two-arm studies [
Higgins, JPT. Cochrane Collaboration Handbook for Systematic Reviews of Interventions Version 5.1.0 [Updated March 2011]. The Cochrane Collaboration, 2011. Available from: www.cochrane-handbook.org.
The primary outcome measures were changes of HOMA-IR from baseline in pre-diabetic and non-diabetic patients receiving CPAP treatment. Secondary outcome included change in FBG and fasting insulin from baseline after CPAP treatment.
2.4 Statistical analysis
The change of outcome measures from pre-CPAP therapy were summarized as mean ± standard deviation (SD), mean (standard error of mean [SEM]), median (inter-quartiles [IQR]), or mean (95% confidence intervals [95% CI]) for studies. The combined effect was derived as difference (diff.) in mean change of pre- to post-CPAP treatments with 95% CI. Additionally, a combined effect was also calculated as standardized diff. in mean change of pre- to post-CPAP treatments with 95% CI for FBG and fasting insulin because of multiple usage of unit. Moreover, an effect on HOMA-IR, FBG, and fasting insulin between CPAP and control groups in the RCT studies were also performed. The combined effect > 0 indicates that change in the CPAP group was greater than the control group; <0 indicates that the change in the CPAP group was greater than the control group; 0 indicates that the change between CPAP and control groups was similar.
Heterogeneity among the studies was assessed by the Cochran Q and the I2 statistic. Either Q statistics (P < 0.1) or I2 statistic (>50%) indicated heterogeneity existed between studies and the random-effects model was used (DerSimonian–Laird method). Otherwise, the fixed-effect model (Mantel-Haenszel method) was used. Sensitivity analysis to test the robustness of the pooled estimates was performed using a leave-one-out approach. The publication bias among the included studies was evaluated by the funnel plot and the Egger's test. A 2-sided P-value < 0.05 was considered as statistical significant [
]. Statistical analyses were performed using the statistical software Comprehensive Meta-Analysis, version 2.0 (Biostat, Englewood, NJ, USA).
3. Results
3.1 Search results and study characteristics
A PRISMA flow diagram summarizing the results of the literature search is shown in Fig. 1. Of the 273 studies initially identified by keywords, 187 unique publications were screened by title and abstract using the inclusion/exclusion criteria. Of these, 152 were eliminated for not being relevant. Thirty-five studies underwent full-text review for eligibility, and 13 were excluded for not meeting inclusion/exclusion criteria (n = 7), having no quantitative outcome or no outcome of interest (n = 5), or being a duplicate publication (n = 1).
Fig. 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2004; 26(Chinese): 168-171
]. Nineteen studies were prospective in design and four were RCTs. Across the studies, the mean age ranged from 30.6 years to 64 years and most patients were male. The participants of all included studies were either pre-diabetes or a mixed population of non-diabetic and pre-diabetic patients. The duration of and specific type of CPAP intervention varied among the studies (Table 1). The length of CPAP treatment ranged from one night to about 32 months. The AHI cut-off points were diverse, ranged from five events per hour to 20 events per hour.
Table 1Summary of basic characteristics of selected studies for meta-analysis.
Based on the American Diabetes Association criteria, patients who met the impaired fasting glucose (fasting plasma glucose of 100–125mg/dL), oral glucose tolerance (2-hour plasma glucose of 140–199mg/dL) and/or HbA1c value ranged from 5.7 to 6.4% were diagnosed as pre-diabetes.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2004; 26(Chinese): 168-171
b Based on the American Diabetes Association criteria, patients who met the impaired fasting glucose (fasting plasma glucose of 100–125 mg/dL), oral glucose tolerance (2-hour plasma glucose of 140–199 mg/dL) and/or HbA1c value ranged from 5.7 to 6.4% were diagnosed as pre-diabetes.
Not all the studies included in the systematic review were included in the meta-analysis. Czupryniak et al. was included in systematic review but was excluded from meta-analysis since the length of treatment was only one night [
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
], but only the RCTs analyzed HOMA-IR, FBG and fasting insulin. In addition, how studies reported the data also influenced inclusion in the meta-analysis. Five studies were only included in the systematic review for the following reasons: one study selected controls from a database [
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2004; 26(Chinese): 168-171
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2004; 26(Chinese): 168-171
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2004; 26(Chinese): 168-171
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
]. No apparent heterogeneity was observed among the studies (Q-value = 13.20, P = 0.355, I2 = 9.10%), thus a fixed effect model was used. The combined effect of diff. in means of HOMA-IR of −0.442 (P = 0.001) found that CPAP was associated with a significant greater reduction in HOMA than control (Fig. 2A ). The corresponding sensitivity analysis, using the leave-one-out approach, showed the pooled estimates had the same direction and magnitude regardless of which study was removed indicating the findings are robust (Fig. 2B). Analysis of publication bias by the Egger's test for the HOMA-IR findings found the one-tailed P-value to be significant (0.040), suggesting publication bias may confound these results (Fig. 2C). The study of Nena et al. [
] may be one reason causing publication bias, as the bias was reduced when study was excluded (one-tailed P = 0.128) (Data not shown).
Fig. 2Meta-analysis for the effect of CPAP intervention on HOMA-IR for excluding RCT studies; (A) the pooled estimate, (B) sensitivity analysis for the pooled estimate, and (C) evaluation for publication bias by a funnel plot and Egger's test. Abbreviations: Diff. difference; Std, standard; CI, confidence interval, lower limit and upper limit.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2004; 26(Chinese): 168-171
]. Heterogeneity was observed among these studies (Q-value = 25.26, P-value = 0.008, I2 = 56.45%), thus a random effect model was used. The combined effect of standardized diff. in means of FBG of −0.167 (P = 0.062) showed CPAP was not associated with a greater reduction in change of FBG from pre-CPAP levels compared with control (Fig. 3A ). The corresponding sensitivity analysis, using the leave-one-out approach, showed the pooled estimates had the same direction and magnitude regardless of which study was removed indicating the findings are robust (Fig. 3B). Analysis of publication bias by the Egger's test for the FBG findings found the one-tailed P-value to be significant (0.001), suggesting publication bias may confound these results (Fig. 3C).
Fig. 3Meta-analysis for the effect of CPAP intervention on fasting blood glucose (FBG); (A) the pooled estimate, (B) sensitivity analysis for the pooled estimate, and (C) evaluation for publication bias by a funnel plot and Egger's test. Abbreviations: Diff. difference; Std, standard; CI, confidence interval, lower limit and upper limit.
CPAP therapy induces favorable short-term changes in epicardial fat thickness and vascular and metabolic markers in apparently healthy subjects with obstructive sleep apnea-hypopnea syndrome (OSAHS).
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
Markers of glycemic control and insulin resistance in non-diabetic patients with Obstructive Sleep Apnea Hypopnea Syndrome: does adherence to CPAP treatment improve glycemic control?.
Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2004; 26(Chinese): 168-171
]. No heterogeneity was observed among these studies (Q-value = 20.74, P = 0.054, I2 = 42.14%), thus a fixed effect model was used. The combined effect of standardized diff. in means of fasting insulin was −0.039 (P = 0.457) indicating CPAP did not result in a greater reduction in fasting insulin levels compared with controls (Fig. 4A ). The corresponding sensitivity analysis, using the leave-one-out approach, showed the pooled estimates had the same direction and magnitude regardless of which study was removed indicating the findings are robust (Fig. 4B). Analysis of publication bias by the Egger's test for the fasting insulin findings found the one-tailed P-value to be significant (0.171), suggesting there was no publication bias (Fig. 4C).
Fig. 4Meta-analysis for the effect of CPAP intervention on fasting insulin (FInsulin); (A) the pooled estimate, (B) sensitivity analysis for the pooled estimate, and (C) evaluation for publication bias by a funnel plot and Egger's test. Abbreviations: Diff. difference; Std, standard; CI, confidence interval, lower limit and upper limit.
3.2.4 Effect between CPAP and control groups in the RCT studies
The RCT studies were evaluated separately regarding HOMA-IR, FBG, and fasting insulin. Two RCTs were included for the meta-analyses for HOMA-IR (Hoyos [
Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
] for FBG and fasting insulin. No significantly difference in change of HOMA-IR and FBG between the CPAP group and the control group were seen (Fig. 5A, and B ). The combined effect of diff in means showed that CPAP was associated with a significant greater reduction in fasting insulin than in control groups (standardized diff. in means between groups = −0.479, P-value = 0.003) (Fig. 5C).
Fig. 5Meta-analysis for the effect on HOMA-IR (A), fasting blood glucose (B), and fasting insulin (C) between CAPA and control groups for four RCT studies Abbreviations: Diff. difference; Std, standard; CI, confidence interval, lower limit and upper limit.
Quality assessment of the eight two-armed studies found that there was overall a high risk of selection and performance bias (Fig. 6). This is unavoidable due to the nature of intervention. Some studies provided oral placebo instead of sham-CPAP as control groups, making it not possible for random allocation, concealment, and blinding. There was also moderate to high risk of intention to treat analysis. Due to the discomfort of CPAP treatment, many patients across the studies dropped out or were noncompliant with treatment.
Fig. 6Quality assessment of the two-arm prospective studies.
Quality assessment of the 15 single arm studies indicated most studies included the 18 items on the Delphi checklist, with exception of a few common points (Supplementary Table 1). Only three out of 15 studies reported consecutive recruitment of participants, and none of the studies reported additional intervention to CPAP. Only six of the 15 studies provided estimates of random variability, which may cause potential selection bias, and only two studies reported adverse events. CPAP is non-invasive treatment thus adverse events due to treatment are not common.
4. Discussion
The purpose of this study was to assess the effect of CPAP therapy on the risk of developing type 2 diabetes by evaluating change from baseline in HOMA-IR following CPAP treatment in non-diabetic and pre-diabetic patients with OSA. The study found that the reduction in HOMA was greater in the CPAP group than in the control group. However, CPAP therapy did not result in a greater reduction in FBG or fasting insulin levels compared with control Our findings support the use of CPAP in patients with OSA to improve biomarkers of diabetes and possibly reduce the risk of developing type 2 diabetes in this patient population. HOMA-IR, as compared with the “gold” standard euglycemic clamp method for quantifying insulin resistance, is more convenient, is widely used in research, and is highly accurate [
]. The participants in all included studies were either pre-diabetic or non-diabetic. Based on the American Diabetes Association criteria, patients who met the FBG levels of 100–125 mg/dL, an oral glucose tolerance test (OGTT) of 2-hour plasma glucose of 140–199 mg/dL and/or HbA1c value ranging from 5.7% to 6.4% were diagnosed as pre-diabetes. Some of the included articles that did not show FBG, OGTT and HbA1c value, the status of the patients could be determined based on the level of fasting plasma insulin (≥10 μU/mL) and/or HOMA-IR (≥2.5) insulin resistance level [
]. Yang et al. also found that three to 24 weeks of CPAP therapy did not improve glycemic control as measured by change in FBG in non-diabetic patients (P = 0.20). We also saw no effect of CPAP on FBG levels. Although there seemed to be a decrease in FBG levels in many of the included studies, the heterogeneity in treatment protocols used among studies makes it difficult to evaluate the true effects of FBG. It may also reflect, in part, the fact that not all studies reported both HOMA-IR and FBG, and that differences in study design, patient populations etc. could have impacted the outcomes of the two measurements.
In contrast to our findings, another meta-analysis by Hecht et al., which evaluated only randomized controlled trials in patients with OSA, found no change in insulin resistance following CPAP therapy [
Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
]. The difference in findings between ours and the study of Hecht et al. may reflect the types of studies included. The study by Hecht et al. included trials that measured insulin resistance by HOMA-index, adiponectin, or Kitt-insulin-sensitivity index [
Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
]. In contrast, we included RCTs and single-arm prospective studies. Our study measured insulin resistance by HOMA-index. In addition, we excluded studies that were designed for patients with diagnostically confirmed diabetes.
HOMA-IR is calculated by multiplying fasting plasma insulin (μU/ml) by fasting plasma glucose (FPG) (mmol/l), then dividing by the constant 22.5 [
Comparative evaluation of whole body and hepatic insulin resistance using indices from oral glucose tolerance test in morbidly obese subjects with nonalcoholic fatty liver disease.
]. Therefore, we evaluated FBG and fasting insulin in the meta-analysis. The reason why CPAP was associated with a significant reduction in change of HOMA-IR, but not for FBG before and after the intervention is unknown. We did not include ISI as it was evaluated differently across the studies, including frequently sampled intravenous glucose tolerance test (FSIGTT) [
Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
Our study indirectly demonstrated the association between OSA and diabetes since CPAP was the first line treatment for OSA. Improvement of OSA enhanced the glycemic control or insulin resistance in both pre-diabetic and non-diabetic patients. The higher insulin resistance (HOMA-IR) in OSA patients is of importance as well since it is a known risk factor for diabetes and cardiovascular disease [
Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: the Bruneck study.
]. Intermittent hypoxia and sleep fragmentation induced by OSA may cause disorders in various systems, such as the sympathetic nervous system, oxidative stress reactions, systemic inflammation, hormone system that regulate appetite, and the hypothalamic–pituitary–adrenal axis, which in turn contribute to the development of insulin resistance, poor blood glucose control, and increase the risk of type II diabetes mellitus [
Several aspects of our meta-analysis limit the interpretation of the findings. This study included pooled data from RCTs and single-arm prospective studies. The level of evidence and the number of articles included in meta-analysis are relatively low. For example, for the combined effect of diff. in means of HOMA-IR (primary outcome), only two RCTs (Level 1a) and 13 single-arm prospective studies (Level 2b) were included in meta-analysis. Only prospective studies showed a significant association between CPAP and reduction in HOMA-IR. For the combined effect of diff. in means of fasting insulin (secondary outcome), only three RCTs (Level 1a) and 13 non-randomized two-arm prospective studies (Level 1c) were included in meta-analysis. RCTs showed a significant association between CPAP and a reduction in fasting insulin but the number of articles was too low to draw a conclusion. The AHI cut-off point was diverse among the included studies. In some studies, patients with AHI >5 events/h were considered as diagnosed of OSA. Other studies considered AHI > 10, 15 or 20 as the cut-off point for OSA. In addition, the studies were heterogeneous with respect to the CPAP treatment regimen including number of hours per day and duration of therapy. The treatment duration ranged from one night to 954 days. This large range in treatment duration may have resulted in different treatment effects across the studies, which could have confounded our results. Another factor that may have influenced findings is difference in patient adherence to therapy across the studies, which we did not evaluate. Sensitivity analysis and publication bias assessment indicate that the findings may be overly influenced by one or more studies.
5. Conclusions
In conclusion, this study updates current information on the benefit of CPAP in non-diabetic patients with OSA. These findings support the use of CPAP in non-diabetic and pre-diabetic patients with OSA to reduce HOMA-IR from pre-CPAP levels and possibly reduce the risk of developing type 2 diabetes. CPAP is non-invasive, easily available, and is currently the gold standard for treating OSA. CPAP may serve as a prophylactic, non-invasive management for pre-diabetic patients, possibly preventing or delay-onset of type 2 diabetes.
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