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Continuous positive airway pressure and diabetes risk in sleep apnea patients: A systemic review and meta-analysis

Published:December 02, 2016DOI:https://doi.org/10.1016/j.ejim.2016.11.010

      Highlights

      • The improvement of CPAP in glucose control is a conflict in prior studies.
      • CPAP was associated with a decrease in HOMA-IR following CPAP intervention.
      • 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.

      Graphical abstract

      Keywords

      1. Introduction

      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 [
      • Young T.
      • Palta M.
      • Dempsey J.
      • Skatrud J.
      • Weber S.
      • Badr S.
      The occurrence of sleep-disordered breathing among middle-aged adults.
      ]. In the adult population, OSA is an independent risk factor for development of type 2 diabetes [
      • Ip M.S.
      • Lam B.
      • Ng M.M.
      • Lam W.K.
      • Tsang K.W.
      • Lam K.S.
      Obstructive sleep apnea is independently associated with insulin resistance.
      ,
      • Punjabi N.M.
      • Beamer B.A.
      Alterations in glucose disposal in sleep-disordered breathing.
      ,
      • Punjabi N.M.
      • Shahar E.
      • Redline S.
      • Gottlieb D.J.
      • Givelber R.
      • Resnick H.E.
      • et al.
      Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study.
      ,
      • Punjabi N.M.
      • Sorkin J.D.
      • Katzel L.I.
      • Goldberg A.P.
      • Schwartz A.R.
      • Smith P.L.
      Sleep-disordered breathing and insulin resistance in middle-aged and overweight men.
      ,
      • Yang D.
      • Liu Z.
      • Yang H.
      • Luo Q.
      Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
      ,
      • Botros N.
      • Concato J.
      • Mohsenin V.
      • Selim B.
      • Doctor K.
      • Yaggi H.K.
      Obstructive sleep apnea as a risk factor for type 2 diabetes.
      ]. Cross-sectional epidemiologic studies and cohort and clinical studies found an association between OSA and deterioration in glycemic control, insulin resistance, and metabolic syndrome [
      • Yang D.
      • Liu Z.
      • Yang H.
      • Luo Q.
      Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
      ,
      • Botros N.
      • Concato J.
      • Mohsenin V.
      • Selim B.
      • Doctor K.
      • Yaggi H.K.
      Obstructive sleep apnea as a risk factor for type 2 diabetes.
      ,
      • Levy P.
      • Bonsignore M.R.
      • Eckel J.
      Sleep, sleep-disordered breathing and metabolic consequences.
      ,
      • Spiegel K.
      • Tasali E.
      • Leproult R.
      • Van Cauter E.
      Effects of poor and short sleep on glucose metabolism and obesity risk.
      ,
      • Aronsohn R.S.
      • Whitmore H.
      • Van Cauter E.
      • Tasali E.
      Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes.
      ,
      • Okada M.
      • Takamizawa A.
      • Tsushima K.
      • Urushihata K.
      • Fujimoto K.
      • Kubo K.
      Relationship between sleep-disordered breathing and lifestyle-related illnesses in subjects who have undergone health-screening.
      ,
      • Papanas N.
      • Steiropoulos P.
      • Nena E.
      • Gottlieb D.J.
      • Givelber R.
      • Resnick H.E.
      • et al.
      HbA1c is associated with severity of obstructive sleep apnea hypopnea syndrome in nondiabetic men.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Bouros D.
      • Maltezos E.
      Obstructive sleep apnea aggravates glycemic control across the continuum of glucose homeostasis.
      ,
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ]. OSA is present in patients with type 2 diabetes, ranging from 58% to 77% [
      • Aronsohn R.S.
      • Whitmore H.
      • Van Cauter E.
      • Tasali E.
      Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes.
      ], and there is some evidence of a direct relationship of OSA and the risk of developing the disease [
      • Punjabi N.M.
      • Beamer B.A.
      Alterations in glucose disposal in sleep-disordered breathing.
      ,
      • Botros N.
      • Concato J.
      • Mohsenin V.
      • Selim B.
      • Doctor K.
      • Yaggi H.K.
      Obstructive sleep apnea as a risk factor for type 2 diabetes.
      ]. 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 [
      • Martínez Cerón E.
      • Casitas Mateos R.
      • García-Río F.
      Sleep apnea-hypopnea syndrome and type 2 diabetes. A reciprocal relationship?.
      ].
      Continuous positive airway pressure (CPAP) is the primary treatment for OSA, which reduces hypoxia and improve subjective sleep quality [
      • Loredo J.S.
      • Ancoli-Israel S.
      • Kim E.J.
      • Lim W.J.
      • Dimsdale J.E.
      Effect of continuous positive airway pressure versus supplemental oxygen on sleep quality in obstructive sleep apnea: a placebo-CPAP-controlled study.
      ,
      • Lau E.Y.
      • Eskes G.A.
      • Morrison D.L.
      • Rajda M.
      • Spurr K.F.
      Executive function in patients with obstructive sleep apnea treated with continuous positive airway pressure.
      ]. 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 [
      • Steiropoulos P.
      • Papanas N.
      • Bouros D.
      • Maltezos E.
      Obstructive sleep apnea aggravates glycemic control across the continuum of glucose homeostasis.
      ,
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Babu A.R.
      • Herdegen J.
      • Fogelfeld L.
      • Shott S.
      • Mazzone T.
      Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea.
      ,
      • Shpirer I.
      • Rapoport M.J.
      • Stav D.
      • Elizur A.
      Normal and elevated HbA1C levels correlate with severity of hypoxemia in patients with obstructive sleep apnea and decrease following CPAP treatment.
      ,
      • Yang D.
      • Liu Z.
      • Yang H.
      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.
      ], while other studies found no effect of CPAP on diabetes-related outcomes [
      • Dawson A.
      • Abel S.L.
      • Loving R.T.
      • Dailey G.
      • Shadan F.F.
      • Cronin J.W.
      • et al.
      CPAP therapy of obstructive sleep apnea in type 2 diabetics improves glycemic control during sleep.
      ,
      • Harsch I.A.
      • Schahin S.P.
      • Bruckner K.
      • Radespiel-Tröger M.
      • Fuchs F.S.
      • Hahn E.G.
      • et al.
      The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes.
      ,
      • Hassaballa H.A.
      • Tulaimat A.
      • Herdegen J.J.
      • Mokhlesi B.
      The effect of continuous positive airway pressure on glucose control in diabetic patients with severe obstructive sleep apnea.
      ,
      • Smurra M.
      • Philip P.
      • Taillard J.
      • Guilleminault C.
      • Bioulac B.
      • Gin H.
      CPAP treatment does not affect glucose-insulin metabolism in sleep apneic patients.
      ,
      • West S.D.
      • Nicoll D.J.
      • Wallace T.M.
      • Matthews D.R.
      • Stradling J.R.
      Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes.
      ]. Similarly, some but not all studies, found CPAP therapy improved insulin sensitivity [
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Babu A.R.
      • Herdegen J.
      • Fogelfeld L.
      • Shott S.
      • Mazzone T.
      Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea.
      ,
      • Yang D.
      • Liu Z.
      • Yang H.
      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.
      ,
      • Dawson A.
      • Abel S.L.
      • Loving R.T.
      • Dailey G.
      • Shadan F.F.
      • Cronin J.W.
      • et al.
      CPAP therapy of obstructive sleep apnea in type 2 diabetics improves glycemic control during sleep.
      ,
      • Harsch I.A.
      • Schahin S.P.
      • Bruckner K.
      • Radespiel-Tröger M.
      • Fuchs F.S.
      • Hahn E.G.
      • et al.
      The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes.
      ,
      • West S.D.
      • Nicoll D.J.
      • Wallace T.M.
      • Matthews D.R.
      • Stradling J.R.
      Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes.
      ,
      • Brooks B.
      • Cistulli P.A.
      • Borkman M.
      • Ross G.
      • McGhee S.
      • Grunstein R.R.
      • et al.
      Obstructive sleep apnea in obese noninsulin-dependent diabetic patients: effect of continuous positive airway pressure treatment on insulin responsiveness.
      ,
      • Hecht L.
      • Mohler R.
      • Meyer G.
      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 [
      • Yang D.
      • Liu Z.
      • Yang H.
      • Luo Q.
      Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
      ,
      • Hecht L.
      • Mohler R.
      • Meyer G.
      Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
      ,
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. Among those studies, two meta-analyses found CPAP was associated with improved homeostasis model assessment of insulin resistance (HOMA-IR) [
      • Yang D.
      • Liu Z.
      • Yang H.
      • Luo Q.
      Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
      ,
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. However, another article reported no change in insulin resistance following CPAP therapy [
      • Hecht L.
      • Mohler R.
      • Meyer G.
      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 [
      • American Diabetes Association
      Standards of medical care in diabetes—2014.
      ]. 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.

      ] and Modified 18-items Delphi checklist [
      • Moga C.
      • Guo B.
      • Schopflocher D.
      • Harstall C.
      Development of a Quality Appraisal Tool for Case Series Studies Using a Modified Delphi Technique.
      ] for single-arm studies.

      2.3 Outcome measures

      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 [
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ]. 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. 1.
      Fig. 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.
      Twenty-three articles were included in the systematic review and meta-analysis with 965 OSA patients (Table 1) [
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ,
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      ,
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      ,
      • Chirinos J.A.
      • Gurubhagavatula I.
      • Teff K.
      • Rader D.J.
      • Wadden T.A.
      • Townsend R.
      • et al.
      CPAP, weight loss, or both for obstructive sleep apnea.
      ,
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ,
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández de Rota L.
      • Fernández-Ramos A.
      • Cardona F.
      • et al.
      Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
      ,
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      ,
      • Tasali E.
      • Chapotot F.
      • Leproult R.
      • Whitmore H.
      • Ehrmann D.A.
      Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome.
      ,
      • Garcia J.M.
      • Sharafkhaneh H.
      • Hirshkowitz M.
      • Elkhatib R.
      • Sharafkhaneh A.
      Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity.
      ,
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      ,
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ,
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ,
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      ,
      • Carneiro G.
      • Togeiro S.M.
      • Ribeiro-Filho F.F.
      • Truksinas E.
      • Ribeiro A.B.
      • Zanella M.T.
      • et al.
      Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
      ,
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      ,
      • Trenell M.I.
      • Ward J.A.
      • Yee B.J.
      • Phillips C.L.
      • Kemp G.J.
      • Grunstein R.R.
      • et al.
      Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
      ,
      • Czupryniak L.
      • Loba J.
      • Pawlowski M.
      • Nowak D.
      • Bialasiewicz P.
      Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.
      ,
      • Huang R.
      • Huang X.Z.
      • Wang H.G.
      • Li M.
      • Xiao Y.
      Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
      ,
      • Harsch I.A.
      • Schahin S.P.
      • Radespiel-Troger M.
      • Weintz O.
      • Jahreiss H.
      • Fuchs F.S.
      • et al.
      Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome.
      ]. 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.
      1st AU (year)InterventionNo. of ptsTreatment protocolAge (yr), mean (SD)Male, n (%)AHI cut-off for diagnosed OSA (events/h)Diagnosis of diabetes
      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.
      LengthPressureDuration (h/day)
      Kostopoulos K (2015)
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      CPAP283 monthsNANA47.2 (10.6)23 (82.1%)5Pre-diabetes
      Pamidi S (2015)
      Randomized Controlled Trial (RCT).
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      CPAP262 wkNA853.8 (6.2)16 (62%)5Pre-diabetes
      Oral placebo13NAEvery night55.2 (8.4)10 (77%)
      Chirinos JA (2014)
      Randomized Controlled Trial (RCT).
      • Chirinos J.A.
      • Gurubhagavatula I.
      • Teff K.
      • Rader D.J.
      • Wadden T.A.
      • Townsend R.
      • et al.
      CPAP, weight loss, or both for obstructive sleep apnea.
      Weight loss6124 wkNAN/A48.336 (59%)15 for moderate-to-severe OSANA
      CPAP58NA449.835 (60.3%)
      CPAP + weight loss62NA44933 (53.2%)
      Baburao A (2014)
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      CPAP301 months14 (12–18)* cmH2O4.549.9 (6.00)21 (70%)5Non-diabetes/pre-diabetes
      Yang D (2013b)
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      CPAP2293(5) daysNA5(1)60 (7)20 (90.9%)5Pre-diabetes
      Control22NANA61 (7)20 (90.9%)
      Hoyos CM (2012)
      Randomized Controlled Trial (RCT).
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      CPAP 12 wk then additional CPAP 12 wk3424 wkNAFirst 12 wk: 3.6; following 12 wk: 451.0 (12.3)100%5Pre-diabetes
      Sham CPAP 12 wk then real CPAP 12 wk31NAFirst 12 wk: 2.8; following 12 wk: 446.4 (10.4)NA
      Tasali E (2011)
      • Tasali E.
      • Chapotot F.
      • Leproult R.
      • Whitmore H.
      • Ehrmann D.A.
      Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome.
      CPAP198 wkNA6.6 (0.4)†30.6 (1.7)†05Pre-diabetes
      Garcia JM (2011)
      • Garcia J.M.
      • Sharafkhaneh H.
      • Hirshkowitz M.
      • Elkhatib R.
      • Sharafkhaneh A.
      Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity.
      CPAP20165(17)† daysNA5.3 (0.35)†59.7 (2)†17 (85%)5Pre-diabetes
      Murri M (2011a)
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      CPAP131 monthsNANA47.5 (10.2)100%5Pre-diabetes
      Healthy control14NANA45.8 (8.8)NA
      Murri M (2011b)
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández de Rota L.
      • Fernández-Ramos A.
      • Cardona F.
      • et al.
      Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
      CPAP261 monthsNANA52.15 (13.41)100%5Pre-diabetes
      Healthy control16NANA47.62 (7.40)NA
      Chung S (2011)
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      CPAP52138.7 (42.6) daysNANA51.4 (11.5)22 (88%)15 for moderate-to-severe OSANon-diabetes/pre-diabetes
      Lam JC (2010)
      Randomized Controlled Trial (RCT).
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      CPAP311wkAutotitrationNA46.5 (10.8)NA15 for moderate-to-severe OSANon-diabetes
      Sham CPAP300–1 cmH2ONA46.1(9.8)NA
      Nena E (2010)
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      CPAP, no IFG476 months4.72(0.66)45.2 (11.4)85.50%15Pre-diabetes
      CPAP, IFG15NANA49.8 (10.4)NA
      Murri M (2009)
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      CPAP7852.32 (11.28)† daysNANANA67 (85.9%)10Non-diabetes/pre-diabetes
      Carneiro G (2009)
      • Carneiro G.
      • Togeiro S.M.
      • Ribeiro-Filho F.F.
      • Truksinas E.
      • Ribeiro A.B.
      • Zanella M.T.
      • et al.
      Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
      CPAP163 months11.5 (2)# cmH2O6.6 (0.4)#NA100%5Pre-diabetes
      Steiropoulos P (2009)
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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, good adherence (≥4 h nightly)216 monthsNA4.71 (0.55)46.07 (10.67)50 (89.3%)15Non-diabetes/pre-diabetes
      CPAP, poor adherence (<4 h nightly)20NA2.5 (1.06)NANA
      No CPAP15NA0.01 (0.04)NANA
      Cuhadaroğlu C (2009)
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      CPAP448wk7.8 (2.6) cmH2O453.9 (9.7)27 (61.4%)15Non-diabetes/pre-diabetes
      Vgontzas AN (2008)
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      CPAP163 monthsNA4.6 (0.4)†48.1 (5.6)†100%5Pre-diabetes
      Schahin SP (2008)
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      CPAP9954 (57) days9.8 (2.9) mbar5.2 (1.6)64 (10)100%10Pre-diabetes
      Trenell MI (2007)
      • Trenell M.I.
      • Ward J.A.
      • Yee B.J.
      • Phillips C.L.
      • Kemp G.J.
      • Grunstein R.R.
      • et al.
      Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
      Regular CPAP (≥4 nightly)1912 wkNA6 (1)49 (12)100%(RDI) > 30Non-diabetes/pre-diabetes
      Czupryniak L (2005)
      • Czupryniak L.
      • Loba J.
      • Pawlowski M.
      • Nowak D.
      • Bialasiewicz P.
      Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.
      CPAP91 night4 or 5 to 14 mbarNA53.0 (8.0)7 (77.8%)15Non-diabetes/pre-diabetes
      Huang R (2004)
      • Huang R.
      • Huang X.Z.
      • Wang H.G.
      • Li M.
      • Xiao Y.
      Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
      CPAP87.50 (0.43)† months11.45 (0.49)† cmH2O6.98 (0.48)†46.13 (1.60)†NA5Pre-diabetes
      Harsch IA (2004)
      • Harsch I.A.
      • Schahin S.P.
      • Radespiel-Troger M.
      • Weintz O.
      • Jahreiss H.
      • Fuchs F.S.
      • et al.
      Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome.
      CPAP4093.97 (25.22) daysNA5.2 (0.91)53.81 (11.84)34 (85%)20Pre-diabetes
      Data are presented by mean (SD), *mean (Range), †mean (SEM).
      AHI, Apnea–hypopnea index; OSA, obstructive sleep apnea; CPAP, continuous positive airway pressure; IFG, impaired fasting glucose; RDI, Respiratory disturbance index; NA, not available.
      a Randomized Controlled Trial (RCT).
      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.

      3.2 Meta-analysis

      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 [
      • Czupryniak L.
      • Loba J.
      • Pawlowski M.
      • Nowak D.
      • Bialasiewicz P.
      Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.
      ]. Four studies were RCTs [
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ,
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      ,
      • Chirinos J.A.
      • Gurubhagavatula I.
      • Teff K.
      • Rader D.J.
      • Wadden T.A.
      • Townsend R.
      • et al.
      CPAP, weight loss, or both for obstructive sleep apnea.
      ,
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ], 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 [
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ], two studies compared patients with sleep apnea-hypopnea syndrome with healthy controls [
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández de Rota L.
      • Fernández-Ramos A.
      • Cardona F.
      • et al.
      Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
      ], one report divided the patients into good adherence, poor adherence, and no use of CPAP at the end of follow-up [
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ], and one study divided the patients into impaired fasting glucose (IFG) group and no IFG group [
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ]. Of these five studies, only the data from the CPAP-treated patients with good adherence [
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ] and without IFG [
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ] are included in the meta-analysis.
      The outcomes measurements are summarized in Table 2. Seventeen studies reported complete date for HOMA-IR [
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ,
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      ,
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ,
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández de Rota L.
      • Fernández-Ramos A.
      • Cardona F.
      • et al.
      Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
      ,
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      ,
      • Garcia J.M.
      • Sharafkhaneh H.
      • Hirshkowitz M.
      • Elkhatib R.
      • Sharafkhaneh A.
      Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity.
      ,
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      ,
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ,
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ,
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      ,
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      ,
      • Czupryniak L.
      • Loba J.
      • Pawlowski M.
      • Nowak D.
      • Bialasiewicz P.
      Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.
      ], including two RCTs [
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ,
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ]. Sixteen studies reported FBG levels before and after CPAP treatment [
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ,
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      ,
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      ,
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      ,
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      ,
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      ,
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ,
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ,
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      ,
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      ,
      • Trenell M.I.
      • Ward J.A.
      • Yee B.J.
      • Phillips C.L.
      • Kemp G.J.
      • Grunstein R.R.
      • et al.
      Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
      ,
      • Czupryniak L.
      • Loba J.
      • Pawlowski M.
      • Nowak D.
      • Bialasiewicz P.
      Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.
      ,
      • Huang R.
      • Huang X.Z.
      • Wang H.G.
      • Li M.
      • Xiao Y.
      Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
      ], including three RCTs [
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ,
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      ,
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ]. Seventeen studies reported fasting insulin levels before and after CPAP treatment [
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ,
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      ,
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      ,
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ,
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández de Rota L.
      • Fernández-Ramos A.
      • Cardona F.
      • et al.
      Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
      ,
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      ,
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      ,
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ,
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ,
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      ,
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      ,
      • Trenell M.I.
      • Ward J.A.
      • Yee B.J.
      • Phillips C.L.
      • Kemp G.J.
      • Grunstein R.R.
      • et al.
      Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
      ,
      • Czupryniak L.
      • Loba J.
      • Pawlowski M.
      • Nowak D.
      • Bialasiewicz P.
      Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.
      ,
      • Huang R.
      • Huang X.Z.
      • Wang H.G.
      • Li M.
      • Xiao Y.
      Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
      ], including three RCTs [
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ,
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      ,
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ]. Five studies reported HbA1c levels before and after CPAP treatment [
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      ,
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ,
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ].
      Table 2Summary of outcomes of selected studies for meta-analysis.
      1st AU (year)InterventionHOMA-IRFBG (mg/dL)Fasting insulin (μU/ml)
      Pre-treatmentPost-treatmentChangePre-treatmentPost-treatmentChangePre-treatmentPost-treatmentChange
      Kostopoulos K (2015)
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      CPAP4.61 (3.28–6.5)†2.89 (2.07–4.43)†1.67 (−2.560 to −0.780)‡113.1 ± 28.61105.7 ± 20.267.4 (−17.39 to 2.586)‡17 (12.75–33) mg/dL †13 (9–18) mg/dL†3.750 (−5.472, −2.028)‡
      Pamidi S (2015)a
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      CPAPNANANA104.1 (100.7 to 107.5)‡NA4.1 (−7.2 to −1.0)‡73.6 (60.0 to 87.3)‡pmol/LNA5.7 (−16.5 to 5.1)‡ pmol/L
      Oral PlaceboNANANA100.9 (95.8 to 105.9)NA1.3 (−5.6 to 3.1)

      Diff between groups: −2.8 (−8.1 to 2.5)
      69.7 (49.4 to 90.0)‡NA13.0 (−2.1 to 28.1)‡

      Diff between groups: −18.7 (−37.3 to −0.1)
      Chirinos JA (2014)a
      • Chirinos J.A.
      • Gurubhagavatula I.
      • Teff K.
      • Rader D.J.
      • Wadden T.A.
      • Townsend R.
      • et al.
      CPAP, weight loss, or both for obstructive sleep apnea.
      Weight lossNANANANANANANANANA
      CPAPNANANANA
      CPAP + weight lossNANANANANANANANANA
      Baburao A (2014)
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      CPAP5.78 ± 6.014.82 ± 4.390.960 (−2.887 to 0.967)‡100.36 ± 19.2498.76 ± 19.451.600 (−8.523 to 5.323)‡21.75 ± 19.48 μU/ml19.39 ± 17.54 μU/ml2.360 (−9.011 to 4.291)‡
      Yang D (2013b)
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      CPAP3.55 ± 1.723.01 ± 1.280.540 (−0.187 to 0.107)‡5.78 ± 0.69 mmol/L5.58 ± 0.59 mmol/L0.200 (−0.470 to 0.070)‡13.5 ± 5.9 μU/ml12.0 ± 4.7 μU/ml1.500 (−3.757 to 0.757)‡
      Control3.04 ± 0.863.65 ± 1.175.69 ± 0.76 mmol/L5.94 ± 0.61 mmol/L12.2 ± 3.9 μU/ml13.8 ± 4.1 μU/ml
      Hoyos CM (2012)a
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      CPAP 12 wk then additional CPAP 12 wk2.9 ± 2.5NA-0.31 (−0.85 to 0.22)‡5.3 ± 0.7NA0.13 (−0.07 to 0.33)‡11.8 ± 7.8NA2.62 (−4.85 to −0.39)‡
      Sham CPAP 12wk then real CPAP 12wk2.9 ± 1.8NA0.50 (−0.23 to 1.23)‡5.2 ± 0.5NA0.15 (−0.06 to 0.36)‡12.5 ± 7.7NA1.4 (−1.3 to 4.1)‡
      Tasali E (2011)
      • Tasali E.
      • Chapotot F.
      • Leproult R.
      • Whitmore H.
      • Ehrmann D.A.
      Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome.
      CPAPNANANANANANANANA
      Garcia JM (2011)
      • Garcia J.M.
      • Sharafkhaneh H.
      • Hirshkowitz M.
      • Elkhatib R.
      • Sharafkhaneh A.
      Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity.
      CPAP5.9 (1)*7.5 (1.2)*1.600 (−3.783 to 0.583)‡105 (4)*NANANA
      Murri M (2011a)
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      CPAP7 ± 5.65.7 ± 3.71.300 (−3.981 to 1.381)‡NANANA17.7 ± 8.117.2 ± 8.80.500 (−5.105 to 4.105)‡
      Healthy control
      Murri M (2011b)
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández de Rota L.
      • Fernández-Ramos A.
      • Cardona F.
      • et al.
      Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
      CPAP4.713 ± 2.3674.472 ± 2.4130.241 (−1.160 to 0.678)‡NANANA18.46 ± 8.0919.11 ± 10.950.650 (−3.131 to 4.431)‡
      Healthy control
      Chung S (2011)
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      CPAP3.5 ± 1.94.4 ± 4.90.900 (−2.577 to 0.777)‡110.3 ± 36.6103.5 ± 29.66.800 (−19.991 to 6.391)‡12.4 ± 6.116.1 ± 13.53.700 (−0.890 to 8.290)‡
      Lam JC (2010)
      Randomized Controlled Trial (RCT).
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      CPAP2.5 (1.5–3.4)†2.1 (1.5–3.4)†4.9 (4.7–5.4)†5.1 (4.7–5.3)†10.9 (7.3–14.0)†10.7 (7.1–15.4)†
      Sham CPAP2.9 ± 2.12.8 ± 1.90.19 ± 1.235.2 ± 0.65.2 ± 0.60.002 ± 0.3912.2 ± 7.611.6 ± 7.10.63 ± 3.89
      Nena E (2010)
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      CPAP, no IFG2.8 ± 22.7 ± 1.5-0.190 (−0.611 to 0.230)‡94.1 ± 8.996.3 ± 9.73.095 (0.477 to 5.713)‡12.4 ± 8.911.5 ± 6.30.158 (−2.771 to 3.087)‡
      CPAP, IFG6.3 ± 4.67.4 ± 8.3117.9 ± 5123.8 ± 16.321.7 ± 15.323.2 ± 22.2
      Murri M (2009)
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      CPAP4.51(3.13)*4.29(2.95)*0.220 (−6.836 to 5.746)‡104.42 (18.96)*102.96 (17.33)*1.460 (−37.131 to 34.211)‡16.64(8.63)*16.43(8.95)*0.210 (−17.447 to 17.027)‡
      Carneiro G (2009)
      • Carneiro G.
      • Togeiro S.M.
      • Ribeiro-Filho F.F.
      • Truksinas E.
      • Ribeiro A.B.
      • Zanella M.T.
      • et al.
      Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
      CPAP7.6 (1.7)*5.9 (1.5)*1.7 (1.2)*NANANANANANA
      Steiropoulos P (2009)
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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, good adherence (≥4 h nightly)3.48 ± 4.154.18 ± 3.310.700 (−2.325 to 0.925)‡102.57 ± 14.36104.57 ± 12.392.000 (−3.767, 7.767)‡13.08 ± 13.3915.87 ± 11.522.790 (−2.582 to 8.162)‡
      CPAP, poor adherence (<4 h nightly)4.08 ± 3.094.62 ± 5.3299.55 ± 15.62104.3 ± 19.0116.36 ± 10.9316.7 ± 14.39
      no CPAP4.6 ± 3.482.89 ± 1.85101.73 ± 14.3897.27 ± 14.6417.44 ± 11.5413.09 ± 8.44
      Cuhadaroğlu C, (2009)
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      CPAP3.65 ± 1.913.61 ± 1.800.040 (−0.694 to 0.614)‡5.42 ± 1.01 mol/L5.13 ± 1.00 mol/L0.290 (−0.644 to 0.064)‡13.98 ± 7.23 mU/L14.36 ± 6.97 mU/L0.380 (−2.658 to 3.418)‡
      Vgontzas AN (2008)
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      CPAP4.6 (0.8)*4.3 (0.7)*0.300 (−1.780 to 1.180)‡96.6 (5.8)*93.3 (3.0)*3.500 (−13.347 to 6.347)‡18.2 (2.1)*18.7 (2.6)*0.500 (−4.183 to 5.183)‡
      Schahin SP (2008)
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      CPAPNANA5.9 ± 0.5 mmol/l5.4 ± 0.3 mmol/l0.500 (−0.785 to −0.215)‡
      Trenell MI (2007)
      • Trenell M.I.
      • Ward J.A.
      • Yee B.J.
      • Phillips C.L.
      • Kemp G.J.
      • Grunstein R.R.
      • et al.
      Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
      Regular CPAP (≥4 nightly)NANANA5.6 ± 0.7 mmol/l5.4 ± 0.6 mmol/l0.200 (−0.495 to 0.095)‡125 ± 74 pmol/l123 ± 89 pmol/l2.000 (−39.109 to 35.109)‡
      Irregular CPAP (≥4 nightly)NANANA5.3 ± 0.8 mmol/l5.1 ± 0.6 mmol/l148 ± 104 pmol/l123 ± 67 pmol/l
      Czupryniak L (2005)
      • Czupryniak L.
      • Loba J.
      • Pawlowski M.
      • Nowak D.
      • Bialasiewicz P.
      Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.
      CPAP3.6 ± 2.23.9 ± 2.6-0.300 (−1.884 to 1.284)‡63 ± 780 ± 1117.000 (10.700 to 23.300)‡84.3 ± 43.4 pmol98.4 ± 51.0 pmol14.100 (−17.025 to 45.235)‡
      Huang R (2004)
      • Huang R.
      • Huang X.Z.
      • Wang H.G.
      • Li M.
      • Xiao Y.
      Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
      CPAPNANANA5.96 (0.26)* mmol/L5.31 (0.20)* mmol/L0.650 (−1.107 to −0.193)‡13.96 (4.75)* μIU/ml7.44 (1.99)* μIU/ml6.520 (−14.618 to 1.578)‡
      Harsch IA (2004)
      • Harsch I.A.
      • Schahin S.P.
      • Radespiel-Troger M.
      • Weintz O.
      • Jahreiss H.
      • Fuchs F.S.
      • et al.
      Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome.
      CPAPNANANANANANANANANA
      CPAP, continuous positive airway pressure; IFG, impaired fasting glucose; FBG, fasting blood glucose; NA, not available.
      Data are presented by mean ± SD, mean (SEM)*, median (IQR)†, Mean (95%CI)‡.
      a Randomized Controlled Trial (RCT).

      3.2.1 HOMA-IR

      Thirteen studies were included for analysis of HOMA-IR [
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      ,
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández de Rota L.
      • Fernández-Ramos A.
      • Cardona F.
      • et al.
      Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
      ,
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      ,
      • Garcia J.M.
      • Sharafkhaneh H.
      • Hirshkowitz M.
      • Elkhatib R.
      • Sharafkhaneh A.
      Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity.
      ,
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      ,
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ,
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ,
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      ,
      • Carneiro G.
      • Togeiro S.M.
      • Ribeiro-Filho F.F.
      • Truksinas E.
      • Ribeiro A.B.
      • Zanella M.T.
      • et al.
      Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
      ,
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      ]. 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. [
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ] 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. 2.
      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.

      3.2.2 FBG

      Twelve studies were included for analysis of FBG [
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      ,
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ,
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      ,
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      ,
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ,
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ,
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      ,
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      ,
      • Trenell M.I.
      • Ward J.A.
      • Yee B.J.
      • Phillips C.L.
      • Kemp G.J.
      • Grunstein R.R.
      • et al.
      Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
      ,
      • Huang R.
      • Huang X.Z.
      • Wang H.G.
      • Li M.
      • Xiao Y.
      Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
      ]. 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. 3.
      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.

      3.2.3 Fasting insulin

      Thirteen studies were included for the analysis of fasting insulin [
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Kostopoulos K.
      • Alhanatis E.
      • Pampoukas K.
      • Georgiopoulos G.
      • Zourla A.
      • Panoutsopoulos A.
      • et al.
      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).
      ,
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández-Ramos A.
      • Alcaide J.
      • Cardona F.
      • et al.
      Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
      ,
      • Baburao A.
      • Souza G.D.
      Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
      ,
      • Chung S.
      • Yoon I.Y.
      • Lee C.H.
      • Kim J.W.
      The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
      ,
      • Nena E.
      • Steiropoulos P.
      • Constantinidis T.C.
      • Perantoni E.
      • Tsara V.
      Work productivity in obstructive sleep apnea patients.
      ,
      • Murri M.
      • Alcazar-Ramirez J.
      • Garrido-Sanchez L.
      • Linde F.
      • Alcaide J.
      • Cardona F.
      • et al.
      Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
      ,
      • Steiropoulos P.
      • Papanas N.
      • Nena E.
      • Tsara V.
      • Fitili C.
      • Tzouvelekis A.
      • et al.
      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?.
      ,
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      ,
      • Vgontzas A.N.
      • Zoumakis E.
      • Bixler E.O.
      • Lin H.M.
      • Collins B.
      • Basta M.
      • et al.
      Selective effects of CPAP on sleep apnoea-associated manifestations.
      ,
      • Trenell M.I.
      • Ward J.A.
      • Yee B.J.
      • Phillips C.L.
      • Kemp G.J.
      • Grunstein R.R.
      • et al.
      Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
      ,
      • Huang R.
      • Huang X.Z.
      • Wang H.G.
      • Li M.
      • Xiao Y.
      Effects of nasal continuous positive airway pressure on serum leptin concentration and the metabolic parameters in obstructive sleep apnea hypopnea syndrome.
      ]. 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. 4.
      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 [
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ], and Lam [
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ], and three RCT (Pamidi [
      • Pamidi S.
      • Wroblewski K.
      • Stepien M.
      • Sharif-Sidi K.
      • Kilkus J.
      • Whitmore H.
      • et al.
      Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
      ], Hoyos [
      • Hoyos C.M.
      • Killick R.
      • Yee B.J.
      • Phillips C.L.
      • Grunstein R.R.
      • Liu P.Y.
      Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
      ], and Lam [
      • Lam J.C.
      • Lam B.
      • Yao T.J.
      • Lai A.Y.
      • Ooi C.G.
      • Tam S.
      • et al.
      A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
      ] 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. 5.
      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.

      3.3 Quality assessment

      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. 6.
      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 [
      • Han M.S.
      • Lim Y.M.
      • Quan W.
      • Kim J.R.
      • Chung K.W.
      • Kang M.
      • et al.
      Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance.
      ,
      • Matthews D.R.
      • Hosker J.P.
      • Rudenski A.S.
      • Naylor B.A.
      • Treacher D.F.
      • Turner R.C.
      Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
      ]. 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 [
      • Qu H.Q.
      • Li Q.
      • Rentfro A.R.
      • Fisher-Hoch S.P.
      • McCormick J.B.
      The definition of insulin resistance using HOMA-IR for Americans of Mexican descent using machine learning.
      ,
      • Ghosh C.
      • Mukhopadhyay P.
      • Ghosh S.
      • Pradhan M.
      Insulin sensitivity index (ISI0, 120) potentially linked to carbon isotopes of breath CO2 for pre-diabetes and type 2 diabetes.
      ,
      • Gutch M.
      • Kumar S.
      • Razi S.M.
      • Gupta K.K.
      • Gupta A.
      Assessment of insulin sensitivity/resistance.
      ].
      Our findings are consistent with two prior meta-analyses that evaluated the effect of CPAP on HOMA-IR in non-diabetic patients [
      • Yang D.
      • Liu Z.
      • Yang H.
      • Luo Q.
      Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
      ,
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. The meta-analysis of Yang et al. included 15 studies with 367 patients with OSA. Most of the studies were observational in design (13/15) [
      • Yang D.
      • Liu Z.
      • Yang H.
      • Luo Q.
      Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
      ]. Across the studies, patients used CPAP from 4 to 6 h/day for a range of 3 to 24 weeks [
      • Yang D.
      • Liu Z.
      • Yang H.
      • Luo Q.
      Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
      ]. The study of Iftikhar et al. included five randomized studies with a total of 244 non-diabetic OSA patients [
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. In the Iftikhar, study the duration of CPAP was from one to eight weeks and the CPAP was used between 3.9 and 5.3 h per day [
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. Like our findings, both prior meta-analyses found CPAP was associated with improved (lower) HOMA-IR (P ≤ 0.02) [
      • Yang D.
      • Liu Z.
      • Yang H.
      • Luo Q.
      Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
      ,
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. 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 [
      • Hecht L.
      • Mohler R.
      • Meyer G.
      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 [
      • Hecht L.
      • Mohler R.
      • Meyer G.
      Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
      ], and some studies included patients with type 2 diabetes [
      • Hecht L.
      • Mohler R.
      • Meyer G.
      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 [
      • Qu H.Q.
      • Li Q.
      • Rentfro A.R.
      • Fisher-Hoch S.P.
      • McCormick J.B.
      The definition of insulin resistance using HOMA-IR for Americans of Mexican descent using machine learning.
      ,
      • Matthews D.R.
      • Hosker J.P.
      • Rudenski A.S.
      • Naylor B.A.
      • Treacher D.F.
      • Turner R.C.
      Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
      ,
      • Qureshi K.
      • Clements R.H.
      • Saeed F.
      • Abrams G.A.
      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) [
      • Chirinos J.A.
      • Gurubhagavatula I.
      • Teff K.
      • Rader D.J.
      • Wadden T.A.
      • Townsend R.
      • et al.
      CPAP, weight loss, or both for obstructive sleep apnea.
      ,
      • Tasali E.
      • Chapotot F.
      • Leproult R.
      • Whitmore H.
      • Ehrmann D.A.
      Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome.
      ,
      • Bergman R.N.
      • Prager R.
      • Volund A.
      • Olefsky J.M.
      Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp.
      ], HOMA-S [
      • Yang D.
      • Liu Z.H.
      • Zhao Q.
      • Luo Q.
      Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
      ,
      • Murri M.
      • Garcia-Delgado R.
      • Alcazar-Ramirez J.
      • Fernández de Rota L.
      • Fernández-Ramos A.
      • Cardona F.
      • et al.
      Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
      ,
      • Cuhadaroglu C.
      • Utkusavas A.
      • Ozturk L.
      • Salman S.
      • Ece T.
      Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
      ,
      • Trenell M.I.
      • Ward J.A.
      • Yee B.J.
      • Phillips C.L.
      • Kemp G.J.
      • Grunstein R.R.
      • et al.
      Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
      ], quantitative insulin sensitivity check index (QUICKI) [
      • Garcia J.M.
      • Sharafkhaneh H.
      • Hirshkowitz M.
      • Elkhatib R.
      • Sharafkhaneh A.
      Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity.
      ,
      • Ghosh C.
      • Mukhopadhyay P.
      • Ghosh S.
      • Pradhan M.
      Insulin sensitivity index (ISI0, 120) potentially linked to carbon isotopes of breath CO2 for pre-diabetes and type 2 diabetes.
      ], insulin sensitivity index for glycemia [Belfiore index] [
      • Carneiro G.
      • Togeiro S.M.
      • Ribeiro-Filho F.F.
      • Truksinas E.
      • Ribeiro A.B.
      • Zanella M.T.
      • et al.
      Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
      ,
      • Belfiore F.
      Insulin sensitivity indexes calculated from oral glucose tolerance test data.
      ] and euglycemic insulin clamp technique [
      • Schahin S.P.
      • Nechanitzky T.
      • Dittel C.
      • Fuchs F.S.
      • Hahn E.G.
      • Konturek P.C.
      • et al.
      Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
      ,
      • Harsch I.A.
      • Schahin S.P.
      • Radespiel-Troger M.
      • Weintz O.
      • Jahreiss H.
      • Fuchs F.S.
      • et al.
      Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome.
      ].
      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 [
      • Reaven G.M.
      Banting lecture 1988. Role of insulin resistance in human disease.
      ,
      • Bonora E.
      • Kiechl S.
      • Willeit J.
      • Oberhollenzer F.
      • Egger G.
      • Meigs J.B.
      • et al.
      Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: the Bruneck study.
      ,
      • Gotoh S.
      • Doi Y.
      • Hata J.
      • Ninomiya T.
      • Mukai N.
      • Fukuhara M.
      • et al.
      Insulin resistance and the development of cardiovascular disease in a Japanese community: the Hisayama study.
      ]. The higher HOMA-IR in OSA patients might or might not associate with obesity [
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. 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 [
      • Martínez Cerón E.
      • Casitas Mateos R.
      • García-Río F.
      Sleep apnea-hypopnea syndrome and type 2 diabetes. A reciprocal relationship?.
      ,
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ]. However, the exact mechanism is not conclusive at this point [
      • Iftikhar I.H.
      • Blankfield R.P.
      Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
      ].
      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.
      The following are the supplementary data related to this article.

      Funding

      None.

      Conflict of interests

      All authors declare that they have no conflict of interests.

      Acknowledgements

      None.

      References

        • Young T.
        • Palta M.
        • Dempsey J.
        • Skatrud J.
        • Weber S.
        • Badr S.
        The occurrence of sleep-disordered breathing among middle-aged adults.
        N Engl J Med. 1993; 328: 1230-1235
        • Ip M.S.
        • Lam B.
        • Ng M.M.
        • Lam W.K.
        • Tsang K.W.
        • Lam K.S.
        Obstructive sleep apnea is independently associated with insulin resistance.
        Am J Respir Crit Care Med. 2002; 165: 670-676
        • Punjabi N.M.
        • Beamer B.A.
        Alterations in glucose disposal in sleep-disordered breathing.
        Am J Respir Crit Care Med. 2009; 179: 235-240
        • Punjabi N.M.
        • Shahar E.
        • Redline S.
        • Gottlieb D.J.
        • Givelber R.
        • Resnick H.E.
        • et al.
        Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study.
        Am J Epidemiol. 2004; 160: 521-530
        • Punjabi N.M.
        • Sorkin J.D.
        • Katzel L.I.
        • Goldberg A.P.
        • Schwartz A.R.
        • Smith P.L.
        Sleep-disordered breathing and insulin resistance in middle-aged and overweight men.
        Am J Respir Crit Care Med. 2002; 165: 677-682
        • Yang D.
        • Liu Z.
        • Yang H.
        • Luo Q.
        Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis.
        Sleep Breath. 2013; 17: 33-38
        • Botros N.
        • Concato J.
        • Mohsenin V.
        • Selim B.
        • Doctor K.
        • Yaggi H.K.
        Obstructive sleep apnea as a risk factor for type 2 diabetes.
        Am J Med. 2009; 122: 1122-1127
        • Levy P.
        • Bonsignore M.R.
        • Eckel J.
        Sleep, sleep-disordered breathing and metabolic consequences.
        Eur Respir J. 2009; 34: 243-260
        • Spiegel K.
        • Tasali E.
        • Leproult R.
        • Van Cauter E.
        Effects of poor and short sleep on glucose metabolism and obesity risk.
        Nat Rev Endocrinol. 2009; 5: 253-261
        • Aronsohn R.S.
        • Whitmore H.
        • Van Cauter E.
        • Tasali E.
        Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes.
        Am J Respir Crit Care Med. 2010; 181: 507-513
        • Okada M.
        • Takamizawa A.
        • Tsushima K.
        • Urushihata K.
        • Fujimoto K.
        • Kubo K.
        Relationship between sleep-disordered breathing and lifestyle-related illnesses in subjects who have undergone health-screening.
        Intern Med. 2006; 45: 891-896
        • Papanas N.
        • Steiropoulos P.
        • Nena E.
        • Gottlieb D.J.
        • Givelber R.
        • Resnick H.E.
        • et al.
        HbA1c is associated with severity of obstructive sleep apnea hypopnea syndrome in nondiabetic men.
        Vasc Health Risk Manag. 2009; 5: 751-756
        • Steiropoulos P.
        • Papanas N.
        • Bouros D.
        • Maltezos E.
        Obstructive sleep apnea aggravates glycemic control across the continuum of glucose homeostasis.
        Am J Respir Crit Care Med. 2010; 182: 286
        • Schahin S.P.
        • Nechanitzky T.
        • Dittel C.
        • Fuchs F.S.
        • Hahn E.G.
        • Konturek P.C.
        • et al.
        Long-term improvement of insulin sensitivity during CPAP therapy in the obstructive sleep apnoea syndrome.
        Med Sci Monit. 2008; 14: CR117-CR121
        • Lam J.C.
        • Lam B.
        • Yao T.J.
        • Lai A.Y.
        • Ooi C.G.
        • Tam S.
        • et al.
        A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea.
        Eur Respir J. 2010; 35: 138-145
        • Martínez Cerón E.
        • Casitas Mateos R.
        • García-Río F.
        Sleep apnea-hypopnea syndrome and type 2 diabetes. A reciprocal relationship?.
        Arch Bronconeumol. 2015; 51: 128-139
        • Loredo J.S.
        • Ancoli-Israel S.
        • Kim E.J.
        • Lim W.J.
        • Dimsdale J.E.
        Effect of continuous positive airway pressure versus supplemental oxygen on sleep quality in obstructive sleep apnea: a placebo-CPAP-controlled study.
        Sleep. 2006; 29: 564-571
        • Lau E.Y.
        • Eskes G.A.
        • Morrison D.L.
        • Rajda M.
        • Spurr K.F.
        Executive function in patients with obstructive sleep apnea treated with continuous positive airway pressure.
        J Int Neuropsychol Soc. 2010; 16: 1077-1088
        • Babu A.R.
        • Herdegen J.
        • Fogelfeld L.
        • Shott S.
        • Mazzone T.
        Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea.
        Arch Intern Med. 2005; 165: 447-452
        • Shpirer I.
        • Rapoport M.J.
        • Stav D.
        • Elizur A.
        Normal and elevated HbA1C levels correlate with severity of hypoxemia in patients with obstructive sleep apnea and decrease following CPAP treatment.
        Sleep Breath. 2012; 16: 461-466
        • Yang D.
        • Liu Z.
        • Yang H.
        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.
        Diabetes Metab Res Rev. 2012; 28: 499-504
        • Dawson A.
        • Abel S.L.
        • Loving R.T.
        • Dailey G.
        • Shadan F.F.
        • Cronin J.W.
        • et al.
        CPAP therapy of obstructive sleep apnea in type 2 diabetics improves glycemic control during sleep.
        J Clin Sleep Med. 2008; 4: 538-542
        • Harsch I.A.
        • Schahin S.P.
        • Bruckner K.
        • Radespiel-Tröger M.
        • Fuchs F.S.
        • Hahn E.G.
        • et al.
        The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes.
        Respiration. 2004; 71: 252-259
        • Hassaballa H.A.
        • Tulaimat A.
        • Herdegen J.J.
        • Mokhlesi B.
        The effect of continuous positive airway pressure on glucose control in diabetic patients with severe obstructive sleep apnea.
        Sleep Breath. 2005; 9: 176-180
        • Smurra M.
        • Philip P.
        • Taillard J.
        • Guilleminault C.
        • Bioulac B.
        • Gin H.
        CPAP treatment does not affect glucose-insulin metabolism in sleep apneic patients.
        Sleep Med. 2001; 2: 207-213
        • West S.D.
        • Nicoll D.J.
        • Wallace T.M.
        • Matthews D.R.
        • Stradling J.R.
        Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes.
        Thorax. 2007; 62: 969-974
        • Brooks B.
        • Cistulli P.A.
        • Borkman M.
        • Ross G.
        • McGhee S.
        • Grunstein R.R.
        • et al.
        Obstructive sleep apnea in obese noninsulin-dependent diabetic patients: effect of continuous positive airway pressure treatment on insulin responsiveness.
        J Clin Endocrinol Metab. 1994; 79: 1681-1685
        • Hecht L.
        • Mohler R.
        • Meyer G.
        Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis.
        Ger Med Sci. 2011; 9: Doc20
        • Iftikhar I.H.
        • Blankfield R.P.
        Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.
        Lung. 2012; 190: 605-611
        • American Diabetes Association
        Standards of medical care in diabetes—2014.
        Diabetes Care. 2014; 37: S14-S80
      1. 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.

        • Moga C.
        • Guo B.
        • Schopflocher D.
        • Harstall C.
        Development of a Quality Appraisal Tool for Case Series Studies Using a Modified Delphi Technique.
        Edmonton, Alberta, Canada, Institute of Health Economics2012
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Kostopoulos K.
        • Alhanatis E.
        • Pampoukas K.
        • Georgiopoulos G.
        • Zourla A.
        • Panoutsopoulos A.
        • et al.
        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).
        Sleep Breath. 2015; 20: 483-493
        • Pamidi S.
        • Wroblewski K.
        • Stepien M.
        • Sharif-Sidi K.
        • Kilkus J.
        • Whitmore H.
        • et al.
        Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial.
        Am J Respir Crit Care Med. 2015; 192: 96-105
        • Chirinos J.A.
        • Gurubhagavatula I.
        • Teff K.
        • Rader D.J.
        • Wadden T.A.
        • Townsend R.
        • et al.
        CPAP, weight loss, or both for obstructive sleep apnea.
        N Engl J Med. 2014; 370: 2265-2275
        • Yang D.
        • Liu Z.H.
        • Zhao Q.
        • Luo Q.
        Effects of nasal continuous positive airway pressure treatment on insulin resistance and ghrelin levels in non-diabetic apnoeic patients with coronary heart disease.
        Chin Med J (Engl). 2013; 126: 3316-3320
        • Hoyos C.M.
        • Killick R.
        • Yee B.J.
        • Phillips C.L.
        • Grunstein R.R.
        • Liu P.Y.
        Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.
        Thorax. 2012; 67: 1081-1089
        • Murri M.
        • Garcia-Delgado R.
        • Alcazar-Ramirez J.
        • Fernández-Ramos A.
        • Alcaide J.
        • Cardona F.
        • et al.
        Effect of CPAP on oxidative stress and circulating progenitor cell levels in sleep patients with apnea-hypopnea syndrome.
        Respir Care. 2011; 56: 1830-1836
        • Murri M.
        • Garcia-Delgado R.
        • Alcazar-Ramirez J.
        • Fernández de Rota L.
        • Fernández-Ramos A.
        • Cardona F.
        • et al.
        Continuous positive airway pressure therapy reduces oxidative stress markers and blood pressure in sleep apnea-hypopnea syndrome patients.
        Biol Trace Elem Res. 2011; 143: 1289-1301
        • Baburao A.
        • Souza G.D.
        Insulin resistance in moderate to severe obstructive sleep apnea in nondiabetics and its response to continuous positive airway pressure treatment.
        N Am J Med Sci. 2014; 6: 500-504
        • Tasali E.
        • Chapotot F.
        • Leproult R.
        • Whitmore H.
        • Ehrmann D.A.
        Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome.
        J Clin Endocrinol Metab. 2011; 96: 365-374
        • Garcia J.M.
        • Sharafkhaneh H.
        • Hirshkowitz M.
        • Elkhatib R.
        • Sharafkhaneh A.
        Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity.
        Respir Res. 2011; 12: 80
        • Chung S.
        • Yoon I.Y.
        • Lee C.H.
        • Kim J.W.
        The effects of nasal continuous positive airway pressure on vascular functions and serum cardiovascular risk factors in obstructive sleep apnea syndrome.
        Sleep Breath. 2011; 15: 71-76
        • Nena E.
        • Steiropoulos P.
        • Constantinidis T.C.
        • Perantoni E.
        • Tsara V.
        Work productivity in obstructive sleep apnea patients.
        J Occup Environ Med. 2010; 52: 622-625
        • Murri M.
        • Alcazar-Ramirez J.
        • Garrido-Sanchez L.
        • Linde F.
        • Alcaide J.
        • Cardona F.
        • et al.
        Oxidative stress and metabolic changes after continuous positive airway pressure treatment according to previous metabolic disorders in sleep apnea-hypopnea syndrome patients.
        Transl Res. 2009; 154: 111-121
        • Steiropoulos P.
        • Papanas N.
        • Nena E.
        • Tsara V.
        • Fitili C.
        • Tzouvelekis A.
        • et al.
        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?.
        Sleep Med. 2009; 10: 887-891
        • Cuhadaroglu C.
        • Utkusavas A.
        • Ozturk L.
        • Salman S.
        • Ece T.
        Effects of nasal CPAP treatment on insulin resistance, lipid profile, and plasma leptin in sleep apnea.
        Lung. 2009; 187: 75-81
        • Carneiro G.
        • Togeiro S.M.
        • Ribeiro-Filho F.F.
        • Truksinas E.
        • Ribeiro A.B.
        • Zanella M.T.
        • et al.
        Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.
        Metab Syndr Relat Disord. 2009; 7: 537-542
        • Vgontzas A.N.
        • Zoumakis E.
        • Bixler E.O.
        • Lin H.M.
        • Collins B.
        • Basta M.
        • et al.
        Selective effects of CPAP on sleep apnoea-associated manifestations.
        Eur J Clin Invest. 2008; 38: 585-595
        • Trenell M.I.
        • Ward J.A.
        • Yee B.J.
        • Phillips C.L.
        • Kemp G.J.
        • Grunstein R.R.
        • et al.
        Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome.
        Diabetes Obes Metab. 2007; 9: 679-687
        • Czupryniak L.
        • Loba J.
        • Pawlowski M.
        • Nowak D.
        • Bialasiewicz P.
        Treatment with continuous positive airway pressure may affect blood glucose levels in nondiabetic patients with obstructive sleep apnea syndrome.
        Sleep. 2005; 28: 601-603
        • Huang R.
        • Huang X.Z.
        • Wang H.G.
        • Li M.
        • Xiao Y.
        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
        • Harsch I.A.
        • Schahin S.P.
        • Radespiel-Troger M.
        • Weintz O.
        • Jahreiss H.
        • Fuchs F.S.
        • et al.
        Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome.
        Am J Respir Crit Care Med. 2004; 169: 156-162
        • Han M.S.
        • Lim Y.M.
        • Quan W.
        • Kim J.R.
        • Chung K.W.
        • Kang M.
        • et al.
        Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance.
        J Lipid Res. 2011; 52: 1234-1246
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • Naylor B.A.
        • Treacher D.F.
        • Turner R.C.
        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Qu H.Q.
        • Li Q.
        • Rentfro A.R.
        • Fisher-Hoch S.P.
        • McCormick J.B.
        The definition of insulin resistance using HOMA-IR for Americans of Mexican descent using machine learning.
        PLoS One. 2011; 6e21041
        • Ghosh C.
        • Mukhopadhyay P.
        • Ghosh S.
        • Pradhan M.
        Insulin sensitivity index (ISI0, 120) potentially linked to carbon isotopes of breath CO2 for pre-diabetes and type 2 diabetes.
        Sci Rep. 2015; 5: 11959
        • Gutch M.
        • Kumar S.
        • Razi S.M.
        • Gupta K.K.
        • Gupta A.
        Assessment of insulin sensitivity/resistance.
        Indian J Endocrinol Metab. 2015; 19: 160-164
        • Matthews D.R.
        • Hosker J.P.
        • Rudenski A.S.
        • Naylor B.A.
        • Treacher D.F.
        • Turner R.C.
        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
        Diabetologia. 1985; 28: 412-419
        • Qureshi K.
        • Clements R.H.
        • Saeed F.
        • Abrams G.A.
        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.
        J Obes. 2010; 2010
        • Bergman R.N.
        • Prager R.
        • Volund A.
        • Olefsky J.M.
        Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp.
        J Clin Invest. 1987; 79: 790-800
        • Belfiore F.
        Insulin sensitivity indexes calculated from oral glucose tolerance test data.
        Diabetes Care. 2000; 23: 1595-1596
        • Reaven G.M.
        Banting lecture 1988. Role of insulin resistance in human disease.
        Diabetes. 1988; 37: 1595-1607
        • Bonora E.
        • Kiechl S.
        • Willeit J.
        • Oberhollenzer F.
        • Egger G.
        • Meigs J.B.
        • et al.
        Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population: the Bruneck study.
        Diabetes Care. 2007; 30: 318-324
        • Gotoh S.
        • Doi Y.
        • Hata J.
        • Ninomiya T.
        • Mukai N.
        • Fukuhara M.
        • et al.
        Insulin resistance and the development of cardiovascular disease in a Japanese community: the Hisayama study.
        J Atheroscler Thromb. 2012; 19: 977-985