Camilla M. Hoyos

Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study

Rationale and objectives Impaired insulin sensitivity (ISx), increased visceral abdominal fat (VAF) and liver fat are all central components of the metabolic syndrome and characteristics of men with obstructive sleep apnoea (OSA). The reversibility of these observed changes with continuous positive airway pressure (CPAP) treatment in men with OSA has not been systematically studied in a randomised sham-controlled fashion. Methods 65 men without diabetes who were CPAP naïve and had moderate to severe OSA (age=49±12 years, apnoea hypopnoea index (AHI)=39.9±17.7 events/h, body mass index=31.3±5.2 kg/m2) were randomised to receive either real (n=34) or sham (n=31) CPAP for 12 weeks. At 12 weeks, all subjects received real CPAP for an additional 12 weeks. Measurements and main results Main outcomes were the change at week 12 from baseline in VAF, ISx and liver fat. Other metabolic outcomes were changes in the disposition index, total fat, and blood leptin and adiponectin concentrations. The AHI was lower on CPAP compared with sham by 33 events/h (95% CI−43.9 to −22.2, p<0.0001) after 12 weeks. There were no between-group differences at 12 weeks in VAF (−13.0 cm3, −42.4 to 16.2, p=0.37), ISx (−0.13 (min−1)(μU/ml))−1, −0.40 to 0.14, p=0.33), liver fat (−0.5 cm3, −3.8 to 2.7, p=0.74) or any other cardiometabolic parameter. At 24 weeks, ISx (3.2×104 (min−1)(μU/ml))−1, 0.9×104 to 6.0×104, p=0.009), but not VAF (−1.4 cm3, −19.2 to 16.4, p=0.87) or liver fat (−0.2 Hounsfield units, −2.4 to 2.0, p=0.83) were improved compared with baseline in the whole study group. Conclusion Reducing visceral adiposity in men with OSA cannot be achieved with CPAP alone and is likely to require weight-loss interventions. Longer-term effects of CPAP on other cardiometabolic markers such as ISx require further investigation to fully examine time dependencies. Trial Registration Number ACTRN12608000301369.

Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnea: a randomized placebo-controlled trial.

Camilla M Hoyos, Brendon J Yee, Craig L Phillips, Elizabeth A Machan, Ronald R Grunstein and Peter Y Liu Endocrine and Cardiometabolic Research Group and Sleep and Circadian Research Group, NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), Woolcock Institute of Medical Research, University of Sydney, Glebe, Australia, Royal Prince Alfred Hospital, Sydney, Australia, Royal North Shore Hospital, Sydney, Australia and Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, 1000 W Carson Street, Torrance, California 90502, USA

Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo‐controlled trial

High doses of short‐term testosterone have been shown to acutely worsen sleep‐disordered breathing in men with obstructive sleep apnoea (OSA). The effects of lower, near‐conventional doses of testosterone in obese men with OSA may differ over the longer term but have not been systematically studied. We assessed sleep and breathing effects of near‐conventional testosterone treatment as an adjunct to weight loss in obese men with severe OSA.

Down-titration from high-dose combination therapy in asthma: Removal of long-acting β2-agonist

BACKGROUND Asthma guidelines recommend reducing inhaled corticosteroids (ICS) to the minimum effective dose, but the timing of long-acting beta(2)-agonist (LABA) withdrawal is unclear. Recent FDA guidelines recommend LABA withdrawal once asthma is well-controlled. This 13-month double-blind study of patients taking high-dose combination therapy investigated the effect of discontinuation of LABA before ICS down-titration. METHODS Adults using salmeterol/fluticasone combination (SFC) 50/500 microg bd were randomized to SFC 50/500 microg bd or fluticasone propionate (FP) 500 microg bd, with subsequent ICS down-titration 8-weekly using a clinical algorithm. The primary outcome was mean daily FP dose, including ICS for exacerbations. RESULTS 82 subjects were randomized. Asthma was well-controlled at baseline, with mean FEV(1) 84.8% predicted and Asthma Control Questionnaire (ACQ) score 0.9. There was no significant difference in mean daily FP dose (SFC: 721 microg, FP:816 microg, p = 0.3), but final dose was lower with SFC (534 microg cf. 724 microg, p = 0.005). ICS dose was reduced by >or=80% in 41% SFC and 15% FP patients. Ambulatory lung function was significantly higher with SFC, but there were no differences between groups in rescue beta(2)-agonist use, clinic spirometry, airway responsiveness, ACQ, sputum eosinophils or FeNO. Baseline airway responsiveness, and pre-reduction blood eosinophils, were significant predictors of mean daily FP dose and dose reduction failure respectively. CONCLUSIONS Many patients prescribed high-dose combination therapy may be over-treated. Substantial reductions in dose can be achieved with a clinical algorithm, reaching lower FP doses with SFC than FP without losing asthma control or increasing disease activity. TRIAL REGISTRATION This study was commenced before mandatory registration of clinical trials.

Does obstructive sleep apnea cause endothelial dysfunction? A critical review of the literature

Endothelial dysfunction is characterized by impaired endothelium-dependent vasodilatation and is an independent predictor of adverse cardiovascular consequences. The ease with which endothelial function can be assessed has led to it becoming a useful marker of cardiovascular diseases in research studies. Obstructive sleep apnea (OSA) has been independently associated with endothelial dysfunction which may explain the increased risk for cardiovascular and all-cause mortality in this population. One possible mechanism for the development of endothelial dysfunction in OSA is through the cyclical pattern of hypoxia and re-oxygenation. This creates a haemostatic imbalance in which nitric oxide bio-availability is reduced and pro-inflammatory and pro-thrombotic forces prevail. Furthermore the repair capacity of the endothelium to protect itself against this increased damage is diminished. All of these pathways contribute to vascular disease which ultimately gives rise to adverse cardiovascular consequences. This review aims to provide a critical appraisal of the cross-sectional and interventional studies which have investigated micro- and macro-vascular endothelial dysfunction in OSA with emphasis on randomised controlled studies.

Meta-analyses of the Association of Sleep Apnea with Insulin Resistance, and the Effects of CPAP on HOMA-IR, Adiponectin, and Visceral Adipose Fat

OBJECTIVE We sought to conduct an updated meta-analysis of randomized controlled trials (RCTs) on the effect of continuous positive airway pressure (CPAP) on insulin resistance, as measured by homeostasis model assessment of insulin resistance (HOMA-IR), visceral abdominal fat (VAF), and adiponectin. Additionally, we performed a separate meta-analysis and meta-regression of studies on the association of insulin resistance and obstructive sleep apnea (OSA). METHODS All included studies were searched from PubMed (from conception to March 15, 2014). Data were pooled across all included RCTs as the mean difference in HOMA-IR and VAF, and as the standardized mean difference in the case of adiponectin analysis. From the included case-control studies, data on the difference of HOMA-IR between cases and controls were pooled across all studies, as the standardized mean difference (SMD). RESULTS There was a significant difference in HOMA-IR (-0.43 [95% CIs: -0.75 to -0.11], p = 0.008) between CPAP treated and non CPAP treated participants. However, there was no significant difference in VAF or adiponectin; (-47.93 [95% CI: -112.58 to 16.72], p = 0.14) and (-0.06 [95% CI: -0.28 to 0.15], p = 0.56), respectively. Meta-analysis of 16 case-control studies showed a pooled SMD in HOMA-IR of 0.51 (95% CI: 0.28 to 0.75), p ≤ 0.001, between cases and controls. CONCLUSIONS The results of our meta-analyses show that CPAP has a favorable effect on insulin resistance. This effect is not associated with any significant changes in total adiponectin levels or amount of VAF. Our findings also confirm a significant association between OSA and insulin resistance.

The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised, placebo-controlled trial

We recently showed that testosterone therapy worsens sleep‐disordered breathing at 6–7 weeks, but not after 18 weeks, in men with obstructive sleep apnea. Changes in ventilatory chemoreflexes may be responsible. The effect of testosterone on ventilatory chemoreflexes in men with obstructive sleep apnea has not been systematically studied before. Twenty‐one obese men with obstructive sleep apnea, a subgroup of our recent report, were randomised in an 18‐week, randomised, double‐blind, placebo‐controlled, parallel group trial to three intramuscular injections (0, 6, 12 weeks) of either 1000 mg testosterone undecanoate (n = 10) or placebo (n = 11). Awake ventilatory chemoreflex testing was performed before (week 0), during (week 6) and at the end of treatment (week 18) to determine the ventilatory carbon dioxide recruitment threshold and chemosensitivity. Sleep and breathing was assessed by overnight polysomnography at 0, 7 and 18 weeks. Serum hormones levels were measured at every visit. A significant increase in blood testosterone levels (5.65 nmol L−1, 0.51–10.8 nmol L−1, P = 0.03) and lean muscle mass (2.36 kg, 0.8–3.9 kg, P = 0.007) between the two groups was observed as expected. No significant differences were seen in ventilatory chemoreflexes between the two groups at 6 weeks or at 18 weeks. However, positive correlations were observed between changes in serum testosterone and hyperoxic ventilatory recruitment threshold (r = 0.55, P = 0.03), and between changes in hyperoxic ventilatory recruitment threshold and time spent with oxygen saturations during sleep <90% (r = 0.57, P = 0.03) at 6–7 weeks, but not at 18 weeks. Time‐dependent alterations in ventilatory recruitment threshold may therefore mediate the time‐dependent changes in sleep breathing observed with testosterone.

Metabolic and hormonal effects of ‘catch-up’ sleep in men with chronic, repetitive, lifestyle-driven sleep restriction

Acutely restricting sleep worsens insulin sensitivity in healthy individuals whose usual sleep is normal in duration and pattern. The effect of recovery or weekend ‘catch‐up’ sleep on insulin sensitivity and metabolically active hormones in individuals with chronic sleep restriction who regularly ‘catch‐up’ on sleep at weekends is as yet unstudied.

Effect of CPAP on the metabolic syndrome: a randomised sham-controlled study

A recently published editorial1 concluded that severity of disease, Continuous Positive Airway Pressure (CPAP) compliance and comorbidities might explain discrepancies between a randomised sham-controlled crossover study2 which showed that CPAP reversed metabolic syndrome (metS) and reduced weight, body mass index (BMI) and visceral abdominal fat and our findings from a randomised sham-controlled parallel-group study.3 Whether CPAP might be a novel method to reverse metS in those with Obstructive Sleep Apnea (OSA) is an intriguing possibility, since diagnosing and treating metS is important.1 We omitted to examine the effect of CPAP on metS in our population, a typical OSA cohort with treated long-standing metabolic comorbidites and less than ideal CPAP usage.1 To rectify this, we retrospectively assayed stored blood …

Effects of continuous positive airway pressure on endothelial function and circulating progenitor cells in obstructive sleep apnoea: A randomised sham-controlled study

OBJECTIVE Obstructive sleep apnoea (OSA) is characterised by reoccurring apnoeas and hypopneas, causing repetitive hypoxia and reoxygenation, and is associated with endothelial dysfunction and reduced levels of circulating progenitor cells (CPCs). The potential to improve endothelial function and CPC levels in people with OSA by preventing hypoxic episodes with Continuous Positive Airway Pressure (CPAP) was investigated in a sham-controlled CPAP study. METHODS Men with moderate-to-severe OSA (mean ± SD: age=49 ± 12 y, apnoea hypopnea index (AHI)=37.6 ± 16.4 events/h, body mass index=31.5 ± 5.7 kg/m(2)) who were CPAP naïve without diabetes mellitus were randomised in a 12-week double-blind sham-controlled parallel group study to receive either active (n=25) or sham (n=21) CPAP. CPCs, isolated from blood, were measured by flow cytometry and by co-staining cultured cells (7 days) with acetylated low-density lipoprotein (acLDL) and lectin. Endothelial function was assessed by peripheral arterial tonometry (PAT). RESULTS Compared to sham, CPAP significantly decreased AHI (mean between-group difference -36.0 events/h; 95%CI, -49.7 to -22.3, p<0.0001) after 12 weeks. Despite this improvement in AHI, CPAP had no effect on change in CPC levels (including CD34(+)/KDR(+) (565 cells/mL; -977 to 2106, p=0.45), CD34(+)/KDR(+)/CD45(-) (37.0 cells/mL; -17.7 to 85.7, p=0.13), acLDL(+)/lectin(+) (-43.1 cells/field, -247 to 161, p=0.67)) or change in endothelial function (0.27; -0.14 to 0.67, p=0.19) compared to sham therapy. CONCLUSIONS Despite the improvement in OSA parameters and ablation of apnoeic events by CPAP, CPC counts and endothelial function in men with moderate-to-severe OSA were not significantly improved after 12 weeks of therapeutic CPAP when compared to sham control.