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Abstract

Obstructive sleep apnoea (OSA) is very common in patients with Type 2 diabetes (T2D), which is not surprising considering that obesity is a common risk factor for both conditions. In general population studies, OSA has been shown to be associated with several comorbidities including increased risk of road traffic accidents, T2D, hypertension and lack of nocturnal dipping of blood pressure, hyperlipidaemia, increased inflammation, increased risk of cardiovascular disease and mortality, increased risk of atrial fibrillation, worse quality of life, and erectile dysfunction. However, the impact of OSA on diabetes-related vascular and metabolic outcomes remains unclear. Furthermore, the impact of continuous positive airway pressure (CPAP) treatment in patients with T2D is also unclear. This unclarity regarding the impact of OSA and CPAP in patients with T2D has possibly contributed to the lack of screening for OSA in patients with T2D in the UK despite the high prevalence of OSA in patients with T2D. In this commentary, I provide an overview about OSA with a particular focus on its role and impact in patients with T2D.

Keywords

Type 2 diabetes obstructive sleep apnoea neuropathy retinopathy chronic kidney disease hypertension cardiovascular disease continuous positive airway pressure

Introduction

Obstructive sleep apnoea (OSA) is a common medical disorder. While earlier estimates suggested a 4% prevalence in men and 2% prevalence in women, more recent studies indicate a prevalence of 17%–26% of men and 9%–28% of women.¹ This increase in OSA prevalence is likely to reflect the global increase in obesity, which is a major risk factor of OSA,^2,3 and/or may reflect higher awareness of this condition leading to increased diagnosis.

As obesity is a common risk factor for OSA and type 2 diabetes (T2D), it is not surprising that these conditions commonly co-exist.^2,4 The prevalence of OSA is high in people with T2D (8.5%–86%, with 23.8%–70% for moderate-to-severe OSA);^3–10 the variation in OSA prevalence between studies is due to multiple factors including differences in studies populations (e.g. primary care vs secondary care), the methods of diagnosing OSA (polysomnography vs portable devices) and the criteria used to diagnose OSA [apnoea hypopnoea index (AHI) of 5 vs 10 vs 15 or using the oxygen desaturations index rather than AHI]. Similarly, the prevalence of T2D is high patients with OSA (15%–30%).¹¹ As a result, the International Diabetes Federation (IDF) recommended in 2008 routine screening for OSA in patients with T2D,¹² but despite the IDF statement, a recent survey in the United Kingdom showed that two-thirds of diabetes healthcare professionals were unaware of these recommendations and only 19% had the local diabetes guidelines incorporated assessment for OSA in those at risk.¹³

This lack of OSA screening in patients with T2D might be related to the reduced awareness of the associations between OSA and T2D and might also reflect the lack of clear screening strategies and clinical pathways that inform practicing clinicians who to screen, how to screen, what to do after screening and how often to screen. Screening for OSA is further complicated by the fact that many of the symptoms that can be attributed to OSA can also be attributed to diabetes (see below), which makes identifying patients purely on clinical grounds more difficult. Furthermore, there is lack of data regarding the clinical, metabolic and economic impacts of OSA in patients with T2D, the cost-effectiveness of OSA screening and treatment in diabetes and the impact of OSA treatment on diabetes-related outcomes; these issues can make it difficult to justify routine screening for OSA.¹⁴

OSA overview

OSA is characterised by upper airway instability during sleep which results in recurrent episodes of complete or partial upper airway obstruction that leads to recurrent episodes of either complete (apnoea) or partial (hypopnoea) cessation of airflow.¹⁵ These apnoea and hypopnoea events usually result in altered intrathoracic pressure and increased breathing efforts as the patient attempts to breath against a blocked upper airway; this leads to a brief awakening (microarousal) and restoration of upper airway patency with termination of the apnoea/hypopnoea event.^2,4 Following restoration of upper airway patency, the same cycle of events will repeat itself resulting in recurrent oxygen desaturations. These cyclical changes in intrathoracic pressure and recurrent microarousals result in sleep fragmentation and disruption of sleep architecture [loss of deep sleep and rapid eye movement (REM) sleep], which in part contribute to the excessive daytime sleepiness (EDS) observed in patients with OSA.¹⁵ In addition to the above-mentioned changes, the apnoea/hypopnoea events are frequently associated with cyclical changes in blood pressure (BP), heart rate and sympathetic activity.¹⁵

Polysomnography (that typically records 12–16 channels) remains the gold standard for diagnosing OSA.¹⁵ However, as polysomnography is time-consuming, resourceful, expensive and requires a hospital stay overnight, other alternatives have been developed. Portable home-based cardio-respiratory Type III devices (typically recording 4–7 channels) are widely used in clinical practice as well as research, and their use is supported by the latest statement from the American Academy of Sleep Medicine (AASM).¹⁶ Type III portable devices have a sensitivity and specificity of 87%–96% and 60%–76%, respectively, to diagnose OSA defined AHI ⩾5 events/hour and 49%–92% and 79%–95%, respectively, for OSA diagnosed as AHI ⩾15 events/hour.¹⁷

Clinically, OSA is associated with a variety of non-specific symptoms. Snoring is the most common symptom, occurring in 95% of patients with only 6% of OSA patients (or their partners) not reporting any snoring. However, it has a poor positive predictive value due to the high prevalence of snorers who don’t have OSA.¹⁵ Witnessed apnoeas can be reported by the partner but they do not correlate with disease severity and can occur in up to 6% of the ‘normal’ population without OSA.¹⁵ EDS is another important feature of OSA, but many OSA patients do not suffer from EDS, at least if measured using the Epworth Sleepiness Scale (ESS). Other OSA symptoms include choking, insomnia, nocturia, sweating, fatigue, morning headaches, erectile dysfunction and autonomic symptoms.^15,18 However, many of the above-mentioned OSA-related symptoms are either common in patients without OSA or can be attributed to a diabetes-related cause such as hyperglycaemia, hypoglycaemia, diabetic neuropathy, cardiovascular disease (CVD) or drug-related adverse events, which makes it difficult to suspect OSA on clinical grounds only in patients with T2D.

OSA is associated with several comorbidities including increased risk of road traffic accidents, incipient hypertension and lack of nocturnal dipping of BP, hyperlipidaemia, increased inflammation, increased risk of CVD and mortality, increased risk of atrial fibrillation, worse quality of life and erectile dysfunction.^{1,10,17,19–28}

Continuous positive airway pressure (CPAP) is the mainstay treatment for moderate to severe OSA. CPAP usage for ⩾4 h/night resulted in reduction of the risk of road traffic accidents.²⁹ In a recent meta-analysis of randomised controlled trials (RCTs), CPAP (compared to sham) was associated with reduction of AHI [weighted mean difference (WMD), −33.8, 95% confidence interval (CI): −42.0 to −25.6]; ESS (−2.0, 95% CI: −2.6 to −1.4); diurnal systolic BP (−2.4, 95% CI: −3.9 to −0.9) and diurnal diastolic BP (−1.3, 95% CI: −2.2 to −0.4) and improved quality of life.¹⁷ One RCT showed that 4 weeks of CPAP improved cognitive function following a stroke compared rehabilitation treatment.³⁰ Lifestyle and dietary interventions and the use of mandibular advancement devices were also associated with significant improvements in AHI and ESS, but the effect sizes were smaller than CPAP.^17,31 Bariatric surgery has also been shown to result in a significant reduction in AHI (weighted decrease 29/h; 95% CI: 22.41 to 36.74).³² Despite the favourable impact of CPAP on BP and erectile dysfunction when compared to placebo, it was less efficacious in treating erectile dysfunction and hypertension than sildenafil^33–36 and valsartan,³⁷ respectively.

It must be emphasised that while CPAP is the ‘gold-standard’ treatment for patients with OSA in terms of the impact on AHI and EDS, weight loss also has a major role, particularly as it reduces CVD while the evidence for CPAP in altering vascular events is based on observational studies rather than RCTs. In addition, the combination of CPAP and weight loss has been shown to have greater impact on some cardiovascular risk factors compared to CPAP alone.^38,39

In the United Kingdom, National Institute for Health and Care Excellence (NICE) recommended the use of CPAP in patients with moderate to severe OSA with EDS (https://www.nice.org.uk/guidance/ta139/chapter/1-Guidance); but despite NICE guidance, the availability and delivery of OSA services vary considerably across the United Kingdom (https://www.blf.org.uk/sites/default/files/OSA_Toolkit_2015_BLF_0.pdf).

OSA and T2D: a chicken and egg?

As highlighted above, OSA and T2D commonly co-exist, but is there a causative relationship between the two conditions and, if so, which one comes first? Most of the literature is focussed on examining the impact of OSA on incident T2D. Indeed, several longitudinal studies and meta-analyses have shown that OSA is a risk factor for the development of T2D independent of obesity and other traditional risk factors [relative risk (RR), 1.4–1.63 depending on the study].^2,10,40,41 It is plausible that OSA can lead to the development of T2D as OSA is associated with insulin resistance and β-cell dysfunction; this relationship is mediated by several neurohormonal and inflammatory mechanisms and increased oxidative stress.^2,10,42 However, whether CPAP treatment might reduce the incidence of T2D is awaiting the results of ongoing RCTs, but early evidence suggests potential benefit. In one recent RCT, 8 h of CPAP reduced the area under the curve for the 2-h overall glucose response during oral glucose tolerance test (OGTT) compared to placebo and improved insulin sensitivity, 24-h BP and norepinephrine levels.⁴³ Nonetheless, this study was small (n = 39), of short duration (2 weeks) and was conducted in laboratory environment to ensure high compliance with CPAP under direct supervision which might prove difficult to achieve in real life. In another RCT in patients with severe OSA but without diabetes, CPAP for 12 weeks reversed impaired glucose tolerance in 9/42 patients versus 5/38 patients in the life style counselling group (p = 0.039) without any changes in weight or Homeostatic model assessment- insulin resistance (HOMA-IR).⁴⁴ In another observational study, the incidence of T2D over a median of 5 months was lower in patients who had outstanding (⩾90% of nights and 8 h/night), excellent (⩾80% nights and ⩾6 h/night) and good (⩾70% nights and ⩾4 h/night) compliance with CPAP compared to those who were non-adherent to CPAP (0%, 0%, 0.8% and 4%, respectively).⁴⁵ The impact of OSA on dysglycaemia, insulin resistance and beta-cell dysfunction is mediated by multiple mechanisms including increased oxidative stress, sympathetic overactivity, activation of the hypothalamic pituitary adrenal access, increased inflammation and adipokine changes; most of which is improved by CPAP.⁴²

On the other hand, it is also plausible that T2D might also be a risk factor for OSA or worsening of pre-existing OSA, but this has not been explored widely in the literature. One longitudinal study showed that baseline HOMA-IR was an independent predictor of incident witnessed apnoeas [odds ratio (OR): 1.31, 95% CI: 1.13–1.51] after adjustment for age, sex and waist circumference over a period of 6 years.⁴⁶ Other independent predictors of witnessed sleep apnoeas included waist circumference, triglycerides levels and smoking.⁴⁶ All these factors are common in patients with T2D and hence might increase the risk of developing apnoeas and OSA in patients with T2D. In addition, the weight gain that occurs in patients with T2D with treatment intensification might result in the development of, or worsening of pre-existing, OSA,^47–49 while weight loss in patients with T2D improved AHI in a longitudinal study.⁵⁰ Furthermore, the development of autonomic neuropathy in patients with T2D might have an impact on upper airway innervation and collapsibility, ventilatory drive and central respiratory centre responses to hypercapnic stimulus, all of which contribute to the pathogenesis of OSA.^51,52

It is likely that the relationship between OSA and T2D is bidirectional and that each of these conditions can contribute to the development or worsening of the other. However, understanding this complex relationship is important to develop the appropriate screening and treatment strategies. While both conditions (OSA and T2D) are associated with similar comorbidities [such as hypertension, CVD, hyperlipidaemia and chronic kidney disease (CKD)], whether the impact of having both conditions (i.e. OSA and T2D) on CVD and other comorbidities is greater than having either OSA or T2D alone is the focus of several ongoing studies. In addition, the impact of OSA on the above-mentioned comorbidities in patients with T2D might differ whether OSA was present before or developed after the onset of T2D. In OSA patients who subsequently develop T2D, it is possible that the combination of OSA and T2D results in greater impact on diabetes-related outcomes and intervention targeting OSA might produce larger benefits as the diabetes-related comorbidities are still at earlier stages of development with the potential of reversibility. On the other hand, if OSA developed after the onset of diabetes, then targeting OSA might produce less effects as many complications have already been established and therefore less likely to reverse. However, these hypotheses remain to be examined and explored in ongoing studies and trials.

OSA and glycaemic control in T2D

OSA has been linked to worse glycaemic measures (such as HbA1c, fasting plasma glucose or glucose variability) following adjustment for a wide range of confounders in several cross-sectional studies.^2,4,53 However, though biologically plausible, causality between OSA and worse glycaemic control has not been proven as yet due to the lack of longitudinal studies and the conflicting results of clinical trials. The impact of OSA on HbA1c ranged between 0.7% and 3.69%; this variation between studies is likely to be due to methodological differences and variability in OSA severity between studies.^2,4,53

Overall, uncontrolled studies of short duration (⩾4 months) showed that CPAP improved glycaemic variability, postprandial glucose levels and HbA1c in patients with T2D, but RCTs did not overall show such benefits.^2,4,53 In a small RCT of 42 men with T2D and OSA who were randomised to CPAP versus sham CPAP, 3 months of treatment did not show any impact of CPAP on HbA1c but CPAP compliance was poor, preventing definitive conclusions.⁵⁴ In a more recent study of patients with T2D and moderate to severe OSA in which 298 patients were randomised to CPAP versus usual care, CPAP again failed to show an impact on HbA1c but glucose control was fairly good at baseline (HbA1c 7.3%), which may have contributed to the negative findings.⁵⁵ In contrast, another RCT in which 50 patients with T2D and OSA were randomised to CPAP versus no CPAP for 6 months, CPAP resulted in greater HbA1c reductions compared to no CPAP (between group adjusted difference, −0.4%; 95% CI: −0.7 to −0.04, p = 0.029). Of note, the compliance in this study was good with average CPAP usage of 5.2 h per night.⁵⁶ The conflicting results of these studies might be related to multiple factors including differences in CPAP compliance, baseline glycaemic control and the reserve in β-cell function. Other factors related to OSA might also play an important part; for example, some studies showed that the impact of CPAP might be greater in patients with OSA and EDS versus OSA but not EDS,⁵⁷ whereas others showed that the relation between OSA and glycaemic measures mainly relate to apnoea/hypopnoea events that occur in REM sleep compared to non-REM sleep.⁵⁸ Further large RCTs that will include patients in the early stages of T2D and that consider factors such as EDS and REM-related AHI and in which CPAP compliance is high are still needed to answer the question whether CPAP treatment improves glycaemic control in patients with T2D.

OSA and hypertension

Epidemiological studies and RCTs have shown a causal link between OSA and incident hypertension and non-dipping BP and that CPAP lowered BP compared to no CPAP or sham CPAP but the impact of CPAP was less than that of valsartan in one RCT (Table 1).^21,37,59 However, data in patients with T2D are limited. In an observational retrospective cohort study in patients with OSA and T2D, CPAP was associated with improvements in systolic (−6.81, 95% CI: −9.94 to −3.67 mmHg) and diastolic (−3.69, 95% CI: −5.53 to −1.85 mmHg) BP over 9–12 months period.⁶⁰ Similar reductions in BP levels were found after 3 months of CPAP in a RCT in which patients were randomised to early (<1 week) or late (1–2 months)⁶¹ intervention.

Table 1.

Summary of the evidence regarding the relationships between OSA and diabetes-related macro- and microvascular complications and the impact of CPAP.

	Relationship with OSA		Impact of CPAP
	In general population studies	In patients with T2D	In general population studies	In patients with T2D
Hypertension	Observational cross-sectional and longitudinal studies and interventional trials	Limited but similar to patients without T2D	Favourable impact based on multiple RCTs	Favourable impact based on limited RCTs
Cardiovascular disease	Observational cross-sectional and longitudinal studies	Observational cross-sectional study showed an association with stroke Longitudinal observational study showed association with the development of coronary artery disease and heart failure	Observational studies showing favourable impact of CPAP. No evidence from RCTs	Unknown
Mortality	Observational longitudinal studies	Unknown	Observational studies	Unknown
Chronic kidney disease	Observational cross-sectional and longitudinal studies	Mostly observational cross-sectional studies and limited longitudinal studies	Favourable impact on albuminuria and renal function mainly from limited non-randomised trials and 1 pilot RCT	One observational study suggests favourable impact on renal function
Peripheral neuropathy	Observational cross-sectional studies and limited longitudinal studies and non-randomised interventional trial	Observational cross-sectional study	Favourable impact based on a non-randomised trial	Unknown
Retinopathy	None available	Observational cross-sectional and 1 longitudinal study	None available	Observational study and a non-randomised trial showed favourable impact

OSA: obstructive sleep apnoea; CPAP: continuous positive airway pressure; T2D: type 2 diabetes; RCT: randomised controlled trial.

OSA and CVD

In general population studies, several cross-sectional and longitudinal studies showed a link between OSA and CVD (Table 1). Based on intravascular ultrasound and CT coronary angiogram, OSA and AHI were found to be associated with a larger atherosclerotic plaque volume.^62,63 In addition, a study found a diurnal variation in the occurrence of acute myocardial infarction in that patients with OSA were at increased risk of acute myocardial infarction overnight (midnight to 6 am) compared to those without OSA, suggesting a possible role for the nocturnal OSA-associated events in the development of CVD.⁶⁴ Longitudinal observational studies have shown increased risk of incident CVD and mortality in patients with OSA compared to those without OSA over 3–10 years [adjusted OR/hazard ratio (HR) for incident CVD of 1.97–4.9] and that CPAP treatment was associated with lower vascular events and mortality.^{22–24,65–69} While this looks encouraging, there is no evidence from RCTs that CPAP lowered mortality or CVD.^17,70,71 However, most of these RCTs were ⩾12 weeks duration and only one showed a follow-up of more than 1 year; therefore, the number of vascular events and mortality was small.

Data regarding the impact of OSA on CVD in diabetes are rather limited. In the SleepAhead study, AHI was associated with history of stroke (adjusted OR, 2.57; 95% CI: 1.03–6.42), but not coronary artery disease.⁷² OSA was found to predict incident coronary artery disease (adjusted HR, 2.2; 95% CI: 1.2–3.9; p = 0.01) and heart failure (adjusted HR, 3.5; 95% CI: 1.4–9.0; p < 0.01) in 132 patients with T2D and a normal baseline exercise echocardiography test over a median follow-up of 4.9 years.⁷³ It remains unclear, however, whether treating OSA in these patients alters vascular outcome or heart failure in this high-risk population.

OSA and microvascular complications in T2D

OSA shares many of its molecular consequences with hyperglycaemia which can lead to microvascular complications in patients with T2D (Table 1). OSA can result in increased oxidative stress and nitrosative stress, poly (ADP-ribose) polymerase (PARP) activation, increased advanced glycation end-products (AGE), protein kinase C (PKC) activation, inflammation and endothelial dysfunction in patients with and without T2D,^2,53,74,75 all of which are involved in the pathogenesis of microvascular complications in T2D.⁷⁶

OSA and retinopathy

During darkness, retinal oxygen demand increases and in the context of diabetes the retina cannot meet the added metabolic load imposed by the dark-adapted rod photoreceptors. This exacerbates retinal hypoxia and results in vascular endothelial growth factor (VEGF) secretion, with the consequent development of diabetic retinopathy (DR).⁷⁷ Hence, it is plausible that the presence of OSA, with recurrent nocturnal oxygen desaturations, might increase the burden of nocturnal hypoxia on the retina and might result in the development or progression of DR.

OSA is not known to be associated with retinal changes similar to DR in patients without diabetes. However, OSA has been associated with several retinal and ocular manifestations. In one study, an increase of respiratory disturbance index (RDI) from 0 to 10 was associated with a decrease in arteriole-to-venule ratio of 0.01.⁷⁸ Other retinal changes described in OSA included retinal arteriolar narrowing and venular widening or branch retinal vein occlusion.^79,80

In patients with T2D, the relationship between OSA and DR is complex and the results of multiple studies were inconsistent; this is, in part, due to the poor methodology of some of the available literature. A recent systematic review found that out of 16 studies that examined the relationship between OSA and DR, 15 were cross-sectional in nature and 1 cohort study,⁸¹ which highlights the need for more robust studies in this area. The above-mentioned systematic review showed that the cross-sectional associations between OSA and retinal microvascular changes were inconsistent, but there seems to be an association between OSA and more advanced DR such as pre-proliferative DR, proliferative DR and maculopathy.⁸¹

Our own data (currently undergoing peer review) showed that OSA was associated with sight-threatening DR and maculopathy, but not with background DR in a cross-sectional analysis. However, longitudinally, we found that OSA was an independent predictor of the development of pre-/proliferative DR in patients with T2D after adjustment for confounders.

So overall, the development of DR in its earlier stages seems to be dependent on the presence of diabetes, and OSA appears to enhance progression of DR into sight-threatening retinopathy through the development of pre-proliferative and proliferative changes.

Whether CPAP has an impact on DR treatment and/or progression remains to be seen with several ongoing RCTs in this area. Our unpublished data showed that the progression to pre-proliferative or proliferative DR was less in OSA patients who were CPAP compliant compared with those who were not compliant. In an uncontrolled, hypothesis generating study, CPAP for 6 months was associated with improvement in visual acuity without an impact on macular oedema/thickness, suggesting improved functionality rather than actual change in the oedema.⁸² Interestingly, the presence of OSA might affect the response to DR treatment as was shown by one study in which poor response to anti-VEGF therapy with bevacizumab (Avastin) was associated with higher prevalence of OSA in patients with diabetic macular oedema and age-related macular degeneration;⁸³ whether CPAP can improve the response to DR treatment requires future studies.

OSA and diabetes CKD

In patients without diabetes, OSA has been associated with CKD in cross-sectional and longitudinal studies.^2,53,84,85 Small studies of short duration suggested potential beneficial effects of CPAP on albuminuria and renal function.^86–89 In patients with T2D, a cross-sectional study of Japanese patients, Oxygen desaturation Index (ODI) ⩾5 was independently associated with microalbuminuria in women but not in men after adjustment for confounders.⁹⁰ In another cross-sectional study from the United Kingdom, OSA was associated with CKD in patients with T2D (adjusted OR, 2.64; 95% CI: 1.13–6.16; p = 0.02).⁹¹ Longitudinally, OSA was associated with greater decline in estimated glomerular filtration rate (eGFR) compared to patients without OSA. Moreover, OSA was an independent predictor of study-end eGFR and eGFR decline after adjustment for potential confunders.⁹¹ The impact of CPAP on CKD in patients with diabetes is unclear, but in a longitudinal study, eGFR decline was lowered in patients with OSA who were compliant with CPAP;⁹¹ ongoing RCTs will help to answer this point.

OSA and peripheral neuropathy

In patients without diabetes, OSA and nocturnal hypoxia were associated with peripheral neuropathy (based on nerve conduction studies) independent of age and obesity.^92,93 Moreover, one small study demonstrated that OSA was associated with axonal dysfunction and that 6 months of CPAP improved the amplitude of action potentials.⁹⁴ Data in patients with T2D are limited with one cross-sectional study showing that OSA was associated with foot insensitivity and clinically evident diabetic peripheral neuropathy, independent of potential confounders.⁹⁵ In addition, OSA was independently associated with lower intra-epidermal nerve fibre density (based on skin biopsies) in patients with T2D compared to those without OSA.⁷⁵ Furthermore, patients with OSA were more likely to have a history of foot ulceration⁷⁵ and one case series suggested that CPAP might aid the healing of foot ulceration in patients with diabetes.⁹⁶

OSA and other diabetes-related outcomes

OSA has been associated with worse quality of life and erectile dysfunction which can be improved by CPAP, but data in patients with T2D are lacking.¹⁰

Summary and conclusion

OSA is a common condition and is associated with EDS, road traffic accidents, hypertension, worse glycaemic control, hypertension, CVD, diabetes-related microvascular complications, erectile dysfunction, impaired quality of life and increased mortality. CPAP treatment improves EDS and other OSA-related symptoms, has favourable impact on BP and lowers the risk of road traffic accidents, but there is currently no evidence from RCTs that CPAP can lower CVD or mortality.

OSA is very common in patients with T2D. The impact of OSA and CPAP in patients with T2D is still unclear with most studies having a cross-sectional nature. The limited number of longitudinal studies suggests that OSA is associated with hypertension, CVD, advanced DR and CKD in patients with T2D. Most RCTs of OSA in the context of T2D were focussed on glycaemic control and the results are conflicting, but ongoing RCTs are assessing the impact of CPAP on other diabetes-related outcomes.

While the impact of OSA and its treatment in patients with T2D remains to be fully explored, it is important to consider OSA in patients who have OSA-related symptoms such as EDS as CPAP treatment can improve symptoms. In addition, considering the increased risk of road traffic accidents in some patients with T2D, it is important to consider the contribution of OSA to this risk as CPAP might have a beneficial impact in this context. How to screen, the frequency of screening and the cost-effectiveness for screening for OSA in patients with T2D are questions that remain to be answered.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

A.A.T. is a clinician scientist supported by the National Institute for Health Research in the United Kingdom. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health.

References

Young

Peppard

Gottlieb

DJ.

Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165: 1217–1239.

Tahrani

AA.

Diabetes and sleep apnea. In: DeFronzo

Ferrannini

Zimmet

. (eds) International textbook of diabetes mellitus. New York: John Wiley & Sons, 2015, pp. 316–336.

Amin

Ali

Altaf

. Prevalence and associations of obstructive sleep apnea in South Asians and white Europeans with type 2 diabetes: a cross-sectional study. J Clin Sleep Med 2017; 13: 583–589.

Tahrani

Ali

Stevens

MJ.

Obstructive sleep apnoea and diabetes: an update. Curr Opin Pulm Med 2013; 19: 631–638.

West

Nicoll

Stradling

JR.

Prevalence of obstructive sleep apnoea in men with type 2 diabetes. Thorax 2006; 61: 945–950.

Foster

Sanders

Millman

. Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care 2009; 32: 1017–1019.

Lam

DCL

Lui

MMS

Lam

JCM

. Prevalence and recognition of obstructive sleep apnea in Chinese patients with type 2 diabetes mellitus. Chest 2010; 138: 1101–1107.

Heffner

Rozenfeld

Kai

. Prevalence of diagnosed sleep apnea among patients with type 2 diabetes in primary care. Chest 2012; 141: 1414–1421.

Lecomte

Criniere

Fagot-Campagna

. Underdiagnosis of obstructive sleep apnoea syndrome in patients with type 2 diabetes in France: ENTRED 2007. Diabetes Metab 2013; 39: 139–147.

10.

Tahrani

AA.

Obstructive sleep apnoea: a diabetologist’s perspective. Br J Diabetes 2016; 16: 107–113.

11.

Pamidi

Tasali

Obstructive sleep apnea and type 2 diabetes: is there a link?

Front Neurol 2012; 3: 126.

12.

Shaw

Punjabi

Wilding

. Sleep-disordered breathing and type 2 diabetes: a report from the International Diabetes Federation Taskforce on Epidemiology and Prevention. Diabetes Res Clin Pract 2008; 81: 2–12.

13.

Seetho

O’Brien

Hardy

. Obstructive sleep apnoea in diabetes-assessment and awareness. Br J Diabetes Vasc Dis 2014; 14: 105–108.

14.

Turnbull

Stradling

To screen or not to screen for obstructive sleep apnea, that is the question. Sleep Med Rev. Epub ahead of print 22 March 2017. DOI: 10.1016/j.smrv.2017.03.002.

15.

McNicholas

WT.

Diagnosis of obstructive sleep apnea in adults. Proc Am Thorac Soc 2008; 5: 154–160.

16.

Kapur

Auckley

Chowdhuri

. Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2017; 13: 479–504.

17.

Jonas

Amick

Feltner

. Screening for obstructive sleep apnea in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA 2017; 317: 415–433.

18.

Martin

Atlantis

Lange

. Predictors of sexual dysfunction incidence and remission in men. J Sex Med 2014; 11: 1136–1147.

19.

Horne

Reyner

LA.

Sleep related vehicle accidents. BMJ 1995; 310: 565–567.

20.

Young

Blustein

Finn

. Sleep-disordered breathing and motor vehicle accidents in a population-based sample of employed adults. Sleep 1997; 20: 608–613.

21.

Hla

Young

Finn

. Longitudinal association of sleep-disordered breathing and nondipping of nocturnal blood pressure in the Wisconsin Sleep Cohort Study. Sleep 2008; 31: 795–800.

22.

Peker

Hedner

Norum

. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up. Am J Respir Crit Care Med 2002; 166: 159–165.

23.

Marin

Carrizo

Vicente

. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005; 365: 1046–1053.

24.

Yaggi

Concato

Kernan

. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353: 2034–2041.

25.

Punjabi

Caffo

Goodwin

. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009; 6: e1000132.

26.

Young

Finn

Peppard

. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008; 31: 1071–1078.

27.

Cadby

McArdle

Briffa

. Severity of OSA is an independent predictor of incident atrial fibrillation hospitalization in a large sleep-clinic cohort. Chest 2015; 148: 945–952.

28.

Lee

Sethi

. Obstructive sleep apnea and cardiovascular events after percutaneous coronary intervention. Circulation 2016; 133: 2008–2017.

29.

Karimi

Hedner

Häbel

. A sleep apnea-related risk of motor vehicle accidents is reduced by continuous positive airway pressure: Swedish traffic accident registry data. Sleep 2014; 38: 341–349.

30.

Aaronson

Hofman

van Bennekom

. Effects of continuous positive airway pressure on cognitive and functional outcome of stroke patients with obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med 2016; 12: 533–541.

31.

Iftikhar

Bittencourt

Youngstedt

. Comparative efficacy of CPAP, MADs, exercise-training, and dietary weight loss for sleep apnea: a network meta-analysis. Sleep Med 2017; 30: 7–14.

32.

Ashrafian

Toma

Rowland

. Bariatric surgery or non-surgical weight loss for obstructive sleep apnoea? A systematic review and comparison of meta-analyses. Obes Surg 2015; 25: 1239–1250.

33.

Hoyos

Melehan

Phillips

. To ED or not to ED – is erectile dysfunction in obstructive sleep apnea related to endothelial dysfunction? Sleep Med Rev 2015; 20: 5–14.

34.

Perimenis

Karkoulias

Markou

. Erectile dysfunction in men with obstructive sleep apnea syndrome: a randomized study of the efficacy of sildenafil and continuous positive airway pressure. Int J Impot Res 2004; 16: 256–260.

35.

Perimenis

Karkoulias

Konstantinopoulos

. Sildenafil versus continuous positive airway pressure for erectile dysfunction in men with obstructive sleep apnea: a comparative study of their efficacy and safety and the patient’s satisfaction with treatment. Asian J Androl 2007; 9: 259–264.

36.

Dong

Wan

. Sildenafil versus continuous positive airway pressure for erectile dysfunction in men with obstructive sleep apnea: a meta-analysis. Aging Male 2010; 13: 82–86.

37.

Pépin

Tamisier

Barone-Rochette

. Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010; 182: 954–960.

38.

Hudgel

DW.

Critical review: CPAP and weight management of obstructive sleep apnea cardiovascular co-morbidities. Sleep Med Rev. Epub ahead of print 18 December 2016. DOI: 10.1016/j.smrv.2016.12.001.

39.

Chirinos

Gurubhagavatula

Teff

. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med 2014; 370: 2265–2275.

40.

Wang

Zhang

. Obstructive sleep apnoea and the risk of type 2 diabetes: a meta-analysis of prospective cohort studies. Respirology 2013; 18: 140–146.

41.

Anothaisintawee

Reutrakul

Van Cauter

. Sleep disturbances compared to traditional risk factors for diabetes development: systematic review and meta-analysis. Sleep Med Rev 2016; 30: 11–24.

42.

Tahrani

Ali

Obstructive sleep apnoea and type 2 diabetes. Eur Endocrinol 2014; 10: 43–50.

43.

Pamidi

Wroblewski

Stepien

. Eight hours of nightly CPAP treatment of obstructive sleep apnea improves glucose metabolism in prediabetes. A randomized controlled trial. Am J Respir Crit Care Med 2015; 192: 96–105.

44.

Salord

Fortuna

Monasterio

. A randomized controlled trial of continuous positive airway pressure on glucose tolerance in obese patients with obstructive sleep apnea. Sleep 2016; 39: 35–41.

45.

Ioachimescu

Anthony

Jr Constantin

. VAMONOS (Veterans affairs’ metabolism, obstructed and non-obstructed sleep) study: effects of CPAP therapy on glucose metabolism in patients with obstructive sleep apnea. J Clin Sleep Med 2017; 13: 455–466.

46.

Balkau

Vol

Loko

. High baseline insulin levels associated with 6-year incident observed sleep apnea. Diabetes Care 2010; 33(5): 1044–1049.

47.

Kline

Reboussin

Foster

. The effect of changes in cardiorespiratory fitness and weight on obstructive sleep apnea severity in overweight adults with type 2 diabetes. Sleep 2016; 39: 317–325.

48.

Peppard

Young

Palta

. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000; 284: 3015–3021.

49.

Newman

Foster

Givelber

. Progression and regression of sleep-disordered breathing with changes in weight: the Sleep Heart Health Study. Arch Intern Med 2005; 165: 2408–2413.

50.

Kuna

Reboussin

Borradaile

. Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes. Sleep 2013; 36: 641–649.

51.

Tantucci

Scionti

Bottini

. Influence of autonomic neuropathy of different severities on the hypercapnic drive to breathing in diabetic patients. Chest 1997; 112: 145–153.

52.

Chester

Gottfried

Cameron

. Pathophysiological findings in a patient with Shy-Drager and alveolar hypoventilation syndromes. Chest 1988; 94: 212–214.

53.

Tahrani

AA.

Obstructive sleep apnoea and vascular disease in patients with type 2 diabetes. Eur Endocrinol 2015; 11: 581–590.

54.

West

Nicoll

Wallace

. Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 2007; 62: 969–974.

55.

Shaw

Punjabi

Naughton

. The effect of treatment of obstructive sleep apnea on glycemic control in type 2 diabetes. Am J Respir Crit Care Med 2016; 194: 486–492.

56.

Martínez-Cerón

Barquiel

Bezos

. Effect of continuous positive airway pressure on glycemic control in patients with obstructive sleep apnea and type 2 diabetes. A randomized clinical trial. Am J Respir Crit Care Med 2016; 194: 476–485.

57.

Barcelo

Barbe

de la Pena

. Insulin resistance and daytime sleepiness in patients with sleep apnoea. Thorax 2008; 63: 946–950.

58.

Grimaldi

Beccuti

Touma

. Association of obstructive sleep apnea in REM sleep with reduced glycemic control in type 2 diabetes: therapeutic implications. Diabetes Care 2014; 37: 355–363.

59.

Peppard

Young

Palta

. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342: 1378–1384.

60.

Prasad

Carley

Krishnan

. Effects of positive airway pressure treatment on clinical measures of hypertension and type 2 diabetes. J Clin Sleep Med 2012; 8: 481–487.

61.

Myhill

Davis

Peters

. Effect of continuous positive airway pressure therapy on cardiovascular risk factors in patients with type 2 diabetes and obstructive sleep apnea. J Clin Endocrinol Metab 2012; 97: 4212–4218.

62.

Turmel

Sériès

Boulet

. Relationship between atherosclerosis and the sleep apnea syndrome: an intravascular ultrasound study. Int J Cardiol 2009; 132: 203–209.

63.

Kent

Garvey

Ryan

. Severity of obstructive sleep apnoea predicts coronary artery plaque burden: a coronary CT angiography study. Eur Respir J 2013; 42: 1263–1270.

64.

Sert Kuniyoshi

Garcia-Touchard

Gami

. Day-night variation of acute myocardial infarction in obstructive sleep apnea. J Am Coll Cardiol 2008; 52: 343–346.

65.

Chen

Zhuo

. Continuous positive airway pressure treatment reduces mortality in elderly patients with moderate to severe obstructive severe sleep apnea: a cohort study. PLoS ONE 2015; 10: e0127775.

66.

Molnar

Mucsi

Novak

. Association of incident obstructive sleep apnoea with outcomes in a large cohort of US veterans. Thorax 2015; 70: 888–895.

67.

Gottlieb

Yenokyan

Newman

. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010; 122: 352–360.

68.

Redline

Yenokyan

Gottlieb

. Obstructive sleep apnea-hypopnea and incident stroke. Am J Respir Crit Care Med 2010; 182: 269–277.

69.

Campos-Rodriguez

Martinez-Garcia

Reyes-Nuñez

. Role of sleep apnea and continuous positive airway pressure therapy in the incidence of stroke or coronary heart disease in women. Am J Respir Crit Care Med 2014; 189: 1544–1550.

70.

McEvoy

Antic

Heeley

. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med 2016; 375: 919–931.

71.

Craig

Kylintireas

Kohler

. Effect of CPAP on cardiac function in minimally symptomatic patients with OSA: results from a subset of the MOSAIC randomized trial. J Clin Sleep Med 2015; 11: 967–973.

72.

Rice

Foster

Sanders

. The relationship between obstructive sleep apnea and self-reported stroke or coronary heart disease in overweight and obese adults with type 2 diabetes mellitus. Sleep 2012; 35: 1293–1298.

73.

Seicean

Strohl

Seicean

. Sleep disordered breathing as a risk of cardiac events in subjects with diabetes mellitus and normal exercise echocardiographic findings. Am J Cardiol 2013; 111: 1214–1220.

74.

Arnardottir

Mackiewicz

Gislason

. Molecular signatures of obstructive sleep apnea in adults: a review and perspective. Sleep 2009; 32: 447–470.

75.

Altaf

Ali

Piya

. The relationship between obstructive sleep apnea and intra-epidermal nerve fiber density, PARP activation and foot ulceration in patients with type 2 diabetes. J Diabetes Complicat 2016; 30: 1315–1320.

76.

Brownlee

The pathobiology of diabetic complications a unifying mechanism. Diabetes 2005; 54: 1615–1625.

77.

Ramsey

Arden

GB.

Hypoxia and dark adaptation in diabetic retinopathy: interactions, consequences, and therapy. Curr Diab Rep 2015; 15: 118.

78.

Boland

Shahar

Wong

. Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the Sleep Heart Health Study. Sleep 2004; 27: 467–473.

79.

Lin

G-M

Redline

Klein

. Sex-specific association of obstructive sleep apnea with retinal microvascular signs: the multi-ethnic study of atherosclerosis. J Am Heart Assoc 2016; 5(7): e003598.

80.

Kwon

Kang

Lee

. Obstructive sleep apnea in patients with branch retinal vein occlusion: a preliminary study. Korean J Ophthalmol 2016; 30: 121–126.

81.

Leong

Jadhakhan

Taheri

. Effect of obstructive sleep apnoea on diabetic retinopathy and maculopathy: a systematic review and meta-analysis. Diabet Med 2016; 33: 158–168.

82.

Mason

Kiire

Groves

. Visual improvement following continuous positive airway pressure therapy in diabetic subjects with clinically significant macular oedema and obstructive sleep apnoea: proof of principle study. Respiration 2012; 84: 275–282.

83.

Nesmith

Ihnen

Schaal

Poor responders to bevacizumab pharmacotherapy in age-related macular degeneration and in diabetic macular edema demonstrate increased risk for obstructive sleep apnea. Retina 2014; 34: 2423–2430.

84.

Chu

Shih

. Association of sleep apnoea with chronic kidney disease in a large cohort from Taiwan. Respirology 2016; 21: 754–760.

85.

Dou

Lan

Reynolds

. Association between obstructive sleep apnea and acute kidney injury in critically ill patients: a propensity-matched study. Nephron 2017; 135: 137–146.

86.

Koga

Ikeda

Yasunaga

. Effects of nasal continuous positive airway pressure on the glomerular filtration rate in patients with obstructive sleep apnea syndrome. Intern Med 2013; 52: 345–349.

87.

Zhang

Jiang

Lin

. Effect of continuous positive airway pressure on serum cystatin C among obstructive sleep apnea syndrome patients. Int Urol Nephrol 2014; 46: 1997–2002.

88.

Comondore

Cheema

Fox

. The impact of CPAP on cardiovascular biomarkers in minimally symptomatic patients with obstructive sleep apnea: a pilot feasibility randomized crossover trial. Lung 2009; 187: 17–22.

89.

Yasar

Ucar

Demir

. Does CPAP therapy alter urinary albumin level in adult patients with moderate to severe obstructive sleep apnea syndrome? Sleep Breath 2014; 18: 525–532.

90.

Furukawa

Saito

Yamamoto

. Nocturnal intermittent hypoxia as an associated risk factor for microalbuminuria in Japanese patients with type 2 diabetes mellitus. Eur J Endocrinol 2013; 169: 239–246.

91.

Tahrani

Ali

Raymond

. Obstructive sleep apnea and diabetic nephropathy: a cohort study. Diabetes Care 2013; 36: 3718–3725.

92.

Mayer

Dematteis

Pepin

. Peripheral neuropathy in sleep apnea. A tissue marker of the severity of nocturnal desaturation. Am J Respir Crit Care Med 1999; 159: 213–219.

93.

Ludemann

Dziewas

Soros

. Axonal polyneuropathy in obstructive sleep apnoea. J Neurol Neurosurg Psychiatry 2001; 70: 685–687.

94.

Dziewas

Schilling

Engel

. Treatment for obstructive sleep apnoea: effect on peripheral nerve function. J Neurol Neurosurg Psychiatry 2007; 78: 295–297.

95.

Tahrani

Ali

Raymond

. Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes. Am J Respir Crit Care Med 2012; 186: 434–441.

96.

Vas

PRJ

Ahluwalia

Manas

. Undiagnosed severe sleep apnoea and diabetic foot ulceration: a case series based hypothesis: a hitherto under emphasized factor in failure to heal. Diabet Med 2016; 33: e1–e4.

Obstructive sleep apnoea in diabetes: Does it matter?

Abstract

Keywords

Introduction

OSA overview

OSA and T2D: a chicken and egg?

OSA and glycaemic control in T2D

OSA and hypertension

OSA and CVD

OSA and microvascular complications in T2D

OSA and retinopathy

OSA and diabetes CKD

OSA and peripheral neuropathy

OSA and other diabetes-related outcomes

Summary and conclusion

Footnotes

Declaration of conflicting interests

Funding

References