Article

New Insight Into Obstructive Sleep Apnea and Diabetic Retinopathy

Treating OSA may stop or reverse retinal disease progression.

Related

Researchers have investigated the relationship between obstructive sleep apnea (OSA) and diabetic retinopathy (DR), with mixed results as to whether this association exists (Table 1).1-18 Recent studies provide new information about this relationship that will be summarized in this article.

Table 1: Summary of Cross-Sectional Studies on Diabetic Retinopathy and Obstructive Sleep Apnea*
STUDY PATIENTS SETTING ANALYSIS MAIN FINDINGS
DIABETIC RETINOPATHY DIABETIC MACULAR EDEMA
POSITIVE ASSOCIATION BETWEEN DR AND OSA AND/OR PSG MEASURES
Unver et al1 2009 (USA) 44 DM Outpatient retina clinic Univariate Significant association between DR and OSA (OR 143.18, 95% CI 7.41-2767.79)†† Significant association between OSA and DME (OR 14.44, 95% CI 2.34 to 147.60)††
Laaban et al2 2009 (France) 303 T2DM Hospital inpatient (DM) Univariate Significant association between DR and OSA (OR 0.56, 95% CI 0.35-0.92)††
Borel et al3 2010 (France) 37 T1DM DM outpatient Univariate Difference in presence of DR between borderline (11.1%) and pathological (73.3%) overnight oximetry recording
West et al4 2010 (UK) 118 T2DM 1 DM outpatient and 5 primary care centers Multivariate Association between retinopathy scores and OSA (R2=.19) Association between DME and OSA (R2=.30)
Shiba et al5 2010 (Japan) 219 T2DM Hospital inpatient (eye disease) Multivariate NPDR versus PDR: Association between PDR and OSA (OR 1.09, 95% CI 1.01-1.06)
Association between PDR and minimum SpO2 (OR 0.93; 95% CI 0.88-0.99)
Kosseifi et al6 2012 (USA) 98 T2DM Outpatient sleep clinic Univariate Higher AHI in DR (44.2) vs no DR
Rudrappa et al7 2012 (UK) 31 T2DM DM outpatient Multivariate Association between retinopathy scores and OSA
No association between PDR and OSA (OR 12.6, 95% CI 0.62-255.76)
No association between DME and OSA (effect size not reported)
Nishimura et al8 2013 (Japan) 136 T2DM N/A Univariate No difference in AHI between patients with no DR (15.1±13.6) and with DR (17.8±15.1)
Multivariate Difference in minimum SpO2 between patients with no DR (81.8±7.4) and with DR (78.2±9.6)
Manin et al9 2014 (France) 67 T1DM 2 DM outpatient Univariate Difference in presence of DR between OSA (84%) and non-OSA (42%) patients
No difference in presence of NPDR between OSA (10%) and non-OSA (6%) patients
No difference in presence of DME between OSA (23%) and non-OSA (8%) patients
Baba et al10 2016 (France) 60 T2DM DM outpatient Univariate Difference in presence of DR between OSA (55%) and non-OSA (15%) patients
Difference in presence of NPDR and PDR between OSA (35%, 20%) and non-OSA (7.5%, 7.5%) patients
Difference in presence of DME in OSA (20%) and non-OSA (5%) patients
Tan et al11 2017 (China) 170 T2DM N/A Univariate Higher prevalence of DR in patients with severe OSA vs patients with mild-to-moderate OSA††
Chang et al12 (USA) 306 T2DM and 11 T1DM Health system Multivariate Association between DR and severe OSA (OR 2.18, 95% CI 1.14-4.18)
Association between PDR and severe OSA when compared to no DR (OR 2.40, 95% CI 1.12-5.14) and all NPDR (OR 2.20, 95% CI 1.03-4.70)
No association between DR and PSG measures
Association between DME and severe OSA (OR 2.89, 95% CI 1.58-5.27)
No association between DME and PSG measures
NO ASSOCIATION BETWEEN DR AND OSA
Schober et al13 2011 (Germany) 498 T2DM and 58 T1DM 14 primary care centers Univariate No difference in presence of DR between no OSA (AHI<15; 13.9%) and moderate-to-severe OSA (AHI≥15; 11.5%)
Mason et al14 2012 (UK) 80 T2DM with DME DME outpatient Univariate No association between DR and OSA
Mehta et al15 2012 (India) 80 T2DM Outpatient retina clinic Multivariate No association between DR and OSA or AHI (effect size not reported)
Banerjee et al16 2013 (UK) 93 T2DM Specialist weight management clinic Multivariate No association between DR and AHI (OR 1.00, 95% CI 0.98-1.02) or PSG measures No association between DME and AHI (OR 1.01, 95% CI 0.98-1.04)
Association between DME and minimum SpO2 (OR 0.79, 95% CI 0.65-0.95)
Storgaard et al17 2014 (Denmark) 180 T2DM DM outpatient Univariate No difference in DR between OSA (26.4%) and non-OSA (19.4%) patients
No difference in AHI between patients with no DR (17±25) and with DR (17±20)
Zhang et al18 2016 (China) 233 T2DM 12 Hospital inpatient (DM) Multivariate No association between DR and AHI or PSG measures
PDR vs NPDR: no association between PDR and minimum SpO2 (OR 0.970, 95% CI 0.932-1.010) or other OSA parameters
*T2DM, type 2 diabetes mellitus; T1DM, type 1 diabetes mellitus; PSG, polysomnography; DR, diabetic retinopathy; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; DME, diabetic macular edema; SpO2, oxygen saturation.
P<.01, P<.05, **P<.10, ††P value significant but not reported.

WHAT IS OBSTRUCTIVE SLEEP APNEA?

Obstructive sleep apnea is a sleep disorder characterized by episodes of shallow or paused breathing during sleep.19 These episodes lead to hypoxemia, arousal, and sleep fragmentation.19 Symptoms of OSA include snoring and daytime somnolence.19 It is caused by obstruction of the upper airway during sleep due to decreased muscle tone and collapse of the soft tissue in the airway.20,21 Obstructive sleep apnea is linked to central obesity and its prevalence continues to rise along with the prevalence of obesity.22 This condition is fairly common in the general population, affecting up to 9% of adult women and 24% of adult men.23

HOW IS OBSTRUCTIVE SLEEP APNEA DIAGNOSED?

Patients can be assessed for OSA using screening tools such as the STOP, STOP-Bang, Berlin, and Wisconsin sleep questionnaires.24 Of these screening tools, the STOP (snoring, tiredness, observed apnea, and high blood pressure) and STOP-Bang (STOP including body mass index, age, neck circumference, gender) are currently recommended due to high sensitivity, ease of use, and availability of supporting data.6 Screening tools are a convenient and cost-effective method for the non-sleep specialist to assess a patient’s risk of having OSA.

A sleep specialist can make a definitive diagnosis of OSA by performing overnight diagnostic polysomnography — the gold standard test — in a sleep laboratory.25 This test consists of concurrent measurement of sleep and respiration in order to calculate the apnea-hypopnea index (AHI).25 The AHI is a measure of the number of apneas (breathing cessation >10 seconds with 90% airway flow decrease) and hypopneas (breathing cessation >10 seconds, with 30% airway flow decrease and associated 3% arterial oxygen desaturation or arousal) per hour of sleep and is used to determine OSA severity (Table 2).25

Table 2: Obstructive Sleep Apnea Severity as Defined by Apnea-Hypopnea Index7
APNEA-HYPOPNEA INDEX OSA SEVERITY
0-5 No OSA
6-15 Mild OSA
16-30 Moderate OSA
>30 Severe OSA

HOW IS OBSTRUCTIVE SLEEP APNEA TREATED?

The first-line treatment of OSA is continuous positive airway pressure (CPAP) therapy.25 Additional treatment options include bilevel positive airway pressure and adaptive servoventilation if CPAP is not tolerated, as well as dental devices, upper airway surgery, and weight loss.25

PATHOPHYSIOLOGY OF THE RELATIONSHIP BETWEEN OSA AND DR

Obstructive sleep apnea affects between 58% and 86% of patients with diabetes mellitus (DM) — a much larger proportion compared to that of the general population.26,27 Although obesity is a key mediator between these conditions, DM has been found to be a significant independent predictor of OSA.28 In addition, OSA has been independently linked to increased insulin resistance and subsequent poor glucose control, which may put DM patients at a higher risk of developing microvascular complications, including DR.29

Obstructive sleep apnea is characterized by hypoxemia, sleep fragmentation, and recurrent arousal.25 It is thought to contribute to the development and progression of DR through several mechanisms: intermittent hypoxia, oxidative stress, inflammation, and endothelial dysfunction. It has been theorized that episodes of transient hypoxemia during apneas lead to oxidative stress and the release of inflammatory markers.30 These inflammatory markers may then accelerate damage to retinal vasculature and contribute to the development of DR.30 Additionally, OSA is linked to sustained increases in diurnal blood pressure and fluctuations in nocturnal blood pressure. These effects, along with associated endothelial dysfunction, may further damage the retinal vasculature.22 These mechanisms may explain why DR and OSA are interrelated conditions.

THE IMPORTANCE OF THE RELATIONSHIP BETWEEN OSA AND DR

Diabetic retinopathy is often asymptomatic until it has reached an advanced stage, at which serious visual loss may have occurred and may be difficult to reverse.31 As such, identifying related conditions such as OSA can be helpful in recognizing at-risk patients in the ophthalmology clinic. Both OSA and DR — if left untreated — have serious potential sequelae. For retina specialists following DR patients, it is important to know that evaluating and treating their patients for OSA may help not only in their management of DR, but also in preventing cardiovascular conditions associated with OSA. These conditions include hypertension, coronary artery disease, myocardial infarction, stroke, decreased daytime alertness, and motor vehicle accidents.25

RESEARCH ON OSA AND DR

In the past decade, several studies have investigated the potential relationship between OSA and DR. Some findings suggest that an association between OSA and DR may exist, though results between studies are inconsistent (Table 1). Comparison of these studies is limited by varying categorizations of OSA and DR severity in their analyses.

Recent research that examines both the presence and severity of DR in relation to that of OSA may explain these conflicting findings; there may be a threshold in OSA severity after which OSA is associated with DR. In a retrospective, cross-sectional study of 317 patients, Chang et al reported a positive association between severe OSA and DR.12 Compared to patients with mild-to-moderate OSA, patients with severe OSA were found to be at a two- to threefold increased likelihood of having DR, proliferative DR (PDR), and diabetic macular edema (DME).12 These findings remained significant after controlling for potential confounding factors.12

In addition to finding a relationship between severe OSA and DR, Chang et al found no relationship between either OSA (encompassing mild, moderate, and severe) and DR or AHI and DR, citing this as further evidence of a threshold in OSA severity after which DR and OSA are linked — a threshold obscured by grouping all severity levels of OSA together as well as by using a continuous variable (AHI) to represent OSA severity.12

Two other cross-sectional studies stratified OSA severity while analyzing the relationship between OSA and DR. Tan et al found a higher prevalence of DR in patients with severe OSA compared to patients with mild-to-moderate OSA in a group of 170 patients, supporting the idea that severe OSA is specifically connected to DR.11 Looking at a larger cohort of 556 patients, Schober et al found no difference in the presence of DR between patients with mild OSA and patients with moderate-to-severe OSA.13

NEED FOR LONGITUDINAL STUDIES

The majority of studies on OSA and DR have been cross sectional. One recent longitudinal study of 230 patients by Altaf et al was conducted in diabetes clinics within 2 UK hospitals.32 After adjustment for confounding factors, OSA was independently associated with sight-threatening DR (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.1-4.9; P=.04) and maculopathy (OR 2.6, 95% CI 1.2-5.8; P=.01).32 At a follow-up period of an average of 43 months, patients with OSA were more likely than patients without OSA to develop preproliferative/proliferative DR (18.4% vs. 61%; P=.02).32 A dose-effect relationship was also noted showing that compared to no OSA, moderate-to-severe OSA was significantly associated with progression to advanced DR (AHI OR 7.5, 95%, CI 1.4-41.3; P=.02).32 No association was seen between OSA and maculopathy progression at 43 months.32 More longitudinal studies need to be conducted to further elucidate the effect of OSA on DR and DME progression.

OBSTRUCTIVE SLEEP APNEA AND DIABETIC MACULAR EDEMA

Few studies have evaluated the relationship between OSA and DME. The largest study of its kind to date by Chang et al found a significant relationship between DME and severe OSA (OR 2.89, 95% CI 1.58-5.27; P=.001) after adjustment, suggesting that a threshold may also exist in the degree of OSA severity after which DME is linked to OSA.12 In addition to the longitudinal study by Altaf et al, 3 cross-sectional studies that controlled for confounding variables were performed. West et al found a positive association, while Banerjee et al and Rudrappa et al found a negative association.4,7,16,32 However, as the latter 2 studies studied male patients exclusively, their results may not be generalizable.7,16 Additional studies on DME and OSA should be conducted for comparison.

DIABETIC RETINOPATHY AND SECONDARY SLEEP PARAMETERS

Researchers have also been interested in whether DR is linked to minimum oxygen saturation during sleep, as some believe that the relationship between OSA and DR/DME is driven partially by transient hypoxemia during apneas causing ischemic damage and retinal neovascularization. In a meta-analysis by Leong et al including 3 studies (n=448), minimum oxygen saturation was significantly associated with DR (pooled OR 0.91, 95% CI 0.87-0.95; I2=0%) in patients with type II diabetes.33 Other respiratory sleep parameters, including oxygen desaturation index (number of oxygen desaturations by ≥4% during sleep per hour), mean oxygen saturation, and percentage of time spent with <90% oxygen saturation, were not significantly linked to DR.33,34

EFFECT OF OSA TREATMENT ON DIABETIC RETINOPATHY

While it is important to determine whether OSA and DR are associated, it is also valuable to investigate whether treatment of OSA may also help treat DR. Notably, CPAP treatment has been found to significantly lower levels of plasma vascular endothelial growth factor (VEGF) in OSA patients that exhibited improvement in hypoxia during sleep.35

In a longitudinal study of 230 patients, Altaf et al found that patients treated with CPAP were significantly less likely to develop preproliferative and proliferative DR, though the study was not randomized.32 In a prospective cohort study from the United Kingdom, 35 people with DME and moderate-to-severe OSA diagnosed by polysomnography were treated with CPAP.36 At a follow-up period of 6 months, patients that were high CPAP compliers (n=13) had a treatment effect equivalent to a one-line improvement on the logMAR chart (treatment effect 0.11, 95% CI 0.21−0.002, P=.047) compared to those who were low CPAP compliers (n=15).36 No significant improvement was seen in DME or fundal photographs.36 Results from these findings are promising, though further studies — especially randomized controlled studies — are necessary to clarify how CPAP can help treat both OSA and DR.

PATIENT MANAGEMENT

While ophthalmologists are already following and screening diabetic patients for signs of DR, it is also important for ophthalmologists to be aware of the association between severe OSA and DR. Patients with both severe OSA and DR should be identified as higher risk patients in the clinical setting. When evaluating diabetic patients, ophthalmologists should consider administering a screening tool such as the STOP-Bang questionnaire to detect mild, moderate, and severe OSA.24 If OSA is detected, patients can then undergo formal diagnostic polysomnography for further evaluation.

In addition to screening diabetic patients for OSA, retina specialists managing DR and DME should also recognize that treating OSA may help stop or reverse DR and DME progression.32,36 CPAP therapy, the first-line treatment for OSA, has been found to lower levels of inflammatory markers implicated in the process of microvascular damage seen in DR patients with OSA.35 As such, retina specialists, sleep specialists, and primary care physicians should work together in the management of patients with both OSA and DR. Doing so may help prevent the serious sequelae of either untreated OSA or DR. RP

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