Diabetic retinopathy is the most common microvascular complication of diabetes mellitus and the leading cause of vision loss and blindness in working-aged American adults.1 Obstructive sleep apnea affects between 4 and 24% of the general U.S. population.2,3 It is associated with numerous comorbidities including cardiovascular disease, atherosclerosis, stroke, peripheral vascular disease, hypertension, and diabetes.4–6
Untreated obstructive sleep apnea is a risk factor for the development and progression of diabetic retinopathy.7–9 It has been linked to increased hyperglycemia and insulin resistance.10,11 Nocturnal hypoxemia in obstructive sleep apnea also leads to oxidative stress, increased inflammation, and endothelial dysfunction.12–16 Body mass index, hemoglobin A1c, hypertension, glomerular filtration rate, and insulin use have been identified as risk factors for diabetic retinopathy development and progression in the setting of untreated obstructive sleep apnea.17–20
Continuous positive airway pressure is the first-line therapeutic intervention for moderate to severe obstructive sleep apnea.21 Continuous positive airway pressure use can eliminate nocturnal hypoxemia, reduce hypertension, and improve microvascular endothelial function and sympathetic autonomic regulation.15,22 However, compliance is a significant barrier in continuous positive airway pressure therapy, with nonadherence rates reportedly as high as 83%.23
The association between obstructive sleep apnea and diabetes mellitus has led to the belief that continuous positive airway pressure may mitigate the risks of diabetic retinopathy. To date, there have been few studies that explore the relationship. The aim of this study was to compare the prevalence of diabetic retinopathy in type 2 diabetic patients with obstructive sleep apnea who were compliant with continuous positive airway pressure therapy with those who were not compliant with continuous positive airway pressure therapy. Several factors that influence obstructive sleep apnea and diabetes mellitus including age, body mass index, duration of disease, hemoglobin A1c, hypertension, and insulin use were considered.
This study was a retrospective cross-sectional review of all type 2 diabetic patients being treated for obstructive sleep apnea who visited the Pulmonary and Eye Clinics at VA Maine between 2011 and 2016. Eligible subjects were seen in the respective clinics to monitor for continuous positive airway pressure compliance and diabetic retinopathy within a 12-month period. In the event multiple visits occurred during the study time frame, the most recent set of visits was used for data collection. This study was approved by the Veterans Institutional Review Board of Northern New England, a research consortium comprising VA Medical Centers from Togus (Augusta), ME; Manchester, NH; and White River Junction, VT.
Average continuous positive airway pressure wear time, percent nights worn, and treated apnea-hypopnea index was obtained from continuous positive airway pressure smart card data of diabetic subjects who visited the Pulmonary Clinic. The baseline apnea-hypopnea index was obtained by diagnostic polysomnography performed before initiation of continuous positive airway pressure use. Successful continuous positive airway pressure compliance was defined in accordance with Centers for Medicare & Medicaid Services guidelines as an average use of at least 4 hours on at least 70% of nights.24
The presence and degree of diabetic retinopathy were assessed through dilated funduscopic evaluation or nonmydriatic teleretinal image screening. For teleretinal image screening, three fundus photographs of each eye were obtained and reviewed using a validated pathway for detecting diabetic retinopathy.25,26 Cases of possible diabetic macular edema were subsequently seen for live examination by an eye care provider. When both eyes from a subject met the inclusion criteria, the eye with the most advanced level of retinopathy was used. Retinopathy was assigned to one of five categories based on the Early Treatment for Diabetic Retinopathy Study grading scale. The presence or absence of diabetic macular edema was also recorded.
Additional information collected was sex, age, body mass index, hemoglobin A1c, duration of diabetes mellitus, duration of obstructive sleep apnea, insulin use, hypertension, hypercholesterolemia, current smoking status, and glomerular filtration rate. The findings obtained closest in time to either of the visits to the pulmonary and eye clinics were used. Hypertension was defined as either systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg, or use of antihypertensive medication. Hypercholesterolemia was defined as serum cholesterol >240 mg/dL or use of cholesterol-lowering medication.
Exclusion criteria were as follows: primary central sleep apnea, complex sleep apnea with history of adaptive servoventilation use, congestive heart failure, chronic obstructive pulmonary disease, anticoagulant use other than aspirin, and/or history of retinopathy or macular edema not due to diabetes.
All statistical analyses were performed using Minitab 17 (Minitab, LLC, State College, PA). Descriptive statistics including mean and standard deviation for normally distributed variables, and median, first quartile, and third quartile values for nonnormally distributed variables were calculated for all quantitative data. The z test for proportions was conducted to test the difference in diabetic retinopathy prevalence between compliant and noncompliant continuous positive airway pressure therapy groups. Differences between diabetic retinopathy and no diabetic retinopathy groups were determined using χ2 tests for categorical data, Student t tests for normally distributed continuous data, and Mann-Whitney U tests for nonparametric results. Multivariate logistic regression was then performed using all variables with a P value of less than .10 in the univariate analysis to assess for factors independently associated with diabetic retinopathy. Average continuous positive airway pressure wear time and percent nights worn were omitted from the logistic regression to avoid the possibility of collinearity with continuous positive airway pressure compliance. Level of significance was set to P = .05 for all statistical analyses. The prevalence of diabetic retinopathy in the United States among diabetic patients 40 years or older has been reported to be 28.5%; using 40% as a significant difference in the relative prevalence of diabetic retinopathy between the compliant and noncompliant continuous positive airway pressure therapy groups, the minimal group size to achieve a power of 0.8 was calculated to be 208 (level of significance, 0.05).27
A total of 1771 patient charts were reviewed, with 321 meeting the inclusion criteria. Of these, 63 (19.6%) had diabetic retinopathy (retinopathy group), and 258 (80.4%) did not have retinopathy (no retinopathy group). In the retinopathy group, 51 had mild nonproliferative disease, 7 had moderate nonproliferative disease, 2 had severe nonproliferative disease, and 3 had proliferative diabetic retinopathy. A total of nine patients had diabetic macular edema. Because of the low prevalence of more advanced stages of disease, retinopathy was grouped together for data analysis, and analysis based on disease severity was not attempted.
The descriptive characteristics and univariate statistical comparison of the retinopathy and no retinopathy groups are shown in Table 1. In the univariate analysis, continuous positive airway pressure compliance was significantly higher in the no retinopathy group than in those with retinopathy. Average wear time and glomerular filtration rate >60 ml/min were also significantly higher in the no retinopathy group, whereas hemoglobin A1c level, diabetes mellitus duration, insulin use, and hypertension were significantly higher in the retinopathy group. The prevalence rates of diabetic retinopathy in the continuous positive airway pressure–compliant group and the noncompliant group were 16.1 and 26.1%, respectively. The continuous positive airway pressure–compliant group was significant less likely to have diabetic retinopathy (odds ratio, 0.54; 95% confidence interval, 0.31 to 0.94; P = .04). Additional information on the groups is provided in Table 2. The number of subjects in the noncompliant group was less than the size required to reach the desired power of 0.8. The resultant power of the study was 0.6.
In the multivariate logistic regression, diabetic retinopathy was assigned as the dependent variable, whereas continuous positive airway pressure compliance, body mass index, hemoglobin A1c, duration of diabetes mellitus, insulin use, hypertension, current smoking status, and glomerular filtration rate >60 ml/min were identified as independent variables. After adjustment, diabetes mellitus duration, insulin use, continuous positive airway pressure compliance, and body mass index were independently correlated with the presence of retinopathy. Continuous positive airway pressure compliance and body mass index were associated with lower retinopathy prevalence, whereas diabetes mellitus duration and insulin use were associated with increased likelihood of retinopathy. Odds ratios for the statistically significant variables in the regression analysis are located in Table 3.
The results of this study show that diabetic retinopathy was significantly less prevalent in a continuous positive airway pressure–compliant group than in a group noncompliant with continuous positive airway pressure therapy. This finding was independent of other factors known to influence obstructive sleep apnea and diabetic retinopathy disease processes including obstructive sleep apnea severity and duration, diabetes mellitus duration, hemoglobin A1c, and insulin use. The groups were similar in many respects including age and obstructive sleep apnea duration and severity. Diabetes mellitus duration, hemoglobin A1c level, insulin use, and hypertension were significantly higher among the retinopathy group, findings that are not surprising given our understanding of risk factors for diabetic retinal disease; however, when these factors were controlled for, the relationship between continuous positive airway pressure compliance and presence of diabetic retinopathy remained.
Several studies have shown that untreated obstructive sleep apnea is a risk factor for the development and progression of diabetic retinopathy, but the impact of continuous positive airway pressure on retinopathy has not been extensively studied.28 To our knowledge, ours is the first study to focus exclusively on the relationship between continuous positive airway pressure compliance and diabetic retinopathy prevalence. Altaf et al.29 followed up 230 patients longitudinally for an average of 43 months and found that obstructive sleep apnea was an independent risk factor for retinopathy progression, and those using continuous positive airway pressure were significantly less likely to progress to proliferative disease or develop maculopathy. In the Retinopathy and Concurrent Obstructive Sleep Apnea Trial (ROSA) study, the only randomized controlled trial examining continuous positive airway pressure and diabetic retinopathy, treatment for 12 months with continuous positive airway pressure failed to improve vision or retinopathy in a group of 131 subjects with macular edema. The findings led the authors to conclude that continuous positive airway pressure may be ineffective in reversing established ocular disease. Potential explanations for the absence of benefit were low continuous positive airway pressure compliance and the use of concurrent interventions for diabetic macular edema in all subjects.30 The ROSA trial was done in follow-up to a prospective uncontrolled trial of subjects with diabetic macular edema who demonstrated visual acuity improvement after 6 months of highly compliant continuous positive airway pressure treatment.31 Because of the low number of subjects in our study with more advanced diabetic retinopathy, no conclusions may be drawn regarding the relationship between continuous positive airway pressure compliance and the different stages of disease, but the results suggest that continuous positive airway pressure may play a potential role in the prevention of diabetic retinopathy.
Continuous positive airway pressure has been shown to benefit several health factors and disease processes known to influence diabetic retinopathy, including hypertension. The greatest benefits are seen in hypertension resistant to standard therapy, in higher baseline systolic and diastolic blood pressure, and in cases of severe obstructive sleep apnea.32,33 In this study, hypertension was more common in the retinopathy group, but the association was not statistically significant when controlling for continuous positive airway pressure use.
Despite the strong association between obstructive sleep apnea and type 2 diabetes, studies examining the effects of continuous positive airway pressure treatment on glucose metabolism have yielded conflicting results. Some studies have failed to demonstrate benefit after more than 6 months of continuous positive airway pressure use, whereas others have shown improvement in as little as 1 week of treatment.34,35 Although differences in study design and patient populations have likely contributed to the heterogeneity in study results, insufficient nightly continuous positive airway pressure use has been cited as a possible explanation for negative findings in most reports.36–38 In contrast, when continuous positive airway pressure adherence is high, the impact on various glycemic factors including fasting blood glucose, mean 24-hour plasma glucose, hemoglobin A1c, and insulin sensitivity has been favorable.39,40 These findings suggest that excellent continuous positive airway pressure adherence is required to achieve improvements in glucose metabolism in diabetic patients being treated for obstructive sleep apnea.
Although our study does not demonstrate causation, it does provide evidence that continuous positive airway pressure compliance is associated with lower prevalence of diabetic retinopathy. Given the significant burden of diabetic eye disease and the incomplete effectiveness of current interventions, the role of continuous positive airway pressure as an adjunctive treatment in the management of diabetes should not be discounted.
The study has several strengths including similarities between retinopathy and no retinopathy groups with respect to age and obstructive sleep apnea. Except for smoking history, all data were obtained via objective measurement rather than by patient report. Limitations include the homogenous patient population, predominantly elderly men, which restricts the generalizability of the findings. The statistical power was lower than desired, thereby increasing the possibility of a type I error. Several risk factors were higher in the noncompliant group (diabetes mellitus duration, hemoglobin A1c, insulin use), which may have contributed to increased retinopathy prevalence despite attempts to statistically control for these differences. A larger study composed of groups with better matched diabetic retinopathy risk profiles is recommended to confirm our findings.
In summary, this study found the prevalence of diabetic retinopathy to be lower in veteran patients with sleep apnea who are compliant with continuous positive airway pressure. This relationship persisted when controlling for other factors known to increase the likelihood of retinopathy including duration of diabetes mellitus and hemoglobin A1c. These findings provide further evidence of the benefits of continuous positive airway pressure use in the management of obstructive sleep apnea–related comorbidities.
1. Shah AR, Gardner TW. Diabetic Retinopathy: Research to Clinical Practice. Clin Diabetes Endocrinol 2017;3:9–22.
2. Young T, Peppard PE, Gottlieb DJ. Epidemiology of Obstructive Sleep Apnea: A Population Health Perspective. Am J Respir Crit Care Med 2002;165:1217–39.
3. Peppard PE, Young T, Barnet JH, et al. Increased Prevalence of Sleep-disordered Breathing in Adults. Am J Epidemiol 2013;177:1006–14.
4. Gozal D, Kheirandish-Gozal L. Cardiovascular Morbidity in Obstructive Sleep Apnea: Oxidative Stress, Inflammation, and Much More. Am J Respir Crit Care Med 2008;177:369–75.
5. Pedrosa RP, Drager LF, Gonzaga CC, et al. Obstructive Sleep Apnea: The Most Common Secondary Cause of Hypertension Associated with Resistant Hypertension. Hypertension 2011;58:811–7.
6. Tahrani AA, Ali A, Stevens MJ. Obstructive Sleep Apnoea and Diabetes: An Update. Curr Opin Pulm Med 2013;19:631–8.
7. Leong WB, Jadhakhan F, Taheri S, et al. Effect of Obstructive Sleep Apnea on Diabetic Retinopathy and Maculopathy: A Systematic Review and Meta-analysis. Diabet Med 2016;33:158–68.
8. Zhu Z, Zhang F, Liu Y, et al. Relationship of Obstructive Sleep Apnea with Diabetic Retinopathy: A Meta-analysis. Biomed Res Int 2017;3:1–5.
9. West SD, Groves DC, Lipinski HJ, et al. The Prevalence of Retinopathy in Men with Type 2 Diabetes and Obstructive Sleep Apnea. Diabet Med 2010;27:423–30.
10. Punjabi NM, Ahmed MM, Polotsky VY, et al. Sleep Disordered Breathing, Glucose Intolerance, and Insulin Resistance. Respir Physiol Neurobiol 2003;136:167–78.
11. Ip MS, Lam B, Ng MM, et al. Obstructive Sleep Apnea Is Independently Associated with Insulin Resistance. Am J Respir Crit Care Med 2002;165:670–6.
12. Lavie L. Oxidative Stress Inflammation and Endothelial Dysfunction in Obstructive Sleep Apnea. Front Biosci (Elite Ed) 2012;4:1391–403.
13. Schulz R, Hummel C, Heinemann S, et al. Serum Levels of Vascular Endothelial Growth Factor Are Elevated in Patients with Obstructive Sleep Apnea and Severe Nighttime Hypoxia. Am J Respir Crit Care Med 2005;165:67–70.
14. Banerjee D, Leong WB, Arora T, et al. The Potential Association between Obstructive Sleep Apnea and Diabetic Retinopathy in Severe Obesity—The Role of Hypoxemia. PLoS One 2013;8:e79521.
15. Buchner NJ, Quack I, Woznowski M, et al. Microvascular Endothelial Dysfunction in Obstructive Sleep Apnea Is Caused by Oxidative Stress and Improved by Continuous Positive Airway Pressure Therapy. Respiration 2011;82:409–17.
16. Nieto FJ, Herrington DM, Redline S, et al. Sleep Apnea and Markers of Vascular Endothelial Function in a Large Community Sample of Older Adults. Am J Respir Crit Care Med 2004;169:354–60.
17. Shiba T, Takahashi M, Hori Y, et al. Evaluation of the Relationship between Background Factors and Sleep-disordered Breathing in Patients with Proliferative Diabetic Retinopathy. Jpn J Ophthalmol 2011;55:638–42.
18. Shiba T, Sato Y, Takahashi M. Relationship between Diabetic Retinopathy and Sleep-disordered Breathing. Am J Ophthalmol 2009;147:1017–21.
19. Nishimura A, Kasai T, Tamura H, et al. Relationship between Sleep Disordered Breathing and Diabetic Retinopathy: Analysis of 136 Patients with Diabetes. Diabetes Res Clin Pract 2015;109:306–11.
20. Unver YB, Yavuz GS, Stafford CA, et al. A Putative Relation between Obstructive Sleep Apnea and Diabetic Macular Edema Associated with Optic Nerve Fiber Layer Infarcts. Open Sleep J 2009;2:11–9.
21. Sanders MH. Sleep Breathing Disorders. In: Kryger MH, Roth T, Dement WE, eds. Principles and Practice of Sleep Medicine. 4th ed. Amsterdam: Elsevier; 2005:969–1121.
22. Maser RE, Lenhard MJ, Rizzo AA, et al. Continuous Positive Airway Pressure Therapy Improves Cardiovascular Autonomic Function for Persons with Sleep-disordered Breathing. Chest 2008;133:86–91.
23. Riachy M, Najem S, Iskandar M, et al. Factors Predicting CPAP Adherence in Obstructive Sleep Apnea Syndrome. Sleep Breath 2017;21:295–302.
25. Gupta A, Cavallerano J, Sun JK, et al. Evidence for Telemedicine for Diabetic Retinal Disease. Semin Ophthalmol 2017;32:22–8.
26. Cavallerano A, Conlin PR. Teleretinal Imaging to Screen for Diabetic Retinopathy in the Veterans Health Administration. J Diabetes Sci Technol 2008;2:33–9.
27. Zhang X, Saaddine JB, Chou CF, et al. Prevalence of Diabetic Retinopathy in the United States, 2005–2008. JAMA 2010;304:649–56.
28. Chang AC, Fox TP, Wang S, et al. Relationship between Obstructive Sleep Apnea and the Presence and Severity of Diabetic Retinopathy. Retina 2018;38:2197–206.
29. Altaf QA, Dodson P, Ali A, et al. Obstructive Sleep Apnea and Retinopathy in Patients with Type 2 Diabetes. A Longitudinal Study. Am J Respir Crit Care Med 2017;196:892–900.
30. West SD, Prudon B, Hughes J, et al. Continuous Positive Airway Pressure Effect on Visual Acuity in Patients with Type 2 Diabetes and Obstructive Sleep Apnoea: A Multicentre Randomized Trial. Eur Respir J 2018;52:1801177.
31. Mason RH, Kiire CA, Groves DC, et al. Visual Improvement Following Continuous Positive Airway Pressure Therapy in Diabetic Subjects with Clinically Significant Macular Edema and Obstructive Sleep Apnea: Proof of Principle Study. Respiration 2012;84:275–82.
32. Lam JC, Lai AY, Tam TC, et al. CPAP Therapy for Patients with Sleep Apnea and Type Diabetes Mellitus Improves Control of Blood Pressure. Sleep Breath 2017;21:377–86.
33. Campos-Rodriguez F, Perez-Ronchel J, Grilo-Reina A, et al. Long-term Effect of Continuous Positive Airway Pressure on BP in Patients with Hypertension and Sleep Apnea. Chest 2017;132:1847–52.
34. Iftikhar IH, Blankfield RP. Effect of Continuous Positive Airway Pressure on Hemoglobin A(1C) in Patients with Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. Lung 2012;190:605–11.
35. Yang D, Liu Z, Yang H, et al. Effects of Continuous Positive Airway Pressure on Glycemic Control and Insulin Resistance in Patients with Obstructive Sleep Apnea: A Meta-analysis. Sleep Breath 2013;17:33–8.
36. Ioachimescu OC, Anthony J Jr., Constantin T, et al. 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;13:455–66.
37. Kaur A, Mokhlesi B. The Effect of OSA Therapy on Glucose Metabolism: It's All about CPAP Adherence! J Clin Sleep Med 2017;13:365–7.
38. Mokhlesi B, Grimaldi D, Beccuti G, et al. Effect of One Week of 8 Hour Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea on Glycemic Control in Type 2 Diabetes: A Proof of Concept Study. Am J Respir Crit Care Med 2016;194:516–9.
39. Grimaldi D, Beccuti G, Tourma C, et al. Association of Obstructive Sleep Apnea in REM Sleep with Reduced Glycemic Control in Type 2 Diabetes: Therapeutic Implications. Diabetes Care 2014;37:355–63.
© 2019 American Academy of Optometry
40. Martínez-Cerón F, Barquiel B, Bezos AM, et al. 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;196:476–85.