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Choi JK, Lym YL, Moon JW, Shin HJ, Cho B. Diabetes Mellitus and Early Age-related Macular Degeneration. Arch Ophthalmol. 2011;129(2):196–199. doi:10.1001/archophthalmol.2010.355
To examine the association of diabetes mellitus and early age-related macular degeneration (AMD) in Korean adults 50 years and older.
This study included 3008 participants aged 50 to 87 years. Early AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Diabetes mellitus was defined as a fasting glucose level of 126 mg/dL or greater or the use of antidiabetic medications. Logistic regression was used to examine the association between diabetes mellitus and early AMD.
There were 88 subjects with early AMD and 315 subjects with diabetes mellitus. After adjusting for age, sex, current smoking, obesity, and hypertension, significant association was found between diabetes mellitus and early AMD. Subjects with diabetes mellitus were more likely to have early AMD (odds ratio, 1.87; 95% confidence interval, 1.07-3.28) than were those without diabetes mellitus.
There is a relationship between diabetes mellitus and early AMD in Korean adults 50 years and older. The underlying biological processes remain to be determined.
In the population 50 years and older, age-related macular degeneration (AMD) is the primary cause of visual impairment in developed countries, and it is the third leading cause of visual impairment worldwide.1,2 The burden of AMD on public health and the economy is expected to rise as a result of the progressive increase in the life expectancy and the proportion of elderly people in the population.3-5 The identification and modification of risk factors related to AMD may improve knowledge regarding its pathogenesis, facilitating prevention, and subsequently reduce the morbidity associated with AMD.
Knowledge about modifiable cardiovascular risk factors related to AMD, including cigarette smoking,6,7 obesity,8 lipid levels,9 and hypertension,10,11 has increased considerably. However, although diabetes mellitus as a major risk factor for cardiovascular disease may be linked with AMD, data from most epidemiologic studies have not been consistent on this point. Some studies have shown an association,12-15 while others have not.9,10,16 Furthermore, even though some studies have found an association between diabetes mellitus and late AMD, to our knowledge, there have been no studies that found an association between early AMD and diabetes mellitus.
In view of these uncertainties and the importance of establishing a relationship, if any, we examined the association of diabetes mellitus and early AMD in Korean adults 50 years and older.
This study is a cross-sectional study of early AMD and diabetes mellitus in Korean adults 50 years and older. Participants were recruited from their visit for general health checkup at the health promotion center, Konkuk University Medical Center, Seoul, Korea. Between July 1, 2006, and June 30, 2008, 3024 participants who were aged 50 to 87 years were identified. After excluding 13 who were unable to complete the study examination and 3 who had the diagnosis of late AMD, 3008 participants were identified as eligible subjects. The study was conducted according to the recommendations of the Declaration of Helsinki and was approved by the institutional review board at Konkuk University Medical Center.
Fundus photographs of both eyes were obtained using a 45° nonmydriatic digital fundus camera (model TRC-NW 100; Topcon Inc, Tokyo, Japan) and examined by 2 experienced ophthalmologists (J.W.M. and H.J.S.). The photographs were evaluated to assess the presence and severity of lesions for AMD using a modification of the Wisconsin AMD grading system.17 Grading was performed by superimposing a standard grid, adapted from the Early Treatment Diabetic Retinopathy Study, over the macular area of the fundus photograph, and only lesions detected in the grid area were considered for AMD diagnosis. Early AMD was defined as the presence of soft drusen alone, retinal pigment epithelial depigmentation alone, or a combination of soft drusen with hyperpigmentation of the retinal pigment epithelium in the absence of late AMD. Late AMD was defined as the presence of exudative AMD (subretinal hemorrhage, subretinal fibrous scar, retinal pigment epithelial detachment, or serous detachment of the sensory retina) or pure geographic atrophy. Two gradings were compared, and intergrader differences were resolved after discussion. Intergrader reliability (κ) for most early AMD signs was assessed with κ values that ranged from 0.47 to 0.77. Late AMD was not assessed owing to the infrequency of these lesions in this study.
Participants underwent an extensive assessment of diabetes mellitus and other risk factors. Anthropometric measurements of individuals wearing light clothing and without shoes were conducted by well-trained examiners. Body mass index was calculated as weight in kilograms divided by height in meters squared. We used the definition of obesity (body mass index ≥25) proposed by the World Health Organization Western Pacific Region, the International Association for the Study of Obesity, and the International Obesity Task Force.18 Waist circumference measurements were taken at the end of normal expiration to the nearest 0.1 cm, measuring from the narrowest point between the lower borders of the rib cage and the iliac crest. The blood pressure of each subject was measured in the sitting position after a 5-minute rest period. Two readings each for the systolic and diastolic blood pressure were recorded, and the average of these measurements was used for data analysis. Blood samples were obtained from an antecubital vein and placed into Vacutainer tubes (Becton Dickinson and Company, Franklin Lakes, New Jersey) in the morning after overnight fasting.
Medical history, medication use, alcohol drinking, smoking, and exercise were categorized based on information from the questionnaire. Medical history included cardiovascular disease (ie, angina pectoris, myocardial infarction, or stroke). Medication use included antihypertensive medication (ie, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, α-blockers, β-blockers, calcium channel blockers, or diuretics), antidiabetic medication (ie, sulphonylureas, biguanides, α-glucosidase inhibitors, or insulin), and lipid-lowering medication. Alcohol consumption was categorized by the average intake of alcoholic beverages per occasion and the frequency per week. At-risk drinking was defined as the consumption of 14 or more drinks per week for men and 7 or more drinks per week for men and women aged 65 years and older. Regarding smoking, individuals were classified as never smoker, former smoker, or current smoker. Participants were also asked about the frequency and extent of exercise on a weekly basis. Regular exercise was defined as the engagement in physical activity for a minimum of 30 minutes at least 3 times per week.
Fasting glucose level, hemoglobin A1c level, lipid profile, and C-reactive protein level were assessed. Diabetes mellitus was defined as a fasting glucose level of 126 mg/dL (to convert to millimoles per liter, multiply by 0.0555) or greater or the use of antidiabetic medications. Hypertension was defined as a systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or the use of antihypertensive medications. C-reactive protein level was measured with a high-sensitivity assay, divided into tertile groups, and computed for each C-reactive protein tertile group relative to the lowest tertile group. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel-III, American Heart Association, and National Heart, Lung, and Blood Institute criteria.19,20 As detailed, participants having 3 or more of the following 5 criteria were defined as having metabolic syndrome: high blood pressure (systolic blood pressure ≥130 and diastolic blood pressure ≥85 mm Hg), elevated fasting plasma glucose level (≥100 mg/dL), hypertriglyceridemia (triglyceride level ≥150 mg/dL [to convert to millimoles per liter, multiply by 0.0113]), low high-density lipoprotein cholesterol level (men, <40 mg/dL; women, <50 mg/dL [to convert to millimoles per liter, multiply by 0.0259]), and abdominal obesity measured by a waist circumference of 90 cm or more for men and 80 cm or more for women using the Asia Pacific criterion for abdominal obesity.21 Participants receiving antihypertensive medication were included in the high blood pressure group and participants receiving antidiabetic medication, in the elevated fasting plasma glucose level group.
For statistical analyses, we examined the relationship between diabetes mellitus, C-reactive protein level, and early AMD. Commercially available software (SPSS, version 16.0; SPSS Institute Inc, Chicago, Illinois) was used to analyze the data. Differences in characteristics between the study population with and without early AMD were assessed using the t test and χ2 test, as appropriate. Logistic regression was constructed to determine the odds ratios (ORs), 95% confidence intervals (CIs), and P values (<.05) for early AMD associated with diabetes mellitus. Multivariate relationships were assessed by adjusting for age, sex, current smoking, obesity, diabetes mellitus, and hypertension.
Of the 3008 participants, early AMD was present in 88 (2.9%). Characteristics of the study population with and without AMD are given in Table 1. Subjects with early AMD were significantly older, more likely to have diabetes mellitus, and more likely to have a higher level of C-reactive protein compared with those without early AMD.
The association between diabetes mellitus and early AMD is shown in Table 2. After adjusting for age, sex, current smoking, obesity, and hypertension in the multivariate logistic regression, a significant association was found between diabetes mellitus and early AMD. Subjects with diabetes mellitus were more likely to have early AMD (OR, 1.87; 95% CI, 1.07-3.28) than those without diabetes mellitus.
In this study, we documented the cross-sectional association between diabetes mellitus and early AMD in Korean adults 50 years and older. After adjusting for age, sex, current smoking, obesity, and hypertension, the association remained statistically significant. There were insufficient numbers to assess for associations with late AMD.
Diabetes-related changes in the function and structure of the retinal pigment epithelium, Bruch membrane, and the choroidal circulation have been hypothesized to increase the risk of AMD.12,15 Histopathologic studies in eyes of diabetic patients have shown thickening of the basement membrane of the choriocapillaris walls, luminal narrowing, dropout of the choriocapillaris, and thickening of the Bruch membrane, which has been attributed to hyperglycemia.22,23 Studies of subfoveal choroidal blood flow have found that it is reduced in patients with both nonproliferative and proliferative diabetic retinopathy.24,25 Few studies have evaluated the limited epidemiologic evidence supporting the association between AMD and diabetes mellitus. The Blue Mountains Eye Study12 reported that diabetes mellitus was significantly associated with the prevalence of geographic atrophy (OR, 4.0; 95% CI, 1.6-10.3). In the Age-Related Eye Disease Study,13 participants with unilateral neovascular AMD and a history of diabetes mellitus had a higher association with incident bilateral neovascular AMD than those without diabetes mellitus (OR, 1.88; 95% CI, 1.07-3.31). The Barbados Eye Study,14 found that, after adjusting for age, there was a 2.7-fold association between a history of diabetes mellitus and incident late AMD. In the cross-sectional population-based EUREYE study,15 a positive association between self-reported diabetes mellitus and neovascular AMD was found (OR, 1.81; 95% CI, 1.10-2.98). In the Women's Health Initiative Sight Exam Study, a history of diabetes was found to be associated with late AMD.26 However, as mentioned, to our knowledge, there has been no documented association in these studies or any other study between early AMD and diabetes mellitus. In this study, we found a significant association between early AMD and diabetes mellitus after adjusting for age, sex, current smoking, obesity, and hypertension.
Atherosclerosis might be hypothesized to increase the risk of AMD by the reduction of blood flow through choroidal vasculature and the lipid deposition in the Bruch membrane with a reduction of permeability leading to upregulation of vascular endothelial growth factor.27 Inflammation has been postulated to be important in the pathogenesis of atherosclerosis and may also be important in AMD.27-29 Several studies have found an association between AMD and inflammation. Cellular remnants and debris from degenerate retinal pigment epithelial cells, sequestered between the retinal pigment epithelial basal lamina and Bruch membrane, may constitute a chronic inflammatory stimulus.28,29 The underlying reasons for the association between diabetes mellitus and early AMD are not known. The further understanding of biological processes underlying our findings are needed.
The strengths of this study include use of standardized methods to assess risk factors and AMD and adjustment for confounders. The results in this study may not represent the general population, but the participants visited the health promotion center for a general health checkup and not for the treatment of confirmed disease; this may lower the selection bias compared with other hospital-based studies. There are several study limitations, however. First, since we studied a large number of possible variables and conducted multiple tests of significance but there was a small number of subjects with early AMD, some of our “significant” findings may be the result of chance alone and the statistical power to identify significant factors may be decreased. Second, there may have been uncontrolled confounding. Third, this study was cross-sectional. Without temporal information, it is impossible to ascertain whether deterioration of glucose control and the onset of diabetes mellitus occurred before or after AMD. Finally, because this study was composed completely of Korean individuals, the results do not necessarily apply to other racial groups.
In conclusion, we found an association between diabetes mellitus and early AMD in Korean adults 50 years and older. Confirmation of these findings in other studies, including larger and prospective studies, and a better understanding of the biological process underlying the present findings are needed.
Correspondence: Belong Cho, MD, PhD, Department of Family Medicine, Seoul National University Hospital, 101 Daehangno, Jongno-gu, Seoul 110-744, Korea (firstname.lastname@example.org).
Submitted for Publication: September 30, 2009; final revision received April 7, 2010; accepted April 9, 2010.
Author Contributions: Dr Choi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None reported.
Funding/Support: This article was supported by Konkuk University in 2008.