Diabetic retinopathy (DR) is an important cause of visual loss in people with diabetes mellitus. Many important systemic risk factors such as age, duration of diabetes, glycemic control, hypertension, renal impairment, and use of insulin were identified in several large epidemiological studies to increase the chance of DR.1 – 4 Multiple ocular risk factors such as intraocular pressure, myopia, and posterior vitreous detachment were also suggested to be associated with development and progression of DR.5,6
In studies since the 1960s, myopia has been suggested as a possible protective factor for DR development in diabetic patients.5 – 9 In some diabetic patients, refractive data can fluctuate because of changes in the lens from the development of cataracts or shifts in blood sugar, both which typically induce myopic shifts.10,11 In addition, preoperative refractive error may not be known for pseudophakic patients. Thus, we felt that axial length would be a more reliable measurement for evaluating the relationship between the myopic eye and the risk of DR. There are only a few studies that have addressed the relationship between axial length and DR,12,13 all of which have certain limitations. Pierro et al.12 evaluated axial length in 157 diabetic patients [44 without DR, 37 with non-proliferative DR (NPDR), and 76 with proliferative DR (PDR)] using A-scan ultrasound and found that the mean axial length to be shorter in patients with DR than in patients without it. However, foveal thickness was not reported in their study. It is unclear whether the shorter axial lengths found in patients with DR were due to increased foveal thickness from macular edema and tractional retinal detachment. Recently, Lim et al.13 conducted a population-based study and identified 675 diabetic patients from screening 3280 participants. They measured axial length by IOLMaster (Carl Zeiss Meditec AG, Jena, Germany) and concluded that myopic refraction and greater axial length are associated with a lower risk of DR, particularly vision-threatening retinopathy. However, 41.8% of their participants were newly diagnosed diabetic patients and the rest were previously diagnosed patients. The duration of diabetes was not evaluated in their statistical models.
Several large studies have shown that the duration of diabetes is one of the major risk factors related to the prevalence of DR.1,2,14 Large variations in prevalence have been observed in patients with different durations of disease. For instance, when the age of diagnosis is ≥30 years, the prevalence of DR varied from 28.8% in persons who had diabetes for less than 5 years to 77.8% in persons who had diabetes for 15 or more years.1 A previous study showed that risk factors for DR may differ between patients with diabetes for 10 years or less and more than10 years.2 For patients with diabetes for 10 years or less, the severity of retinopathy was related to longer disease duration, older age at examination, and higher levels of glycosylated hemoglobin. After 10 years of disease, severity of retinopathy was related to longer disease duration, higher levels of glycosylated hemoglobin, presence of proteinuria, higher diastolic blood pressure, and male gender.
The purpose of this study was to evaluate whether axial length is related to the risk of developing DR and unlike previous studies, duration of diabetes was added as a variable. Patients with diabetes for 10 years or more were included. This subgroup of patients are at high risk for developing DR and the prevalence could be as high as 40 to 60%.1,2 Foveal thickness was also measured by optical coherence tomography (OCT) to rule out the contribution of macular thickness in explaining the differences in axial length. Understanding the ocular risk factors may provide further understanding of the pathophysiologies and facilitate the management of DR.
PATIENTS AND METHODS
A prospective, observational, cross-sectional study was conducted in the Department of Ophthalmology and Department of Internal Medicine (Division of Endocrinology and Metabolism), The Chang Gung Memorial Hospital, Keelung, Taiwan, between August 2007 and December 2008. This study was performed in accordance with the Declaration of Helsinki. Chang Gung Memorial Hospital Institutional Review Board approved this study. In the outpatient clinic of the Department of Internal Medicine, all patients having a diagnosis of diabetic mellitus for 10 years or more and who had undergone regular follow-up in the hospital were invited to participate in the study. Regular follow-up was defined as visiting the hospital at an every 6-month interval or at as directed by a primary care physician. Written consent form was obtained from each eligible patient enrolled in this study. Personal data for the 20% who elected not to participate were not included in the analysis. The exclusion criteria were (1) presence of other significant ocular disease that might be confused with DR such as retinal vein occlusion, age-related macular degeneration, and vitreomacular traction syndrome; (2) any prior ocular surgery except uncomplicated cataract surgery; and (3) inability to complete the ophthalmologic examination. Only one eye of each patient was included in this study. If OU were eligible, one eye was randomly selected as the study eye by randomization envelope.
Clinical Data Collection
A questionnaire was used to collect the medical history of every patient, each of whom underwent a complete and careful ocular examination on the day of enrollment. Best-corrected visual acuity was measured using the Snellen chart and converted to the logarithm of the minimum angle of resolution for data analysis. Other examination components included intraocular pressure measurement by non-contact tonometer, slitlamp examination of the anterior segment, and a dilated fundus examination with both slitlamp biomicroscopy and indirect ophthalmoscopy. The severity of DR was graded according to the modified Early Treatment Diabetic Retinopathy Study severity scale.15 Patients were divided into three groups: group 1 having no DR, group 2 with NPDR, and group 3 with PDR. The OCT (Stratus OCT3; Carl Zeiss Meditec, Oberkochen, Germany) was used to evaluate the macular pathologies. Central subfield thickness (average thickness within a 1 mm radius from the fovea) was obtained by fast macular thickness map protocol. Mean central subfield thickness was used to rule out the contribution of macular thickness in explaining the differences in axial length between groups. Axial length was measured by A-scan ultrasound (10 MHz Transducer, AL-2000 Biometer/Pachymeter; Tomey, Phoenix, AZ). An experienced technician was responsible for all axial length measurements. At least two measurements were taken, and the average was used as the axial length value in our study. If the difference between two measurements was more than 0.1 mm, further measurements were taken until a reliable measurement was noted.
Logistic regression models were used to evaluate the relationship between DR and potential risk factors. Developing any DR (no DR vs. presence of any DR) and developing PDR [(no DR + NPDR) vs. PDR] were used as dependent variables in the models. In the first part of the analysis, all potential risk factors including gender, type of diabetes, age, duration of diabetes, hypertension, dislipidemia, cardiovascular disease, renal impairment, smoking, insulin use, pseduophakia, and axial length were analyzed by univariate logistic regression analysis. In the second part of the analysis, axial length and other variables with p <0.1 in the univariate analysis were included as independent variables in multivariate logistic regression models. Backward selection based on the likelihood ratio statistic was used to select the final models. A two-tailed p value of <0.05 was considered statistically significant in the final models. All the data were analyzed using SPSS Program Package Version 17.0 (SPSS, Chicago, IL).
One hundred seventy-nine patients agreed to receive ocular screening examinations and 166 patients had at least one eye meet the inclusion criteria. Enrollment in the study included 166 eyes from 166 patients (93 female and 73 male). All the participants in this study were Taiwanese. The mean age was 62.1 years (SD, 12.5). There were 17 patients with type 1 diabetes and 149 patients with type 2 diabetes. The mean duration of disease was 15.4 (SD, 6.4) years. All 138 patients with OU eligible for enrollment had the same grading of DR in OU. One eye of each patient was selected randomly as study eye. There were 54 (32.5%) eyes without any DR in group 1, 72 (43.4%) eyes with NPDR in group 2, and 40 (24.1%) eyes with PDR in group 3. The demographic data and clinical characteristic of each group are summarized in Table 1.
The mean axial lengths were 23.47 mm, 23.49 mm, and 23.08 mm in group 1, group 2, and group 3, respectively. Fig. 1 shows the distribution of axial length in each group. The measurements of ocular parameters are summarized in Table 2.
The results of the univariate analysis are shown in Table 3. Hypertension (p = 0.009), renal impairment (p = 0.079), and insulin use (p = 0.009) were associated with developing any DR. Hypertension (p = 0.042), renal impairment (p = 0.014), insulin use (p = 0.040), pseudophakia (p = 0.019), and axial length (p = 0.076) were associated with developing PDR. Axial length and other factors with p value <0.1 were included in multivariate logistic regression models. The results are shown in Table 4. In the final models, hypertension (p = 0.005) and insulin use (p = 0.010) were associated with developing any DR. Hypertension (p = 0.020), renal impairment (p = 0.025), pseudophakia (p = 0.006), and axial length (p = 0.024) were associated with developing PDR. Thus, increased axial length was an independent factor associated with a lower risk of developing PDR (adjusted odds ratio, 0.605; 95% confidence interval, 0.391 to 0.935; p = 0.024; per 1 mm increase) but not associated with developing any DR.
Myopia has been suggested as a possible protective factor against DR since the 1960s.5,7 – 9 However, it is still unclear whether the effect of myopia is related to the increased axial length or due to other refractive components. There are only a few studies addressing the relationship between axial length and DR.12,13 Pierro et al.12 evaluated the axial length in 157 diabetic patients and found that the mean axial length was shorter in patients with DR than in patients without it. Recently, Lim et al.13 conducted a population-based study and identified 675 diabetic patients form a screening of 3280 participants. They concluded myopic refraction and greater axial length are associated with a lower risk of DR, particularly vision-threatening retinopathy. Our study also showed that greater axial length was associated with lower risk of developing PDR.
However, in contrast to the report from Lim et al.,13 greater axial length was not associate with the development of any DR in our study. Similar results were found by Moss et al.5 when they evaluated myopic refractive error and the risk of DR in a longitudinal study. They showed myopia (defined as refractive error of ≤−2 diopters) was associated with lower risk of progression in development of PDR in persons with younger onset diabetes but not in the development of any DR.5 In the study from Lim et al.,13 there was also a trend that the effect of greater axial length was more prominent when the severity of retinopathy increased. Their odds ratios (per 1 mm increase in axial length) were 0.86 (p = 0.041) for any retinopathy, 0.80 (p = 0.108) for moderate retinopathy, and 0.63 (p = 0.044) for vision-threatening retinopathy. Considering the results of the above studies and our study together, we propose that the effect of myopic refraction and axial length may be more prominent for more severe DR.
It is still unclear why myopia or greater axial length is associated with a lower risk of DR. Some anatomical changes such as elongation of the eye, deformation of the posterior pole, and alteration of ocular blood flow in myopic eyes have been proposed as possible mechanisms.5 Studies show that retinal blood flow markedly increases with progressive levels of retinopathy, decreasing finally for PDR when marked arteriolar narrowing is present.16,17 Decreased ocular pulse and blood flow were found in myopic eyes, which could be related to its protective effect in DR.18 – 23 Decreased retinal thickness and macular volume were also found in axial myopia.24 – 26 This can theoretically increase the diffusion of oxygen and decrease the oxygen demand of the retina. However, the exact mechanism is still unclear and requires further study.
The duration of diabetes is one of the major DR risk factors.1,2,14 However, it was not indicated as a significant risk factor in our final regression models. The reason may be that we exclusively enrolled patients with a history of diabetes for 10 years or more. The mean duration of diabetes in our study was around 15 years in all three groups and the SD was between 5.8 and 7.3 years. Relative to previous epidemiologic studies that enrolled patients with any duration of diseases, the disease durations are relatively homogeneous among the patients enrolled in our study making duration less of a distinguishing factor among our subjects.1,2,14 Furthermore, previous studies suggest that the incidence of any DR or PDR reaches a plateau after 10 to 15 years of diabetes.1,2 Thus, duration may play a less important role in our study because all our subjects have a history of diabetes for more than10 years.
There are several limitations to our study. First, the ultrasound A-scan technique, rather than the optical coherence reflectometry method, was used in our study. These are two fundamentally different methods in measuring axial length, and there is currently no available conversion formula between them.27 The ultrasound A-scan measures axial length from the corneal vertex to the vitreoretinal interface, whereas the optical coherence reflectometry measures axial length from the corneal vertex to the retinal pigment epithelium. Theoretically, ultrasound measurements could potentially be affected by pathological changes at vitreoretinal interface in patients suffering from DR (e.g., diabetic macular edema and tractional retinal detachment). In our study, the difference in mean central subfield thickness between patients with and without PDR was ∼40 μm and the difference in mean axial length was ∼400 μm (Table 1). Therefore, it is unlikely that the axial length differences can be completely explained by changes in macular thickness in our patients. Second, although an association was found between axial length and PDR in this study, more studies are needed to evaluate the causality and mechanism between them.
In summary, this observational study of Taiwanese patients in a hospital eye clinic suggests an inverse relationship between axial length and the development of PDR in patients with diabetes for 10 years or more. No relationship was found between axial length and the development of any DR. Further basic science studies and longitudinal cohort studies are necessary to elucidate its mechanism and the causal relationship.
Department of Ophthalmology
Chang Gung Memorial Hospital
222 Mai-Chin Road, Keelung 204
This study was supported by Chang Gung Medical Research Foundation (CMRPG260391 and CMRPG260401).
The authors obtained statistical consultation from Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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Keywords:© 2012 American Academy of Optometry
axial length; diabetes mellitus; diabetic retinopathy; myopia