Systemic and ocular diseases associated with the development of diabetic macular edema among Japanese patients with diabetes mellitus

The prevalence of diabetes mellitus (DM) continues to increase worldwide, and diabetic retinopathy (DR) remains a leading cause of vision loss in many countries [1, 2]. The reported prevalence of DR among patients with DM varies widely, from 1 to 40% [3‐9]. According to Yau et al., approximately 93 million people worldwide develop DR, 17 million are diagnosed with proliferative DR (PDR), and 21 million are diagnosed with diabetic macular edema (DME) [10].

Although PDR is the most common vision-threatening retinopathy, DME is responsible for most of the vision loss experienced by patients with DM and remains the major cause of vision loss among patients with DM with or without PDR. Many previous population-based or hospital-based studies have focused on the prevalence of DME, yet there are few large-scale studies examining the incidence of DME. In addition, the annual incidence rates of DME in previous studies varied widely from 0.01 to 6.0% [11‐15].

Previous epidemiological studies have also identified several risk factors associated with DR, including many systemic and lifestyle factors, nephropathy, obesity, alcohol consumption, hematological markers of anemia, hypothyroidism, inflammation, endothelial dysfunction, hyperglycemia, hypertension, dyslipidemia, diabetes duration, ethnic origin, pregnancy, and puberty [10, 16‐21]. Some risk factors have been associated with DME development, including duration of diabetes, hemoglobin A1c, blood pressure, nephropathy, higher cholesterol, retinal and vitreous inflammation, and oxidative stress in the retina [22], but inconsistencies exist among reports [23]. Furthermore, risk factors for DME may differ from those for DR, and the precise roles of these factors in the pathogenesis of DME are not well defined. Some epidemiological studies have examined the prevalence, incidence, and risk factors for DM and DR, including studies employing the Japan Diabetes Clinical Data Management Study Group (JDDM). Unfortunately, an insufficient number of studies have focused on DME in Japan. Currently, the main therapeutic procedures for DME are laser photocoagulation, vitrectomy, and anti-vascular endothelial growth factor (VEGF) injections, though these approaches are not always effective. In addition to the three approaches mentioned above, targeted therapies can ameliorate some of the identified risk factors. Here, we investigate systemic and ocular factors associated with DME development in a large-scale study based on the health insurance claim database in Japan.

This study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Review Board (IRB) of the University of Yamanashi. The IRB approved this study without requiring written informed consent from any of the patients because no data used in this study contained any personal information.

The total number of subjects registered in the database from 2005 to 2014 was 3,110,867. Of these, the total number of patients with DM was 66,923, with a mean age of 53.4 ± 11.0 years. Overall, 21,463 subjects had a DM-related ocular manifestation. After excluding subjects who did not satisfy the inclusion criteria, 17,403 individuals with a mean age of 55.7 ± 10.8 years were included in the analysis. Four hundred twenty subjects were diagnosed with DME, with a mean age of 55.2 ± 10.0 years, and the demographics of the enrolled subjects are listed in Table 1. DR was significantly more prevalent in males than females, but the incidence of DME development was not significantly different between males and females. Patients with and without DME visited medical institutions for diabetes treatment at frequencies of 3.2 times/year and 2.9 times/1 year, respectively, which was not a significant difference. The two groups also showed the same frequency of ophthalmological examinations (4.3 times/year). Among the 6345 ICD-10 standard disease codes, 86 were selected for investigating ICD-10 codes associated with the development of DME.

Although the global incidence of DM is increasing, that of DR is reported to be decreasing [27]. This finding might be explained by improvements in the control of systemic risk factors in patients with DM. DM-related severe ocular complications are one of the main causes of blindness worldwide. According to a recent study, DME is causing an increasing number of visual impairments in patients with DM [22]. DME, which does not result in total blindness but in severe vision loss, may instead be the main DM-associated severe ocular complication. In addition, advances in optical coherence tomography technology have enabled the identification of DME much more precisely and less invasively than before. Some previous studies have investigated factors associated with DME. However, many of these studies employed a cross-sectional design [8, 22, 23, 28‐31]. Although several studies have investigated factors associated with DME development, [2, 14, 32‐35] associations between concomitant and systemic diseases with DME were not reported. In the present study, we investigated factors associated with DME development among more than 6000 ICD-10 standard disease codes using a large claim dataset in Japan. Many of the systemic factors significantly associated with the development of DME are considered to be related to the presence of severe metabolic impairment, including hyperlipidemia, diabetic ketoacidosis, vessel lumen mass, postoperative percutaneous coronary angioplasty, lower leg skin ulcer, arrhythmia, diabetic nephropathy, and proteinuria. Impairment of microvasculature in the retina results in breakdown of the retinal pigment epithelial barrier, which is one of the key steps in DME development. Many systemic factors, including hyperglycemia, inflammation, and vascular endothelial dysfunction, are associated with DM-related microvasculature damage. Accordingly, there is a clear relationship between systemic microvasculature damage and ocular complications. Yamamoto et al. reported that diabetes, proteinuria and glomerular filtration rate were associated with higher risks of diabetic eye diseases, including DME [36].

DM has been identified as an important risk factor for osteoporosis-associated fracture [37, 38]. Among female subjects with type 1 DM, diabetic ketoacidosis in pregnancy can result in impending abortion. Because DM sometimes results in peripheral vestibular damage and predicts a poor prognosis of typical vestibular pathologies, some patients develop benign paroxysmal positional vertigo, which is one symptom of Ménière syndrome. Poor visual function due to DME may contribute to increased risk of falls, resulting in cervical and chest contusions. Furthermore, female patients with DM are more likely to report very irregular menstrual cycles [39]. Although the present study identified arthritis as a risk factor for developing DME, Tentolouris et al. found a negative correlation between arthritis and DM [40]. Regardless, the impact of DM on the incidence of rheumatoid arthritis is not well established.

The present study also revealed some systemic factors that were negatively associated with the development of DME. Some previous studies reported a significantly higher prevalence of primary osteoarthritis among subjects with DM than among those without DM, as well as significant associations with glycemic control and the duration of diabetes. Obesity may be associated with the onset of osteoarthritis, [41‐43] though we are unsure why our study showed a negative impact of osteoarthritis on DME. According to Taylor et al., diabetes may increase the risk of kidney stone formation by altering the composition of the urine, and insulin resistance may play a role in stone formation [44].

Moreover, several systemic diseases and ocular diseases that have not been reported to be related to DME development were identified. Interestingly, some factors were identified as negative factors. An explanation for the finding that hay fever and chronic eczema were significantly and negatively associated with DME development may be impairment of autoimmune function, as DM deteriorates autoimmune function, and a significantly lower prevalence of allergic rhinitis has been observed in subjects with metabolic syndrome, high blood pressure, or impaired fasting glucose levels [45].

Many previous studies have focused on the effects of DM on pathological conditions and disorders, whereas few have investigated factors associated with the development of DME in a large sample. We were unable to precisely investigate the status of glycemic control and severity of DM complications in the present study, and further studies are thus necessary to clarify these points.Although some significantly associated systemic factors identified in the current study are consistent with previous reports, some of them have never been reported to be associated with the development of DME. In addition to diseases found to act as risk factors to date, such as renal and circulatory disorders, orthopedic and dermatological diseases were identified to be associated with the development of DME, which may be because the current study included more than 6000 diseases in the analysis. Furthermore, some factors were found to be negatively associated with DME. Currently, information about the mechanisms of these factors in DME development is limited, and these data must be confirmed in further investigations.

Previous papers have reported some ocular factors associated with DME development, including DR severity, [2, 32, 46] cataract surgery, [33] and ocular inflammation, [35] consistent with the current results. The present study also revealed some new ocular factors associated with DME development, some of which are related to systemic and ocular DM complications. As possible explanations for these associations, ocular movement disorder and accommodative paralysis or corneal disease and ocular pain may be related to microvasculature destruction or DM-associated loss of tear-film stability, respectively. Additionally, scleritis and conjunctivitis may be related to DM-induced microinflammation. Retinal vessel occlusion showed the highest OR and was selected as a disease often observed in subjects with retinal circulation disorders and severe diabetic retinopathy. Moreover, eye movement disorder and accommodation paralysis are strongly associated with DME development. Further studies are necessary to clarify the mechanism between DME and systemic or ocular risk factors.

This study also has several limitations. Because the subjects were limited to social insurance subscribers and because subscribers of national health insurance, another major insurance provider in Japan, was not considered, the target sample may be biased. National health insurance is managed by each municipality, increasing the difficulty of integrating and collecting data; hence, these data were not included in the study. As subjects in JMDC constitute employees and their dependents, it is possible that a significant number of senior citizens, whose prevalence of DM could be higher than that in JMDC, were not included in the database. National health insurance members must also be considered in the future. The use of diagnosis codes of claims data as diagnostic criteria also has several problems. First, the accuracy of the diagnosis is not necessarily high. The currently used database may include subjects who have not been medically diagnosed with DM to obtain reimbursement from health insurance. Therefore, only patients who were prescribed anti-DM drugs were included in this study. An investigation of whether some reported risk factors are associated with DME development was impossible because the current database does not contain information about certain factors, including hemoglobin A1c levels [14] and the severity of DR [2, 32, 46]. Genetic factors have also been reported to contribute to DME development, such as genes related to VEGF and erythropoietin [47‐51]. Unfortunately, claims data do not contain genetic information. In this study, we worked with epidemiological statisticians to accurately detect risk factors associated with DME development from many disease categories, but it was difficult to completely exclude the influence of confounding factors. Because no accurate information regarding the type of DM was available for approximately half of all subjects, it was impossible to compare risk factors between type 1 DME and type 2 DME. We excluded some diseases due to a small number of patients, which may have involved factors for which we could not detect an association. Inconsistencies between previous reports and the current study may also be partially due to differences in the statistical methods applied. Previous studies have reported differences between DR- and DME-associated factors. In this study, we focused on factors associated with the development of DME. In the future, it will be necessary to examine factors associated with the development of DMR and DME using the same database.

In this study, we clarified systemic and ocular diseases associated with DME development in Japan. Notably, many patients with DM do not undergo periodic eye examinations. Based on the results, factors associated with DME development should be closely monitored. Because DR is may be asymptomatic during the period in which laser photocoagulation should be applied, asymptomatic individuals should be screened to minimize the risk of vision loss. As the number of DME patients is expected to increase, further studies on the early detection and prevention of DME development are needed.