resistance, and relative insulin deficiency), with sight-threatening retinopathy 2.5 times more common in type I. This finding is independent of the duration of diabetes [9, 10]. The pooled data from 35 studies in META-EYE study, after adjusting for other known risk factors, showed type I diabetics with >20 years of disease were 2.7 times more likely to have any DR compared to those with type II diabetes for 10 years. The prevalence of DR increases with duration of diabetes, HbA1c, blood pressure, and cholesterol [3].

The prevalence and incidence of DR in diabetes type I may be declining in industrialized countries. In one study, the incidence of PDR and severe vision loss between a 1986–2008 cohort and a 1975–1985 cohort was 2.6 % vs. 19.5 % and 3.2 % and 9.7 %, respectively [11, 12]. The annual incidence of PDR was also declined in the WESDR cohort, from 3.4 to 1.4 %, among type 1 diabetic patients. The WESDR study reported a 25-year cumulative rate of improvement to be 18 % (95 % CI, 14–21 %) in DR, which was thought to be the result of improved glycemic control and possibly greater access to health care [13].

1.3Risk Factors

The pathogenesis of DR is multifactorial and complex. The META-EYE study found the duration of diabetes, poor glycemic control, and high blood pressure to be the major risk factors for developing DR [3, 14]. Others risk factors include dyslipidemia, socioeconomic status, pregnancy, and puberty [15]. Diabetic retinopathy also may have a genetic component associated with it. Several genetic loci have been associated with the pathogenesis of type I and II diabetes [16, 17].

1.3.1Duration of Diabetes Mellitus

There is a strong positive relationship between the duration of diabetes and prevalence and progression of DR. Almost all type I diabetic patients and over threefourths of type II diabetic patients will have some form of DR after 20 years of the disease [4, 18–21]. The WESDR study showed that among the younger-onset patients with diabetes, the prevalence of any retinopathy progressively increased from 8 % at 3 years, to 25 % at 5 years, to 60 % at 10 years, to 80 % at 15 years, and the prevalence of PDR increased from 0 % at 3 years to 25 % at 5 years [9]. The prevalence of any DR increased from 21.1 % in subjects with diabetes of 10 years duration to 54.2 % with duration between 10 and 20 years, to 76.3 % with ≥20 years disease duration in the META-EYE study [3]. After adjusting for known risk factors, the relative risk of individuals with type 1 diabetes to develop DR increased from 1.38 among those with duration <10 years to 2.69 for those with disease duration ≥20 years; among type II diabetic patients, the relative risk increased from 1.0 to 2.45 [3]. Patients with type I diabetes >20 years duration are 8.7 times more likely to have VTDR compared with type 2 diabetic patients with the disease for <10 years [3].

The Diabetes Control and Complications Trial (DCCT) demonstrated that among insulin-dependent diabetic patients, intensive control of blood sugar reduced risk of DR progression significantly by 54 % (95 % CI: 62–85 %) and the risk of developing DR by 76 % (95 % CI: 62–85 %) [24]. The UK Prospective Diabetes Study (UKPDS) also showed that improved blood glucose control by intensive therapy reduces the overall rate of microvascular complications by 25 % in non-insulin- dependent diabetic patients [25–27].

The International Expert Committee, the World Health Organization (WHO), and the American Diabetes Association (ADA) recently have recommended use of a HbA1c level of 6.5 % or higher to be the diagnostic criterion for DM [20, 28]. The specific cutoff point of 6.5 % for the HbA1c was based on data pooled from nine studies that showed the prevalence of moderate retinopathy increases at the numerical value of 6.5 % [29]. A strong association exists between HbA1c and DR [24, 30].

The accumulated incidence of DR, 10 years after type 1 DM is diagnosed, is approximately 90 % in patients with HbA1c between 10.2 and 11.5 % [31]. Patients with HbA1c levels of 6.5–6.9 % have a 2.35 times higher risk of developing DR at 3 years than those with HbA1c levels of 5.0–5.4 % [32]. The META-EYE study showed the prevalence of DR increased from 18.0 to 51.2 % when HbA1c increased from ≤7.0 to >9.0 % [3]. The WESDR showed that in type 1 DM for every 1 % increase in the HbA1c value, the risk of DR progression increases by 1.21-fold [9]. A 10 % decrease in HbA1c has shown to reduce the risk of microvascular complications by 43 % [33]. Some patients do not develop microvascular complications despite poor control [34], but this outcome is quite rare.

Chronic hyperglycemia promotes oxidative stress and increased production of reactive oxygen species. These moieties initiate a cascade of events that ultimately causes dysfunction of retinal vessel endothelial cells. Animal models of DM have shown an increase in vascular endothelial growth factor (VEGF) receptors in the presence of persistent hyperglycemia [35]. Methods to lower chronic hyperglycemia may be critical to reduce the microvascular and neuronal complications of diabetes.

1.3.3Hypertension

Poor control of hypertension worsens DR [25]. Hypertension may be an independent risk factor for type II diabetes-related DR [27, 36]. The META-EYE study showed that the prevalence of DR increases from 30.8 to 39.6 % and that of VTDR increases from 7.60 to 17.63 % when diabetic patients with blood pressure ≤140/90 mmHg were compared to diabetic patients with blood pressure >140/90 mmHg [3]. The relative risk for developing any DR is 1.5 with systolic pressure between 125 and 139 mmHg and 2.8 for systolic pressure higher than 140 mmHg [27].

The UKPDS showed that intensive blood pressure control (<150/85 mmHg) in hypertensive patients with type 2 DM yielded a significant 34 % reduction in risk of 2-step worsening on the retinopathy grade and a 47 % reduction in risk of