10-year Progression of Diabetic Retinopathy: Identification of Signs and Surrogate Outcomes

Diabetic retinopathy (DR) is the most frequent complication of diabetes mellitus and the leading cause of legal blindness in active populations of industrialized countries. Progression of DR has been up to now classified according to the ETDRS classification, based on a multicentric study that evaluated the effect of laser photocoagulation on advanced stages of DR. Although appropriate for late stages of DR, it does not grade progression well in the initial stages of the disease. Initial stages of DR require urgent characterization and their evolution should be well defined because some of the lesions are still reversible.

The early stages of DR are characterized by 4 main alterations: microaneurysms (MA) and retinal hemorrhages, represented by red dots in the fundus, blood-retinal barrier breakdown, capillary closure and damage of neuronal and glial cells of the retina. Thus, there are both microvascular changes, with endothelial cell and pericyte damage with thickening of basement membrane, and neuronal changes.

Based on previous studies, progression of DR does not occur at the same rate in all patients. Some never develop vision loss, whereas others rapidly progress to macular edema or neovascularization leading to vision loss. The understanding of the mechanisms that balance in different direction is of outmost importance. The duration of diabetes mellitus and the metabolic control are major risk factors for DR progression, but they are insufficient to explain the great variability observed in patients.

Recent data indicate that MA turnover may be an appropriate indicator of DR progression. Our research group has identified different DR progression phenotypes. Phenotype A is characterized by a low MA turnover, phenotype B characterized by increased thickness and phenotype C with predominant ischemia, with a high MA turnover. These phenotypes were defined based on MA turnover (RetmarkerDR) and on central retinal thickness (RT) measured by Optical Coherence Tomography (OCT) and the model was able to correctly identify eyes at risk of progression. 61,8-76,7% of eyes with an increase RT in the central subfield, inner and/or outer ring allowed a MA formation rate ≥ 2 and/or a MA turnover ≥ 6. More recently, some genetic variants have been linked to the different phenotypes and may explain specific progression patterns.

There is emerging evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR and that it could participate in the development of microvascular abnormalities. The understanding of the underlying mechanisms leading to neurodegeneration and the identification of the mediators between neurodegeneration and microangiopathy is essential.