Different retinopathy phenotypes in type 2 diabetes predict retinopathy progression

Abstract

Purpose: To characterize the progression in retinopathy severity of different phenotypes of mild nonproliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes.

Design and methods: Patients with type 2 diabetes and mild NPDR (ETDRS 20 or 35) were followed in a 5-year longitudinal study. Examinations, including color fundus photography (CFP) and optical coherence tomography (OCT and OCTA), were performed at baseline, 6 months and then annually. Phenotype classification was performed based on microaneurysm turnover (MAT, on CFP) and central retinal thickness (CRT, on OCT). Phenotype A is characterized by low MAT (< 6) and normal CRT; Phenotype B by low MAT (< 6) and increased CRT; and Phenotype C by higher MAT (≥ 6) with or without increased CRT. ETDRS grading of seven fields CFP was performed at the initial and last visits.

Results: Analysis of ETDRS grade step changes showed significant differences in diabetic retinopathy (DR) progression between the different phenotypes (p < 0.001). Of the 66 participants with phenotype A only 2 eyes (3%) presented 2-or-more-step worsening. None of the 50 participants characterized as phenotype B developed 2-step worsening, whereas 13 eyes (23.2%) characterized as phenotype C had 2-or-more-steps worsening. Phenotype C presents the higher risk for 2-or-more step worsening (OR: 15.94 95% CI: 3.45-73.71; p < 0.001) and higher sensitivity, correctly identifying 86.7% of cases at risk (AUC: 0.84 95% CI: 0.72-0.96; p < 0.001). Diabetic retinopathy severity progression was associated with HbA_1c (p = 0.019), LDL levels (p = 0.043), and ocular factors as MAT (p = 0.010), MA formation rate (p = 0.014) and MA disappearance rate (p = 0.005). Capillary closure at 5-year follow-up, identified by lower vessel density (VD) on OCTA, was also associated with diabetic DR severity progression (p = 0.035).

Conclusions: Different DR phenotypes in type 2 diabetes show different risks of retinopathy progression. Phenotype C is associated with increased HbA_1c values and presents a higher risk of a 2-or-more-step worsening of the ETDRS severity score.

Keywords: Biomarkers; Microaneurysm; Phenotypes; Retinal thickness; Retinopathy; Type 2 diabetes.

Fig. 1

Representative cases for the three phenotypes of DR progression (color fundus image: MA earmarked using the software RetmarkerDR at 6 months visit: red dots are new MA, yellow dots are MA that disappeared from baseline to V6months, and green dots are MA that were present in both visits; Central Retinal Thickness: central macular thickness maps obtained with the SD-OCT). Reference values from Zeiss SD-OCT

Fig. 2

Correlation between vessel density at last visit with ETDRS step change over time. Vessel density was assessed at last visit of the study and is presented as Median and quartile 1 and 3 range. ETDRS step change was accessed by the difference between ETDRS grades in in the baseline and last visit, considering step improvement, maintenance or worsening and represents diabetic retinopathy progression

Fig. 3

ROC curve for Systemic markers, Systemic markers + MAT and Systemic markers + Phenotype C on the prediction of 2-or-more ETDRS grade step worsening. Includes indication of AUC (95% confidence interval), sensitivity and specificity