Retinal Microvascular and Neuronal Alterations in Type 2 Diabetes: Insights From a Population-Based Screening Program (START2)

Purpose: To explore early microvascular and neuronal retinal alterations in type 2 diabetes mellitus (T2DM) and their associations with lesion distribution, systemic factors, treatment exposure, and lifestyle variables in a real-world screening cohort. Methods: In this retrospective cross-sectional study, 1978 eyes from 998 participants observed in a diabetic retinopathy screening program underwent ultra-widefield fundus photography, optical coherence tomography (OCT), and OCT-angiography (OCTA) (CIRRUS 5000 HD-OCT with AngioPlex). Ganglion cell layer and inner plexiform layer (GCL-IPL) thickness was measured by OCT, and OCTA assessed skeletonized vessel density (SVD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP). Retinal lesions were classified as not visible or as central or peripheral, or both. Mixed-effects models were used to compare lesion groups and assess associations with systemic and lifestyle factors. Results: Of 1978 eyes, 1468 (74%) had no visible lesions, and 510 (26%) showed lesions (229 peripheral only, 132 central only, 149 both). Eyes with both lesions exhibited significantly reduced SVD compared with eyes without lesions (SCP, P = 0.019; DCP, P = 0.035) and with peripheral-only lesions (SCP, P = 0.005; DCP, P = 0.019). No significant differences were found for GCL-IPL. GCL-IPL thickness was associated with older age (P < 0.001) and higher body mass index (P = 0.020), and reduced SVD-SCP was associated with older age (P < 0.001) and higher glycated hemoglobin (P = 0.004). Conclusions: Combined central and peripheral lesions are associated with greater microvascular impairment. Age and glycemic control are key determinants of early retinal microvascular changes in T2DM, and age and body mass index relate to GCL-IPL thickness, highlighting the need for a multidisciplinary approach to improve early detection, risk stratification, and ocular and systemic management.