To determine the ability of peripapillary neurovascular units (NVU) to detect early changes in the retinal microvasculature and microstructure, and to explore systemic factors linked to the peripapillary NVU injury in type 2 diabetic patients without clinically detectable retinopathy (NDR).Fifty-two NDR patients (mean age 51.08 ± 9.60 years; 24 females; diabetes duration 8.74 ± 6.71 years) and 42 age- and sex-matched healthy controls (mean age 50.24 ± 7.97 years, 20 females) were recruited for this prospective, cross-sectional study. Retinal microvascular and microstructural networks were visualized using spectral domain optical coherence tomography angiography (OCTA). Quantitative analysis of radial peripapillary capillary (RPC) density and peripapillary retinal nerve fiber layer (p-RNFL) thickness was automatically performed using the device program, with segmentation of retinal regions into intra-optic disc and peripapillary zones. The peripapillary area was further subdivided into eight sectors for detailed regional assessment.Compared to controls, the RPC density in eight sectors and p-RNFL thickness in four sectors were significantly reduced in NDR patients (P < 0.05). The areas under the receiver operating characteristic curves for the RPC density combined with the p-RNFL thickness were generally larger than those of each single indicator (the highest AUC = 0.745, P < 0.001). Univariate linear regression analysis revealed significant correlations between glycated hemoglobin (HbA1c), urinary microalbuminuria and blood urea with decreased RPC density (P < 0.05). Additionally, age, intraocular pressure, blood urea, blood creatinine and estimated glomerular filtration rate (eGFR) were significantly correlated with p-RNFL thickness thinning (P < 0.05). Multivariate linear regression analysis showed that HbA1c and blood urea were the most significant factors for RPC impairment, while eGFR was correlated with p-RNFL defects (P < 0.05).Peripapillary NVU assessment may be valuable for monitoring and intervening in retinal microvascular and microstructural changes associated with DM. HbA1c level and renal function indicators represented by blood urea and eGFR, were the most important systemic factors underlying peripapillary NVU changes.Copyright © 2025. Published by Elsevier B.V.