Assessment of the association of optical coherence tomography angiography findings in diabetic retinopathy with metabolomic profile, nephropathy, and cardiovascular disease risk

Background: To comprehensively evaluate the associations between retinal microvascular parameters measured by OCTA across different stages of the diabetes spectrum and markers of diabetic nephropathy as well as UKPDS-based cardiovascular risk scores, and to characterize the shared pathophysiological burden along the retina–kidney–heart axis. Methods: In this prospective cross-sectional study, a total of 160 participants were enrolled according to ADA criteria and stratified into five groups: controls (n=37), prediabetes (n=31), type 2 diabetes mellitus without diabetic retinopathy (n=48), mild–moderate NPDR (n=20), and severe NPDR (n=24). Following ETDRS-based staging, OCT/OCTA was performed to quantify FAZ metrics, superficial and deep capillary plexus (SCP/DCP) and peripapillary radial peripapillary capillary (RPC) vessel densities, and retinal thickness parameters. Diabetic nephropathy was assessed using eGFR (CKD-EPI), microalbuminuria, and the albumin-to-creatinine ratio (ACR), while cardiovascular risk was estimated with the UKPDS Risk Engine. Untargeted LC–MS-based metabolomic profiling was conducted on plasma samples, and multivariate analyses (PCA) and pathway enrichment analyses were applied. Results: With increasing retinopathy severity, FAZ area and perimeter increased whereas FAZ circularity decreased (p<0.001). SCP/DCP and RPC vessel densities progressively declined across NPDR stages (p<0.001); macular thickness parameters were higher in the severe NPDR group (p<0.01). Microalbuminuria and ACR increased in the NPDR groups, while eGFR decreased (p<0.001). According to UKPDS, coronary heart disease and stroke risk scores were higher in the diabetes and NPDR groups than in the control/prediabetes groups (p<0.001). PCA demonstrated a stepwise separation between groups (PC1 40.8%; PC2 17.4%), with progression-consistent alterations in pathways related to energy metabolism, lipid peroxidation, inflammation, and oxidative stress. Conclusion: Increasing DR/NPDR severity is accompanied by OCTA-derived retinal microvascular impairment, worsening nephropathy markers, and elevated UKPDS cardiovascular risk. Metabolomic findings support pronounced progression-related changes in energy metabolism and oxidative stress/inflammation axes. These results suggest that retinal OCTA parameters may serve as noninvasive indicators of systemic microvascular burden.