Plasma Metabolomics Identifies Key Metabolites and Improves Prediction of Diabetic Retinopathy: Development and Validation Across Multi-National Cohorts

Purpose To identify longitudinal metabolomic fingerprints of diabetic retinopathy (DR) and evaluate their utility in predicting DR development and progression. Design Multicenter, multi-ethnic cohort study. Participants This study included 17,675 participants with baseline pre-diabetes/diabetes, in accordance with the 2021 American Diabetes Association guideline, and free of baseline DR from the UK Biobank (UKB); and an additional 638 diabetic participants from the Guangzhou Diabetic Eye Study (GDES) for external validation. Methods Longitudinal DR metabolomic fingerprints were identified through nuclear magnetic resonance assay in UKB participants. The predictive value of these fingerprints for predicting DR development were assessed in a fully withheld test set. External validation and extrapolation analyses of DR progression and microvascular damage were conducted in the GDES cohort. Model assessments included the C-statistic, net classification improvement (NRI), integrated discrimination improvement (IDI), calibration, and clinical utility in both cohorts. Main Outcome Measures DR development, progression, and retinal microvascular damage. Results Of 168 metabolites, 118 were identified as candidate metabolomic fingerprints for future DR development. These fingerprints significantly improved the predictability for DR development beyond traditional indicators (C-statistic: 0.802, 95% CI, 0.760–0.843 vs. 0.751, 95% CI, 0.706–0.796; P = 5.56×10−4). Glucose, lactate, and citrate were among the fingerprints validated in the GDES cohort. Using these parsimonious and replicable fingerprints yielded similar improvements for predicting DR development (C-statistic: 0.807, 95% CI, 0.711–0.903 vs. 0.617, 95% CI, 0.494, 0.740; P = 1.68×10−4) and progression (C-statistic: 0.797, 95% CI, 0.712–0.882 vs. 0.665, 95% CI, 0.545–0.784; P = 0.003) in the external cohort. Improvements in NRIs, IDIs, and clinical utility were also evident in both cohorts (all P <0.05). In addition, lactate and citrate were associated to microvascular damage across macular and optic disc regions (all P <0.05). Conclusions Metabolomic profiling has proven effective in identifying robust fingerprints for predicting future DR development and progression, providing novel insights into the early and advanced stages of DR pathophysiology.