Systemic Lactate Dehydrogenase Levels as a Predictor of Progression from Non-Proliferative to Proliferative Diabetic Retinopathy

Background: Diabetic retinopathy (DR) is a leading cause of vision loss, and its progression from non-proliferative (NPDR) to sight-threatening proliferative diabetic retinopathy (PDR) is a critical event. Systemic lactate dehydrogenase (LDH), a marker of cellular hypoxia and turnover, has been implicated in various disease processes. We investigated the association between systemic LDH levels at the time of NPDR diagnosis and the 1-year risk of progression to PDR and other sight-threatening complications. Methods: We conducted a retrospective, propensity-matched cohort study using the TriNetX US Collaborative Network. Patients with a new NPDR diagnosis were stratified into three groups based on a single LDH measurement taken within six months of the index date: low (< 200 U/L), moderate (201–280 U/L), and high (≥281 U/L). Two separate 1:1 nearest-neighbor propensity-matched analyses were performed: one comparing the low-LDH group to the moderate-LDH group, and a second comparing the low-LDH group to the high-LDH group. Matching was performed on a comprehensive set of demographic, metabolic, vascular, and ocular covariates. The primary outcomes were the 1-year absolute risks and risk ratios (RR) for PDR, tractional retinal detachment (TRD), and vitreous hemorrhage (VH). Results: In the first analysis, the low-LDH cohort was compared to the moderate-LDH cohort. The moderate-LDH group had a higher 1-year absolute risk of PDR (3.93 % vs. 2.96 %, RR 1.33, 95 % CI 1.14–1.54), TRD (1.35 % vs. 0.99 %, RR 1.36, 95 % CI 1.07–1.73), and VH (4.38 % vs. 3.51 %, RR 1.25, 95 % CI 1.10–1.42). In the second analysis, comparing the low-LDH group to the high-LDH group, the high-LDH cohort showed an increased risk for PDR (3.66 % vs. 3.00 %, RR 1.22, 95 % CI 1.05–1.42), TRD (1.27 % vs. 0.96 %, RR 1.32, 95 % CI 1.04–1.67), and VH (1.27 % vs. 0.96 %, RR 1.22, 95 % CI 1.08–1.40). Conclusion: Our findings demonstrate a consistent, dose-dependent relationship between higher systemic LDH levels and an increased risk of progression to PDR and its complications. This suggests that systemic LDH levels may be an independent and readily available biomarker for identifying patients with NPDR who are at higher risk for sight-threatening outcomes.