Aqueous VEGF Levels Strongly Correlate with DR Severity

A recent study aimed to establish a reliable biomarker for classifying the severity of diabetic retinopathy (DR) that can help guide preventative treatment. Its authors investigated the correlation between aqueous vascular endothelial growth factor (VEGF-A) levels and DR severity in a large cohort of patients with diabetes, identifying a strong correlation between increasing levels of the protein and worsening DR severity.Conducted at the Vanderbilt Eye Institute in Nashville, the prospective study encompassed a cohort of 328 eyes from 164 adults diagnosed with type 2 diabetes, alongside a control group of 107 eyes from nondiabetic individuals. Following a comprehensive eye examination, including visual acuity measurements and advanced retinal imaging, participants were categorized into groups based on DR severity using the International Clinical Disease Severity Scale: no DR, moderate nonproliferative DR (NPDR) and proliferative DR (PDR). Aqueous humor samples were collected from all participants. The relatively short half-life of VEGF-A allows its levels to reflect real-time biological activity within the retina, providing an immediate indicator of disease status. Researchers argue that the novel biomarker may be more reliable than HbA1c or traditional grading of color fundus photographs for assessing DR severity. These photos from the study show PDR eyes with measured aqueous VEGF-A levels of 177.47 pg/ml (left), 373.57 pg/ml (middle), and 1058.71 pg/ml (right). Photo: Steinkerchner MS, et al. Ophthalmol Sci. September 2025. Click image to enlarge. The findings revealed a positive linear correlation between VEGF-A levels and DR severity. Specifically, median VEGF-A levels were found to increase progressively with the severity of DR, with values reported as 100.3pg/ml in the no DR group, 162.7pg/ml in moderate NPDR and 295.5pg/ml in those with PDR. Odds ratios were calculated to quantify this relationship, indicating a statistically significant increase in odds for elevated VEGF-A levels as DR severity escalated, even after controlling for gender, age and HbA1c. The odds ratios for various severities of retinopathy were as follows: 2.72 for mild-moderate NPDR, 6.79 for moderate-severe NPDR and 15.02 for PDR.In their paper discussing the findings, the researchers explained how VEGF-A presents several benefits as a biomarker for DR when compared to HbA1c or conventional grading of color fundus photographs, which require advanced clinical interpretation and may not accurately reflect the ongoing disease activity. “Due to its relatively short half-life,” they wrote, “VEGF-A levels reflect real-time biologic activity within the retina and therefore should closely reflect disease activity.” Additionally, unlike HbA1c measurements—which reflect long-term glucose control rather than immediate pathological changes in the retina—VEGF-A allows for a more relevant and timely assessment of DR.Furthermore, the authors pointed out that VEGF-A can be objectively measured and quantified with minimal resources—requiring less than 50µl of aqueous humor—enabling practical application in clinical settings. Notably, the study did not find a significant correlation between VEGF-A levels and the presence of diabetic macular edema (DME), suggesting that while VEGF-A plays a critical role in DR progression, its relationship with other pathological features of diabetes may involve additional factors. The researchers noted in their paper that although anti-VEGF agents are the primary treatment for DME, there is a recognized insufficient correlation between aqueous VEGF levels and treatment efficacy. They pointed out that only 40% to 50% of eyes with DME achieve resolution using anti-VEGF therapy alone.“Our findings confirm and expand upon these earlier observations and align with our current understanding of the multifactorial pathogenesis of DME, involving both VEGF-mediated permeability and inflammatory-mediated pathways,” they wrote. “Other mediators such as interleukin (IL)-6 or IL-8 alone or in combination with VEGF-A may ultimately prove to be more viable biomarkers for DME.” Nonetheless, they argued, “monitoring VEGF-A levels in DME could optimize treatment strategies.”In conclusion, the researchers wrote, “These results support VEGF-A as a novel biomarker to classify DR severity and identify eyes at greater risk for progression. Use of VEGF-A levels may guide early treatment, prevent vision loss and allow optimal allocation of healthcare resources.” Click here for the journal source. Steinkerchner MS, Lee LH, Manda AR, et al. Classification of diabetic retinopathy severity with aqueous VEGF levels: a prospective, observational study. Ophthalmol Sci. September 2025. [Epub ahead of print]. View FootnotesThis article was developed by the editorial staff in conjunction with experts in the field. In the process, AI may have been among the editorial tools used to meet the goals of human editors, who approved all content.