Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti–Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema

Diabetic Retinopathy Clinical Research Network

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Purpose: To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. Design: Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. Participants: Participants with available plasma samples (N = 436). Methods: Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. Main Outcome Measures: Changes in the natural log (ln) of plasma VEGF levels. Results: Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61 pg/ml, −0.31±0.54 pg/ml, and −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were −0.01 (−0.12 to +0.10; P = 0.89), −0.31 (−0.44 to −0.18; P < 0.001), and −0.30 (−0.43 to −0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (−0.23 [−0.38 to −0.09]; P < 0.001); the difference between aflibercept and ranibizumab was −0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. Conclusions: These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

Original languageEnglish (US)
Pages (from-to)1054-1063
Number of pages10
Issue number7
StatePublished - Jul 1 2018

Bibliographical note

Funding Information:
C.C.W.: Board member − Alimera Sciences Inc, Allergan Inc, Bayer, Genentech Inc, Regeneron Pharmaceuticals Inc; Consultant − Alimera Sciences Inc, Allergan Inc, Bayer, Clearside Biomedical Inc, Genentech Inc, Regeneron Pharmaceuticals Inc; Grants and/or grants pending − Allergan Inc, Clearside Biomedical Inc, Genentech Inc, Regeneron Pharmaceuticals Inc; Lecture fees − Allergan Inc, Regeneron Pharmaceuticals Inc.

Funding Information:
Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (grant nos. EY14231, EY14229, and EY18817). Regeneron Pharmaceutical provided the aflibercept and Genentech provided the ranibizumab for this study. Genentech also provided funding for the plasma collection from this ancillary study. As per the Industry Collaboration Guidelines (available at ), the had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol. The funding organization (National Institutes of Health) participated in oversight of the conduct of the study and review of the manuscript but not directly in the conduct of the study or in the collection, management, or analysis of the data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2018 American Academy of Ophthalmology


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