Systemic, Ocular Risk Factors Predict Treatment Response to Aflibercept in DME

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Factors including a longer diabetes duration and lower eGFR were associated with suboptimal treatment response to aflibercept in patients with DME.

Real-world data indicate five monthly loading doses of intravitreal aflibercept injection were associated with significant anatomical and visual improvements in patients with diabetic macular edema (DME).1

The investigative team from South Korea revealed those patients with a longer duration of diabetes, a lower estimated glomerular filtration rate (eGFR), higher serum creatinine and potassium levels, and the presence of epiretinal membrane experienced suboptimal treatment response.

“These systemic and ocular risk factors can predict the individual response of patients with DME to intensive aflibercept treatment,” wrote the study authors, led by Junyeop Lee, MD, PhD, department of ophthalmology, Asan Medical Center, University of Ulsan.

Vascular endothelial growth factor (VEGF) is a key mediator of the pathophysiology of DME, making intravitreal anti-VEGF injections the standard of care for the retinal disease. Without consensus on the optimal treatment regimen, intensive loading injections followed by pro re nata (PRN) doses are considered beneficial to alleviate the treatment burden of intravitreal injections.2

To maximize the efficacy of intensive aflibercept treatment, Lee and colleagues indicated the need to clarify the modifiable risk factors that affect treatment response.1 The retrospective cohort study set out to investigate both systemic and ocular factors affecting patient response in a real-world setting between April 2020 and January 2022. Medical records of all consecutive DME patients with received 5 monthly loading doses of 2mg aflibercept were included in the analysis, for a total of 30 eyes of 23 patients with DME.

Patients were followed monthly after the loading phase and received PRN treatment only if their central retinal thickness (CRT) was ≥300 µm and increased to >50 µm compared with the previous measurement. PRN treatment was not limited to aflibercept and could encompass other treatment methods, including bevacizumab and dexamethasone intravitreal implant.

Anatomical and functional treatment response was measured by CRT and BCVA in every monthly visit. The primary treatment outcome for the analysis was determined by mean changes in these variables, as well as the proportion of good responders (<300µm) and suboptimal responders (≥300 µm) based on CRT after the loading phase. To determine the factors affecting treatment response, Lee and colleagues compared baseline ocular and systemic factors between good and suboptimal treatment responders.

After completion of the loading phase with aflibercept, the analysis revealed the mean CRT and BCVA were significantly improved (486.87 ± 95.46 to 334.90 ± 69.47 µm and 0.51 ± 0.30 to 0.35 ± 0.25 logMAR, respectively; all P < .05). Based on CRT at month 5, 11 eyes (36.66%) were good responders, and 19 eyes (63.33%) were suboptimal responders, experiencing persistent DME.

Over the PRN regimen, the mean CRT was found to increase along with deterioration of BCVA, but the study team noted it was not worse than the baseline values. A total of 16 eyes (53.33%) were able to maintain improved CRT without additional treatment, but 14 eyes (46.66%) needed PRN treatment during the 12 months of follow-up.

Logistic regression analysis revealed eyes with diabetes duration ≥15 years (P = .011), eGFR <80mL/min/1.73m2 (P = .046), serum creatinine ≥0.95 mg/dL (P = .026), potassium ≥4.7 mmol/L (P = .026), and the presence of ERM (P = .014) were more likely to have suboptimal treatment response. After tracking longitudinal changes over the 12-month follow-up, investigators found eyes with these factors showed less decreased CRT in response to aflibercept treatment.

The study team noted changes in BCVA were similar to those in CRT during the follow-up period, but were not wholly consistent, with changes in BCVA showing greater fluctuation.

“Interestingly, our study showed that longitudinal changes in CRT and BCVA were similar but not completely consistent, suggesting that the anatomical resolution alone does not fully account for visual function,” investigators wrote.


  1. Han YE, Jo J, Kim YJ, Lee J. Factors Affecting Intensive Aflibercept Treatment Response in Diabetic Macular Edema: A Real-World Study. J Diabetes Res. 2023;2023:1485059. Published 2023 Jul 18. doi:10.1155/2023/1485059
  2. J. A. Wells, A. R. Glassman, A. R. Ayala et al., “Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema,” The New England Journal of Medicine, vol. 372, no. 13, pp. 1193–1203, 2015.