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Original Investigation
January 24, 2019

Factors Associated With Visual Acuity and Central Subfield Thickness Changes When Treating Diabetic Macular Edema With Anti–Vascular Endothelial Growth Factor Therapy: An Exploratory Analysis of the Protocol T Randomized Clinical Trial

Author Affiliations
  • 1Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 2Jaeb Center for Health Research, Tampa, Florida
  • 3Department of Ophthalmology, University of Pennsylvania, Philadelphia
  • 4California Retina Consultants, Santa Barbara, California
  • 5Feinberg School of Medicine, Northwestern University Medical School, Chicago, Illinois
  • 6Southeast Retina Center, P.C., Augusta, Georgia
  • 7Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology, Boston, Massachusetts
JAMA Ophthalmol. 2019;137(4):382-389. doi:10.1001/jamaophthalmol.2018.6786
Key Points

Question  Are there baseline factors other than visual acuity and central thickness that are associated with the magnitude of treatment benefit associated with anti–vascular endothelial growth factor (VEGF) therapy of diabetic macular edema?

Findings  In this secondary analysis of randomized clinical trial data, younger participant age, lower hemoglobin A1c levels, and the absence of prior panretinal photocoagulation were each associated with better 2-year vision outcomes in Protocol T. African American race/ethnicity and the presence of subretinal fluid were associated with a greater central subfield thickness improvement at 2 years.

Meaning  Younger patients and those without prior panretinal photocoagulation may demonstrate more visual acuity improvement, irrespective of the anti–VEGF agent that is used.


Importance  Identifying the factors that are associated with the magnitude of treatment benefits from anti–vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) may help refine treatment expectations.

Objective  To identify the baseline factors that are associated with vision and anatomic outcomes when managing DME with anti-VEGF and determine if there are interactions between factors and the agent administered.

Design, Setting, and Participants  This post hoc analysis of data from the Diabetic Retinopathy Clinical Research Network multicenter randomized clinical trial , Protocol T, was conducted between December 2016 and December 2017. Between August 22, 2012, and August 28, 2013, 660 participants were enrolled with central-involved DME and vision impairment (approximate Snellen equivalent, 20/32-20/320).

Interventions  Repeated 0.05-mL intravitreous injections of 2.0-mg aflibercept (201 eyes), 1.25-mg bevacizumab (185 eyes), or 0.3-mg ranibizumab (192 eyes) per protocol.

Main Outcomes and Measures  Change in visual acuity (VA) and optical coherence tomography (OCT) central subfield thickness at 2 years and change in VA over 2 years (area under the curve [AUC]).

Results  Among 578 participants, the median age (interquartile range) was 61 (54-67) years. Across anti-VEGF treatment groups, each baseline factor was associated with mean improvement in VA and a reduction in central DME compared with the baseline. For every decade of participant age, the mean VA improvement was reduced by 2.1 letters (95% CI, −3.0 to −1.2; P < .001) in the VA and 1.9 letters (95% CI, −2.4 to −1.3; P < .001) in the VA AUC analyses. For each 1% increase in hemoglobin A1c levels, VA improvement was reduced by 1 letter in the VA (95% CI, −1.5 to −0.5; P < .001) and 0.5 letters (95% CI, −0.9 to −0.2; P < .001) in the VA AUC analyses. Eyes with no prior panretinal photocoagulation (PRP) and less than severe nonproliferative diabetic retinopathy had an approximately 3-letter improvement in the VA (95% CI, 0.9-5.4; P = .007) and VA AUC (95% CI, 1.3-4.2; P < .001) analyses compared with eyes with prior PRP. On average, African American participants had greater reductions in central subfield thickness compared with eyes of white participants (−27.3 μm, P = .01), as did eyes with central subretinal fluid compared with eyes without this OCT feature (−22.9 μm, P = .01). There were no interactions between the predictive factors and the specific anti-VEGF agent that was administered for any VA or OCT outcome.

Conclusions and Relevance  Lower hemoglobin A1c levels were associated with the magnitude of vision improvement following anti-VEGF therapy, providing further evidence to encourage glycemic control among persons with diabetes. Younger patients and those without prior PRP might expect greater improvement in VA than older patients or those with prior PRP.