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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bressler reported grants from Jaeb Center, Genentech, Bayer, Novartis, and Boehringer Ingelheim. Dr Odia reported grants from the National Eye Institute (NEI), and nonfinancial support from Genentech and Regeneron. Dr Maguire reported grants from a Jaeb Center subcontract of an NEI grant and personal fees from Genentech/Roche. Dr Dhoot reported grants and personal fees from Regeneron and Genentech and personal fees Alimera Sciences, Allergan, Notal Vision, Santen, and Allegro. Dr Glassman reported grants from NEI, Regeneron, and Genentech. Dr Jampol reported grants from NEI. Dr Marcus reported grants and personal fees from Genentech /Rocher, Regeneron, Alimera, and Apellis; grants from Novartis, Alcon, Thrombogenics, grants from Allergan, Astellas, Acucela, Neurotech, Tyrogenex , Ophthotech, Opthea, Samsung, Mylan, GSK, Pfizer, Ohr, Clearside, Aerpio, Ironwood, and Chengdhu; and having drug delivery patents issued. Dr Sun reported grants from Jaeb Center, Northwestern University, Juvenile Diabetes Research Foundation, NEI, and Boehringer Ingelheim; nonfinancial support from Optovue, Boston Micromachines, Adaptive Sensory Technologies, and Novo Nordisk, grants and nonfinancial support from Genentech and Kalvista; personal fees from Eleven Biotherapeutics, Vindico Medical Education, Current Diabetes Reports, Merck, Allergan, Kowa, Regeneron, and Bayer; and personal fees and nonfinancial support from Novartis. No other disclosures are reported.

Figures

Figure 1.. Adjusted Pairwise Differences for Change in Visual Acuity at 2 Years by Presence of Prior Panretinal Photocoagulation and Severity of Diabetic Retinopathy at Baseline

The estimates were adjusted for treatment, baseline visual acuity, and their interaction along with the age and hemoglobin A1c level. A indicates no prior panretinal photocoagulation and moderately severe nonproliferative diabetic retinopathy or better (levels 10-47; n = 384); B, no prior panretinal photocoagulation and severe nonproliferative diabetic retinopathy through high-risk proliferative diabetic retinopathy (levels 53-75, excluding 60; n = 86); and C, prior panretinal photocoagulation and inactive proliferative diabetic retinopathy (level 60) or mild proliferative diabetic retinopathy or worse (levels 61-75; n = 94). Point estimates were 0.4 for A vs B, 3.1 for A vs C, and 2.7 for B vs C.

Figure 2.. Adjusted Pairwise Differences for Change in Visual Acuity Over 2 Years (Area Under the Curve)

A, Estimates were adjusted for treatment, baseline visual acuity, and their interaction along with age, panretinal photocoagulation (PRP)/proliferative diabetic retinopathy severity, and hemoglobin A1c level. Point estimates were −1.1 for African American vs white, −2.6 for African American vs other, and −1.4 for white vs other. B, Estimates were adjusted for treatment, baseline visual acuity, and their interaction along with age, race/ethnicity, and hemoglobin A1c level. A indicates no prior PRP and moderately severe nonproliferative diabetic retinopathy or better (levels 10-47; n = 383); B, no prior PRP and severe nonproliferative diabetic retinopathy through high-risk proliferative diabetic retinopathy (levels 53-75, excluding 60; n = 86); and C, prior PRP and inactive proliferative diabetic retinopathy (level 60) or mild proliferative diabetic retinopathy or worse (levels 61-75; n = 93). Point estimates were −0.6 for A vs B, 2.7 for A vs C, and 3.4 for B vs C.

Figure 3.. Adjusted Pairwise Differences for Change in Central Subfield Thickness (CST) at 2 Years for Race/Ethnicity

Estimates were adjusted for treatment, baseline visual acuity, baseline optical coherence tomography, and their interaction along with subretinal fluid within 500 μm of the macula center. Point estimates were −27.3 for African American vs white, −12.0 for African American vs other, and 15.3 for white vs other.