Preventive Aflibercept Injections May Stave Off Diabetic Eye Disease Progression

View of retina showing severity 3 of diabetic retinopathy, associated with diabetes mellitus. Venous tortuosity and “beading”, and large patches of yellow exudate are all present.
A study shows periodic dosing can affect the development of proliferative diabetic retinopathy and diabetic macular edema.

Periodic intravitreal aflibercept injections may reduce the likelihood of developing proliferative diabetic retinopathy (PDR) or vision-reducing center-involved diabetic macular edema (DME) in people with moderate-to-severe nonproliferative diabetic retinopathy (NPDR), according to research published in JAMA Ophthalmology. 

Protocol W ( identifier NCT02534333) was conceived as a long-term study to determine if there is a benefit to aflibercept spanning a 2- and 4-year period for the prevention of either PDR or center-involved DME in eyes with moderate to severe NPDR.

Researchers collected data between 2016 and 2020 and included adults with type 1 or type 2 diabetes with severe NPDR across 64 clinical sites in the United States. All eyes were randomly assigned 1:1 to receive either 2 mg of intravitreal aflibercept or sham injections. 

The primary study outcome was the development of either center-involved DME with vision loss or PDR. 

The cohort included 399 eyes from 328 participants (aflibercept n=200, sham n=199). Median participant age was 57 years (interquartile range, 51 to 64 years) and 57.6% of participants were men. At baseline, 17% of eyes had moderate NPDR, 31.6%, and 27.3% had moderately severe NPDR (DRSS level 47A and 47B-D, respectively), and 24.1% of eyes had severe NPDR. Median baseline visual acuity letter score was 88 (Snellen equivalent, 20/20). 

In each group, 84.7% and 87.4% of participants (aflibercept and sham, respectively), completed their 2-year visit (mean 10±3 total visits). 

Among patients who completed their 2-year visit, DR severity improved by 2 steps or more from baseline in 44.8% and 13.7% of eyes in the aflibercept and sham groups, respectively (adjusted odds ratio [aOR], 5.91; 97.5% CI, 3.19-10.95). Severity of DR worsened by 2 or more steps in 5.2% and 12.4% of eyes in each group, respectively (aOR, 0.37; 95% CI, 0.13-1.01), and compared with baseline, mean central subfield thickness at 2 years decreased by 6±27 µm and 1±28 µm (adjusted mean difference, -4 µm). 

Mean change in visual acuity during the study period was -0.9±5.8 and -2.0±6.1 letters in the aflibercept and sham groups, respectively (adjusted mean difference, 0.5 letters). After 2 years, 75% and 71.7% of eyes in each group had a visual acuity of 20/20 or better, and no eyes had a visual acuity of 20/200 or worse. 

Within the group of participants who completed the 2-year visit, mean number of aflibercept injections was 8±1.2 total; a mean of 7.7±0.7 injections were given for prevention alone. The mean number of sham injections was 7.4±1.1. 

In the aflibercept group, there were 3 documented cases of endophthalmitis resulting from preventive injections out of a total of 2406 total injections in both study and nonstudy eyes. Rates of cardiovascular or cerebrovascular adverse events were not different between the 2 groups. 

Study limitations include potential bias in the results due to the number of patients lost to follow-up and the use of a treatment algorithm based on DRCR Retina Network investigator consensus, which may differ when another anti-VEGF agent or treatment approach is used. 

“Through 2 years, preventive treatment with aflibercept did not confer visual benefit, on average, compared with initial observation and intravitreal anti-VEGF therapy given only after PDR or DME development,” the research says. “The 4-year results will be critical to assess whether PDR and DME prevention with aflibercept results in long-term [visual acuity] benefit.” 

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures. 


Maturi RK, Glassman AR, Josic K, et al; for the DRCR Retina Network. Effect of intravitreous anti-vascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of diabetic retinopathy: the Protocol W randomized clinical trial. JAMA Ophthalmol. Published online March 30, 2021. doi:10.1001/jamaophthalmol.2021.0606