A four-year clinical study has found that while early treatment of diabetes-related eye disease using anti-vascular endothelial growth factor (anti-VEGF; aflibercept) slowed progression to severe disease, it did not improve visual acuity compared with treating more severe disease once it developed.

“This study indicates that monitoring patients regularly for vision-threatening diabetes complications and treating eyes only as needed is the best approach,” said Raj Maturi, MD, Indiana University School of Medicine and Retina Partners Midwest, who is the protocol chair for the trial, which was carried out by the DRCR Retina Network and funded by the National Eye Institute. The trial report, titled “Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy,” was published in Journal of the American Medical Association (JAMA).

Diabetic retinopathy occurs when diabetes affects the blood vessels of the eye’s light-sensing retina. In early stages, diabetes weakens retinal blood vessels, causing fluid to leak into the surrounding retina. This stage is called non-proliferative diabetic retinopathy (NPDR). Fluid buildup in the retina, called diabetic macular edema, is a complication of diabetic retinopathy and can lead to vision loss. Progression of the disease to proliferative diabetic retinopathy (PDR), where new, abnormal blood vessels begin to grow in the retina, can also threaten vision.

Anti-VEGF drugs can substantially decrease the risk of vision loss from diabetic retinopathy, but eye care providers have been unsure when treatment should start to achieve the best long-term outcome. Anti-VEGF is given by injection into the eye, so physicians must also weigh the risks for side effects and the expense and inconvenience of treatment against potential treatment benefit. “Anti–vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown,” the authors wrote. The treatment, they pointed out, “… reduces but does not eliminate the incidence of vision-threatening complications of diabetes, and it is highly but not 100% effective for the complications once they occur.”

The NEI-funded researchers wanted to evaluate whether treating people with NPDR using the anti-VEGF drug aflibercept could prevent vision loss. The investigators explained, “The DRCR Retina Network Protocol W aimed to answer the question, ‘does prophylactic anti-VEGF treatment in eyes at high risk of vision-threatening complications of diabetes result in better anatomic and vision outcomes at 4 years when compared with observation with anti-VEGF treatment initiated only after a vision-threatening complication has occurred?’”

The study enrolled 328 participants, and included 399 study eyes (some participants had two eyes that met criteria for enrollment in the study, while others only had one study-eligible eye). Preventive anti-VEGF injections were given in 200 eyes at one month after enrollment, two months, and four months, and then every four months over two years. Preventative treatment continued every four months through four years unless NPDR improved to only mild disease. Sham injections without drug were used in 199 eyes over the same period. Any eye that developed a vision-threatening complication, such as macular edema or PDR, was treated with additional anti-VEGF injections as necessary.

Two year results from the trial had suggested that while preventive treatment reduced the risk of developing diabetic macular edema or PDR, there was no evident benefit to vision. The newly reported final, four-year results reinforced the earlier findings, and demonstrated no statistical difference in either visual acuity or rates of vision loss between the two groups.

Over the four-year study, 34% percent of eyes receiving preventive treatments showed disease progression, compared with 57% of those in the sham group. On average, those in the preventive group received 11 injections, compared with an average of three in the sham group. “The results did show a favorable effect of early treatment on 2-step or more improvement in DRSS from baseline to 4 years (P < .001),” the investigators acknowledged. “Still, given no established meaningful visual acuity advantage, this trial does not support earlier treatment for severe NPDR, at least up to 4 years.”

Noting limitations of their trial, the authors further commented, “Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME.” “We expected early treatment to prevent progression of diabetic retinopathy, but even with preventative injections, about one-third of eyes developed vision-threatening complications,” said Adam Glassman, PhD, Jaeb Center for Health Research, Tampa, Florida, who directs the DRCR Retina Network coordinating center. “While the individual risk of complications per injection is low, the risk increases with each additional injection,” added Jennifer Sun, MD, MPH, Joslin Diabetes Center, Harvard Medical School, Boston, and chair of diabetes initiatives for the DRCR Retina Network. “The results of this study indicate that the anatomic benefit from early anti-VEGF treatment does not result in improved visual acuity, and so it may not be worth the risk and inconvenience to the patient of repeat preventive injections for NPDR.”

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