Anti-VEGF Injections Preserved Vision in Severe Diabetic Retinopathy

Intravitreal injections of a vascular endothelial growth factor (VEGF) inhibitor reduced disease severity and vision-threatening complications in patients with severe nonproliferative diabetic retinopathy (NPDR), the phase III PANORAMA trial found.

After 1 year of treatment with aflibercept (Eylea), approximately 80% of patients who received a more intensive dosing regimen saw a two-step or greater improvement in the Diabetic Retinopathy Severity Scale (DRSS) compared with only 15% of patients who received sham injections (adjusted difference 64.8%, 95% CI 55.8-73.9%, P<0.001), according to Charles Wykoff, MD, PhD, of Retina Consultants of Texas in Houston, and colleagues.

As reported in JAMA Ophthalmology, 65% of patients who received a less intensive dosing regimen showed the same improvement on the DRSS at week 52 (adjusted difference 50.1%, 95% CI 40.1-60.1%, P<0.001).

And at approximately 2 years of follow-up, only 18.7% of patients in the more intensive aflibercept group and 16.3% in the less intensive group developed vision-threatening complications or center-involving diabetic macular edema (CI-DME) versus 50% of the control group (P<0.001).

The trial found no differences in visual acuity among the groups at week 100. But in a post hoc analysis exclusively looking at participants with vision-threatening complications and/or CI-DME, about 29% on sham treatments lost five or more letters on the Early Treatment Diabetic Retinopathy Study chart at some point during the study versus only 9% of either treatment group.

Current diabetic retinopathy treatment guidelines are predominantly reactive, with treatment only recommended when CI-DME and/or proliferative diabetic retinopathy (PDR) develop, Wykoff's group highlighted.

"However, once PDR has developed, retinal damage from fibrosis and contraction may not be reversible, even with intervention, and can be associated with permanent vision loss," they wrote. "Subsequent treatment with [panretinal photocoagulation] leads to visual field loss because the procedure is inherently destructive. Therefore, prevention of progression to PDR and DME represents an important public health goal."

They also noted that the current standard of case for NPDR is simply observation, but pointed out that "the risk of patients with severe NPDR developing potentially irreversible PDR and associated vision loss (approximately 30% at 2 years in the control group of PANORAMA) suggests that implementing anti-VEGF therapy should be considered and discussed with these patients."

Based on this trial, the FDA approved Eylea in May 2019 indicated to treat all stages of diabetic retinopathy and diabetic macular edema. The VEGF inhibitor, which works by blocking the growth of new blood vessels and decreasing vascular permeability, also holds indications for neovascular age-related macular degeneration and macular edema following retinal vein occlusion. For diabetic retinopathy, the recommended dose is 2 mg (0.05 mL) of intravitreal injection every 4 weeks for the first five injections followed by 2 mg via intravitreal injection once every 8 weeks (the more intensive dosing regimen in PANORAMA).

The double-blind, 87-site trial included 402 patients with diabetes and severe treatment-naive NPDR -- defined as a DRSS level of 47 or 53. Participants were free of DME and had a best-corrected visual acuity of 20/40 or better. The cohort's average age was 56 years, 56% were male, and 77% were white.

Participants were randomized to one of three groups. The first group -- less intensive regimen -- received 2 mg of intravitreal aflibercept injections every 16 weeks after three initial monthly doses and one 8-week interval. The second group -- the more intensive regimen -- received 2 mg of intravitreal aflibercept injections every 8 weeks after five initial monthly doses during the first year, with flexible as-needed dosing in the second year if the investigator determined the DRSS level was worse than 35. The third group received sham injections with observation.

The primary endpoint was the proportion of eyes with a two-step or greater improvement in DRSS level from baseline to weeks 24 and 52. Secondary endpoints included the proportion of eyes that developed vision-threatening complications or CI-DME at weeks 52 and 100. Only one eye per participant was measured.

Outcomes for study participants worsened in the second year while on the as-needed dosing, Wykoff's group reported. Participants averaged just 1.8 injections during that year (with a maximum of 6 injections), and those with improvements in the DRSS dropped from 80% to 50%, while the incidence of vision-threatening complications increased.

Although no new safety signals emerged, the most common ocular adverse events -- occurring in 7.5% of eyes in any trial arm -- included conjunctival hemorrhage, DME, vitreous floaters, and eye pain. There were no cases of endophthalmitis reported.

"Thus, although 1 year of aflibercept therapy substantially decreased the occurrence of PDR and CI-DME compared with sham treatment and observation in the PANORAMA study, discontinuation or reduction in the frequency of therapy may lead to PDR-related complications," they wrote.

One important study limitation was the restriction to patients with severe to moderately severe NPDR, the researchers said, adding that it would've been useful to know how eyes with more or less severe retinopathy responded differently to the therapy.

In addition, the as-needed dosing in the second year precluded the ability to determine if continued regular dosing during that time would have been beneficial. Finally, trial participants were evaluated with more frequent visits than are typical in a clinical setting.

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