The threshold for treatment with an anti-VEGF agent for diabetic retinopathy wihtout diabetic macular edema is controversial. Two Phase III studies are now investigating aflibercept for moderately severe to severe nonproliferative diabetic retinopathy.
This article was reviewed by Dr. Charles C. Wykoff, MD, PhD
The threshold for initiating anti-VEGF therapy for an eye with diabetic retinopathy (DR) without diabetic macular edema (DME) is currently a matter of debate, and reasonable arguments can be made both in favour and against treating high-risk eyes with moderately severe to severe high-risk nonproliferative disease (NPDR).
More insight on this issue is expected to be forthcoming as data accumulate from prospective studies and are used to develop prognostic deep-learning algorithms.
In addition to considering interventional management of eyes with NPDR on an individualised basis, ophthalmologists would do well to concentrate on strategies that will bring more patients with diabetes in for ophthalmic care, said Charles C. Wykoff, MD, PhD, at the 2019 meeting of the American Academy of Ophthalmology.
“I do believe there is a signal that some patients with high-risk NPDR benefit from earlier intervention with anti-VEGF therapy,” said Dr Wykoff, director of research, Retina Consultants of Houston and the Greater Houston Retina Research Foundation (GHRRF), and deputy chairman of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USA. “The problem we face is identifying who these patients are.”
Dr Wycoff pointed out that while additional information is gathered, there are additional challenges to be faced.
“I think a greater challenge than whether or not we should treat patients with NPDR without DME is simply to get these patients to undergo the recommended retinal screening exams,” he said. “Unfortunately, a minority of patients with diabetes in the United States today are coming in for screening before they develop visual problems. We can do better.”
The current AAO Preferred Practice Pattern for DR, which was last updated in 2017, states that for severe NPDR, panretinal photocoagulation or intravitreal anti-VEGF therapy can be considered sometimes. Thus, the guidelines suggest individualising therapy decisions rather than providing specific direction on a population basis.
A role for anti-VEGF therapy in the treatment of high-risk NPDR derives from data collected in the DME registration trials for anti-VEGF agents. Data from studies of aflibercept (Eylea, Regeneron) and ranibizumab (Lucentis, Genentech) showed that with regular injections, approximately one-third of eyes with centre-involved DME (CI-DME), vision loss and DR, had a ≥two-step improvement in their Diabetic Retinopathy Severity Scale (DRSS) score.
Stratification showed that eyes with moderate to severe NPDR (DRSS score of 47 to 53) were particularly likely to benefit with the DRSS improvement relative to those with mild disease or PDr.
Because of such data, two large and rigorously designed Phase III trials were initiated to investigate the safety and efficacy of aflibercept treatment for moderately severe to severe NPDR in patients with good baseline vision.
DRCR.net Protocol W, which is fully enrolled with 322 participants that have clinically-diagnosed severe NPDR without DME and VA ≥20/25, is comparing sham treatment and intravitreal aflibercept 2 mg × two monthly injections and then every 16 weeks (Q16W) for 2 years, then treatment as needed for 2 years. Results from the primary endpoint are not anticipated for about 2 years, Dr Wykoff said.
Primary outcome data are available from PANORAMA that randomly assigned 402 patients with moderately severe to severe NPDR without DME and VA ≥20/40 to sham injection, aflibercept 2 mg Q16W (following four loading doses), or aflibercept 2 mg Q8W (following five loading doses).
Baseline data showed that enrolled patients had excellent vision (mean visula acuity 20/25) with normal central retinal thickness in these eyes without DME. Most eyes were asymptomatic
The primary endpoint analysed the proportion of eyes with a ≥two-step improvement in DRSS at weeks 24 and 52, and the results showed a highly statistically significant difference favouring both the aflibercept Q16W and Q8W groups versus sham treatment at 52 weeks. (65% and 80% versus 15%, respectively).