Diabetic Retinopathy Approaches Refined by New Trial Results

Laird Harrison

April 28, 2020

Data from clinical trials are prompting leading diabetic retinopathy specialists to change their approach to treatment.

The Protocol studies conducted by the DRCR Retina Network, which is funded by the National Institutes of Health, and published over the past 2 years have clarified which patients to treat most aggressively, said Jay Sridhar, MD, from the Bascom Palmer Eye Institute in Miami.

Talks on the clinical implications of these studies are scheduled for the Association for Research in Vision and Ophthalmology (ARVO) 2020 Annual Meeting, which will take place online this year.

The randomized Protocol V trial showed that patients with good visual acuity and diabetic macular edema might not need aggressive treatment.

As a result, for "patients with good vision — about 20/25 or better — and macular edema, I'm much more likely to observe or bring them back in a couple months for another appointment and imaging, and not immediately just jump to injection," Sridhar told Medscape Medical News.

His practice has also been shaped by results from the Protocol T trial, which was a head-to-head comparison of aflibercept, ranibizumab, and bevacizumab in patients with diabetic macular edema.

Head-to-Head Comparison

Patients with nonproliferative diabetic retinopathy were more likely to see improvements in disease severity with aflibercept or ranibizumab than with bevacizumab at 1 year, but not at 2 years.

Patients with proliferative diabetic retinopathy were more likely to see improvements in disease severity at 2 years with aflibercept.

Aflibercept was approved for diabetic retinopathy by the US Food and Drug Administration last year.

"If I have a patient with DME who doesn't respond well for my initial therapy — and I usually use bevacizumab first-line — I have a lower threshold after a couple of injections to switch to either ranibizumab or aflibercept because there may be a difference in efficacy," said Sridhar.

The PANORAMA trial, funded by Regeneron, provided some of the most important recent findings, said Diana Do, MD, from Stanford University Medical Center in Palo Alto, California.

Aflibercept cut the risk for complications in half in patients with nonproliferative diabetic retinopathy after 2 years of treatment, according to data presented in February at Angiogenesis, Exudation, and Degeneration 2020. These complications include proliferative diabetic retinopathy, anterior segment neovascularization, and center-involved diabetic macular edema.

The finding is particularly important for patients with moderately severe or severe disease. "One of the things that the study emphasized was that a significant percentage of these patients progressed to worsening diabetic retinopathy proliferative disease," said Sridhar. "So it's really important to monitor these patients closely, and to have a low threshold for starting either laser treatment or anti-VEGF treatment if you see progression."

Proactively treating patients with moderately severe to severe NPDR makes sense because we can finally prevent them from progressing to the most advanced stage of retinopathy.

Other recent research also reinforces the effectiveness of aflibercept and ranibizumab for nonproliferative diabetic retinopathy. "These data have changed my practice patterns and I am routinely treating patients with severe nonproliferative diabetic retinopathy with anti-VEGF therapies," Do told Medscape Medical News. "Proactively treating patients with moderately severe to severe NPDR makes sense because we can finally prevent them from progressing to the most advanced stage of retinopathy."

The CLARITY trial, funded by the National Institute for Health Research in the United Kingdom, demonstrated that, for patients with proliferative diabetic retinopathy, visual acuity outcomes were better with aflibercept alone than with panretinal laser photocoagulation alone.

"Anti-VEGF monotherapy for proliferative diabetic retinopathy is an effective option for patients who are compliant with clinic visits," Do said.

Longer-term results are now starting to become available.

In the recently published Protocol T Extension Study, which followed patients who had been treated for 2 years, visual acuity was better at 5 years than it was at baseline, but had declined from year 2 to year 5.

"The big take-home is that once patients leave Protocol, they don't tend to do as well, and that's been shown in other studies for DME," said Sridhar. "The second big takeaway is that there's still an unmet need, and anti-VEGF therapy alone does not prevent all diabetic macular edema."

Perhaps other VEGF inhibitors now in the pipeline will help meet that need, he pointed out.

Brolucizumab (Novartis) was approved for age-related macular degeneration last year, and it is in phase 3 trials for diabetic macular edema. Abicipar pegol (Roche/Genentech) has shown promise in phase 2 trials for diabetic macular edema. However, concerns about intraocular inflammation have arisen with both drugs in macular degeneration trials.

Faricimab (Roche/Genentech), which targets angiopoietin 2, as well as VEGF, is farthest along in development and is currently in phase 3 trials for diabetic macular edema.

How discussion of these developments will play out at the virtual ARVO meeting remains to be seen. Not all presenters have committed to participating in the new format, and Sridhar said he is unclear what opportunities for casual conversation will be available.

"This is kind of uncharted territory for all of us who are planning or going to meetings," he said.

Association for Research in Vision and Ophthalmology (ARVO) 2020 Annual Meeting.

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