Anti-VEGF Agents and Diabetic Retinopathy Severity Score

Nancy Holekamp, MD: Ehsan, can you discuss the diabetic retinopathy severity scale [DRSS] score and how these anti-VEGF agents had a surprise benefit? It was initially a secondary end point, but it’s becoming something attractive about anti-VEGF therapy.

Ehsan Rahimy, MD: Back to the RISE and RIDE studies, 1 of the secondary end points from those studies is that they saw that patients’ DRSS was improving. There became this metric to look at 2-step progression, to go back in time by 2 steps of severity, so if you’re moderately severe, you go down to moderate and all the way to mild. This was an added benefit that was noted with anti-VEGF treatment in these clinical trials. Similarly, VISTA and VIVID were landmark studies looking at aflibercept, or Eylea, for treatment of DME [diabetic macular edema]. They saw the same thing in both studies: roughly 1 of 3 patients, 33% or so, would experience 2-step improvements. Those observations served as the launching pad to do the PANORAMA study and also Protocol W study through the DRCR [Diabetic Retinopathy Clinical Research Network], which is essentially the same protocol as PANORAMA. In this case, we’re cherry-picking those patients at highest risk for progression to PDR [proliferative diabetic retinopathy], which is that moderately severe to severe group with ETR scores of 47 and 53. We saw in PANORAMA, and again in Protocol W, is that a significantly higher proportion of patients experienced 2-step progression—upward of 60% to 70%, depending on which treatment group you were in, that aflibercept study and PANORAMA.

One way we can reconcile this big difference has to do with what I just said: there was a ceiling effect in place. When you look at the patients enrolled in RISE and RISE or VISTA and VIVID, they may have had mild NPDR [nonproliferative diabetic retinopathy] or moderate NPDR. There’s only so much they can improve. You can’t improve by 2 steps of DRSS, as opposed to these states looking at the treatment of severe NPDR. There’s a lot of potential for improvement, and that’s 1 reason we had such a big disparity in terms of that DRSS improvement. The second reason is that in PANORAMA, all those patients were treatment-naïve. That was a very difficult study to recruit for. Many patients had 20, 25 visits—how long do you want to give monthly injections? it was a difficult and challenging site to recruit for, but all the better for having it been done, because we got some very powerful information, not only from the treatment but also from the observation group.

To that end, our field is all about durability. Is there a permanent benefit or treatment effect from this 2-step progression? In other words, if we stop, do we lose it all? Was it all for nothing? Will it quickly regress back to where it was? We’re seeing mixed studies and mixed results from our peer literature. Some people have hypothesized and decided to study fluorescein angiograms. Are we seeing reperfusion of tissue from earlier treatment, anti-VEGF, and is that sustainable over a longer period of time? When I get to a point in a patient’s treatment course—every 3, 4, 6 months, and their DME has regressed, they want to give a trial coming off therapy—we must be very careful that we’re monitoring that their diabetic retinopathy doesn’t start to progress. I’m reminded of Charlie Wyckoff, who did an open-label extension study of VISTA with aflibercept that looked beyond the 3-year study period and at patients who were getting whatever treatment their clinician decided they should and fewer injections. At that point, there were 60 patients who I studied, but 10% progressed from NPDR to PDR [proliferative diabetic retinopathy]. I tell these patients that we’ll know each other for life in a lot of instances.

Joseph M. Coney, MD: In that study, they didn’t require many injections. They were randomized to either acute QA or Q16 at the loading dose. We know that if individuals don’t have diabetic macular edema, the number of injections they will require will not just save vision—there were people in that study who did not have diabetic edema; their vision improved. There’s something going on that we still don’t know, but there was a visual improvement. There was an OCT [optical coherence tomography], a drying effect, although you couldn’t clinically see any swelling. If you look at the composite of sight-threatening problems, it was 42% compared with 10%. That’s a drastic improvement in someone’s vision that could have potentially been lost vision and that you ordinarily wouldn’t have retained. The study was hard to recruit for. It’s the same reason why people are nervous about treating individuals without sight-threatening problems. To this day, I don’t think it’s caught on as much as it should have, because it’s hard to talk to someone about putting a needle in the eye that’s 20/20.

If we want to try to save an organ, with the eye we still have to find the right people to move the needle. It’s not an emergent thing you must do, but we need to start having the discussion, especially if it’s your patient—you saw the person 5 years ago, when they had moderate disease, and now they’re starting to get severe NPDR. You can see that progression. That may be the perfect person to have that discussion with. It’s difficult when a patient comes in for the first time and they’re healthy and vibrant, playing basketball, running. They didn’t know they had diabetes. They have a severe disease, but they’re not bothered by it. That’s a very hard person to have that discussion with. This is where our optometric colleagues can help us out, by facilitating those questions to the health care professionals to talk about multisystem organs. Once they have kidney, foot, eye, and heart problems, you start to build up a story. This patient’s journey over time is not going to be very good. You have to look at a patient as a composite. Let them know that the same thing going on in your heart, toes, and kidneys and is going on in your eyes, and if we don’t get this under control in the next 3 to 5 years, you can have severe blindness.

Nancy Holekamp, MD: Thanks to all of you for this rich and informative discussion, and thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

Transcript edited for clarity.