Diana V. Do, MD

Let’s shift gears for a few minutes to talk about safety. This came up earlier, we’ve been incredibly fortunate to have 2 agents come to us, in a fairly quick period of time, that have been incredibly effective and very safe for our patients, then stood the test of time for 15 years or so. Diana, are there specific considerations for your patients with diabetes as it pertains to safety? Are there factors that you discuss with them? Or do you approach them in a way similar to patients who need anti-VEGF therapy for other indications?

: We’ve learned over the past decade that interatrial VEGF inhibitors, such as aflibercept and ranibizumab, are extremely safe and effective. We’ve seen that across patient populations, whether it’s patients with diabetes, elderly patients with wet age-related macular degeneration [AMD], or patients with retinal vein occlusion, that the safety profile is consistent across these populations. I’m confident in recommending these treatments for patients with diabetic eye disease.

Let’s look forward into the future. There are a number of different agents for a variety of indications. We have biosimilars coming to the market. What’s going to be most important for you as you consider new therapeutic options in this space? Is it going to be the idea that we’re going to see dramatic improvements in efficacy? Or has safety suddenly become the No. 1 issue, given some of our recent experiences with new agents?

 I must say this has been a disappointing part of our field. We’ve had previous biologics that we looked at that were very efficacious, and because of the rates of inflammation, they did not get approved. It seems as though as we progress in our field, and we have longer-acting agents, this is something that has been a recurring thing. I’m hoping going forward our pipeline is pretty robust. We talked about the KIS-301 antibody biopolymer conjugate earlier today. We may have a PDS [port delivery system] that may be beneficial. There are other agents that may have great efficacy, and they may be a little bit more tolerable to the eye. The studies are ongoing, the preliminary data look good. If we can get the efficacy piece, and to decrease patient burden, to not have the inflammatory piece, that’s really great. It also may be true that it’s about time that we started having these discussions with patients about being comfortable with adverse effects. It’s amazing how cancer physicians prescribe all sorts of medicines, people lose their hair, they get ulcers, all these issues, and if they extend your life for 6 months, it’s a success. But we, as ophthalmologists, don’t like talking about intraocular pressure. We don’t like talking about cataracts. These are reversible, these are things that are treatable. If we’re going to try to maximize the efficacy in our patients by decreasing the unmet need, which is burden, we may have to start talking about some of the adverse effects that we often treat.

: Joe mentioned future agents KSI-301 and the PDS implant. The common thread with those 2 is that they appear to offer the opportunity for significant reductions in treatment burden with perhaps the same clinical efficacy as monthly injections of anti-VEGF therapy. It’s all the good that we get with progressive therapy with reduced treatment burden. That’s obviously an important unmet need in our space. What else would you identify as an unmet need? Or where should we move going forward to push the ball forward in terms of treating our patients?

 Longer term, our goals are obviously to improve efficacy. We care about vision at the end of the day. And ideally, we’d like a few therapeutic targets that we can potentially pair with our VEGF inhibitors to get improved visual acuity gains; reduced treatment burden obviously is a big thing. As far as what’s immediately on the horizon, as you alluded to, is going to be improving durability, reducing treatment burden while maintaining the same degree of vision gains. That being said, we’ve all experienced this in the last year, safety trumps everything now. That pendulum has swung to that extreme due to what we saw with brolucizumab. We saw what happened with abicipar as well. Biosimilars are right around the horizon. There are some potential theoretical and well-founded concerns about their safety in terms of the purification process of how these antibodies are made. Safety is the primary concern now. After that, hopefully, some of these new, longer-duration treatments are going to allow us to reduce injection burden. And deeper into the pipeline, when we look at some of the newer therapeutic targets, we’ll be able to even potentially improve vision further, or at least address some of these parts of the disease process, AMD atrophy for example, where we don’t have any treatment at all.

 And Diana, how about you? What’s the future look like for us as retinal physicians, and for our patients in managing retinal disease? What do we need to take better care of our patients?

: The future is very optimistic and bright because of new agents that are likely going to meet the burden of treatment and reduce the frequency of injections. Having the discussion of treating diabetic retinopathy when there is no vision loss yet, being more proactive, is going to be important. Because, as retina specialists, we do have approved agents that are safe and that can turn back the hands of time and decrease the risk of vision-threatening complications. There is going to be a paradigm shift in the future, and having these discussions will help facilitate that.

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Key opinion leaders emphasize important considerations when discussing the safety of anti-VEGF agents with patients and highlight unmet needs in nonproliferative diabetic retinopathy treatments.

Initiating Conversations with Patients about Anti-VEGF Agents

 Ehsan, we’ve got a lot of data on regression, a reduction in the rates of vision-threatening complications using anti-VEGF agents infrequently as every 4 months. This is not particularly aggressive treatment. There doesn’t appear to be today widespread adoption of this type of management in patients that have the threat for vision loss in diabetes. How does this work for you in clinical practice? How do you apply this data as you see patients with diabetic eye disease?

There are so much great data to unpack from PANORAMA and from Protocol W. As you alluded to, there’s been slow uptake in our field. Although anytime you’re dealing with something that’s potentially paradigm shifting in terms of the way we handle or manage a condition that we used to observe, there’s going to be a gradual phase-in and phase-out to start adopting these therapies. At this point in my practice, I’m fairly comfortable offering anti-VEGF therapy to my patients with severe NPDR [nonproliferative diabetic retinopathy]. If there’s a mistake that colleagues who are a bit averse to it may be making, it’s not even having that discussion with patients. In my practice, I’m all about educating my patients, letting them know what’s available, trying to get them to engage, understanding their disease process, and letting them know that treatment options are available. Here are some studies, here’s what they showed. And I let them be an active decision maker in that process, rather than me practicing paternalistic medicine and saying, “I’m not even going to say anything to this patient other than, ‘Come back in 3 or 4 months.’”

That type of care with diabetic retinopathy potentially lends itself to increased noncompliance more than anything in the long run. I’ve been pleasantly surprised that when I share these data from Protocol W and from PANORAMA, and the findings essentially corroborate one another, that our risk of progressing to vision-threatening complications is substantially reduced. I’ve been pleasantly surprised at the number of patients who want to do therapy.

There are a couple of take-home points from that. No. 1, consistency is more important than frequency. What I mean by that is, we saw in year 2 from PANORAMA, the every-8-weeks arm that switched to as-needed treatment, their level of DRSS [Diabetic Retinopathy Severity Scale] improvement fell off a cliff. It doesn’t get talked about much because that was an as-needed treatment arm. Remember that in year 1 that you had an 80%, 2-step improvement. In year 2, that dropped all the way down to 50%. And the reason was patients were being undertreated and they got an average of 1.8 injections of the 6 eligible injections. Whereas that every-4-month arm group essentially maintained their 2-step improvement. It was 65% in year 1 and 62% in year 2 across much less injections.

The way I look at it is, consistency is more important than the frequency. If we can get a patient to a regular interval that’s comfortable for them, that they’re compliant with, whether it’s 4 months or 6 months, then that’s great. Part of this is also the psychology. I think about things as if I were that patient. I don’t have retinopathy, and I hope I never do, but I think about it in terms of going to the dentist. If I’m going to a clinical care provider, and that visit is being tied to something procedural, then I’m far more likely to be compliant with that visit, knowing that something is being proactively done for me. Rather than just showing up, somebody looking at something and saying, everything is fine.

When push comes to shove, if I have something else going on, as Joe alluded to, diabetes is not entirely a disease of noncompliance. We have patients who care very much about their visits but are forced to choose. They’re working class, so they can’t take that many days off. They may have to juggle seeing the eye care provider with the kidney doctor, with the cardiologist, maybe they’re hospitalized. Sometimes they just end up missing these appointments, not because they don’t want to be there but because they’re forced to. If I can tie in a procedure, my belief is—and we have some real-world data forthcoming that suggest that—adherence to visits ends up increasing when we’re tying that injection to it.

I’ll end with 1 anecdote of a patient I saw earlier this week. We talked about turning back the hands of time. This was probably 1 of my earlier patients who elected to want to start treating his severe NPDR. His right eye had severe NPDR, and his left eye was moderate. We said we’d just start therapy. He had no DME [diabetic macular edema], by the way; his vision was 20/20. He was an engineer, very educated, and wanted to know everything about diabetes. I remember him the first time he came to see me. He presented the PANORAMA paper printed up. He brought it to me, and he wanted to start therapy, and we did so with his right eye. I tried to do my own algorithm, where I extended his treatment. I eventually lost him for over a year.

He came back just this week. His right eye was still at about a severe NPDR state, and the FA [fluorescein angiography] looked somewhat comparable to before. But his fellow eye that was moderate had progressive proliferative diabetic retinopathy with vitreous hemorrhage during that interval period. And it’s just an N-of-1, it’s just 1 anecdote, but that’s the type of patient I’m thinking about. Because you could have the most compliant patient in the world, but diabetes is a terrible multisystem disease that will inevitably cause someone to become noncompliant and miss a visit. But by treating that patient, did we potentially lengthen the leash and help prevent a terrible outcome from coming by the time they do inevitably get back to us?

Joe, these are very powerful data. What do you think it’s going to take for us to change the way we think as a retina community to begin to prevent vision loss vs treating the end-stage complications? Are there data that we need? Is there just time? Are there factors you can identify that may change this line of thinking in the future?

 For 1, training younger physicians to understand the disease is important. When I was training, if it didn’t change an outcome—and at that time it was vision—then we didn’t institute that therapy. I was always trained to look at vision as an outcome. Now we’re talking about trying to change the disease process, so to speak, where vision is not effective, which is a little harder to gauge. By training younger physicians in understanding the historical standpoint of eyes, because the data are prevalent. The progression of retinopathy hasn’t changed since we had been doing the studies in the 1970s. That has been consistent. And if you have an eye that has moderate disease, we know what the rate of progression is over the next 5 years. We know what the rate of progression is—you have severe disease if it’s untreated. And when you have sight-related problems, you know what the progression is. From a historical standpoint, that needs to be told to younger physicians. That’s No. 1.

No. 2, for me, it took a patient to have that outcome where it happened on my watch, and because they missed an appointment, for whatever reason, they got worse. I don’t want that to happen again. When I talk to patients with these issues, she always comes up in my mind. The other eye we were able to save. She also has proliferative disease. She’s still 20/20 in that eye, but in the eye that developed the tractional detachment, we never gained vision better than hand motion. And she never misses an appointment now. She’s 3 years out. She’s constantly undergoing therapy, and the impact that we’ve made on her is important.

When you have personal testimonies, when you have personal patients, that’s a sounding bar that helps us to make a change. It makes the paradigm shift, which may go against what you were originally taught. For me, I’ve learned every day with my patients, and that discussion with my patients is critical; knowing more about their lifestyles, and how this disease is a little different from what we see with our patients with AMD [age-related macular degeneration] who are normally brought in by a caregiver. These are individuals, these are our colleagues, and these are people who work next to you. That’s the reason I find this disease so fascinating. There’s not 1 thing you can point to, but personal stories, and having your patients not do well, is a strong testament to changing your behavior so it won’t happen again. If you can decrease that, it’s just imperative.

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Drs Ehsan Rahimy and Joseph M. Coney analyze the implications of clinical trial data on the management of nonproliferative diabetic retinopathy.

Updates in the Management of Non-Proliferative Diabetic Retinopathy

Joe, I’m going to start with you talking about the role of the available anti-VEGF agents in the treatment of DR [diabetic retinopathy]. We’ve got 2 approved agents, ranibizumab and aflibercept. How do you use these agents overall in managing patients with diabetic eye disease?

 Both are great drugs. Both have turned back the hands of time in terms of their disease. When I was in a residency or fellowship not long ago, everyone had progression of the disease; they were all getting lasers. They would still bleed; you’ll have these tractional components. I just don’t see that with the current landscape. It’s also true for when you have nonproliferative disease. When we did our clinical trials for DME [diabetic macular edema], I don’t think any of us thought about what we were doing to the level of retinopathy. We noticed this as a by-product of how we were treating patients in clinical trials and, obviously, what we saw in our clinics day-to-day.

We have great studies that have shown—PANORAMA being the most recent—that if eyes have come in at the severe nonproliferative state, you can reduce their level of disease 2-fold 65% to 80% of the time. This was by customizing doses that they received injection after loading doses, even if it was at 16, 18, or 8 weeks. You have the flexibility to use these agents how you see them fit into that particular patient. In the long term, I don’t know how long I need to maintain these patients. Those are questions that someone on the panel can ask.

Once I get that improvement, how often should I follow patients? I typically use a widefield angiogram. Sometimes I’ll skip an injection, and I’m surprised when I see the neovascularization come back. That if it was severe or maybe had early PDR with low-risk characteristics, I’m very surprised on the changes I see. I’m starting to treat patients a little longer but space them out further. This is a landscape I’m still getting more comfortable with. The more I see these patients do well, the more I’m a very big proponent that if they have disease states that I know that over the next 4 years can have sight-threatening problems, then I tend to start therapy earlier.

Diana, we’re going to lean on you for some clinical trial results. Joe alluded to the PANORAMA study, talking about a 65% to 80% rate of 2-step reduction in diabetic retinopathy severity. Can you give us your thoughts on the PANORAMA study as well as the recently released data from Protocol W? Both trials evaluated aflibercept for the treatment of nonproliferative diabetic retinopathy [NPDR]. Give us the lowdown on these trials and your thoughts about how they were performed and what the results look like for you in clinical practice.

 Over the past few years, we’ve received an abundance of clinical trial data providing level 1 evidence that demonstrates that intravitreal VEGF inhibition with aflibercept is effective and safe at treating moderately severe to severe nonproliferative diabetic retinopathy. Both the PANORAMA study and Protocol W were randomized clinical trials that looked at different dosing regimens of aflibercept compared with sham treatment. They followed these patients over time to see what the benefits and risks would be for the treatment of moderately severe to severe NPDR. Recall that any patient in these clinical trials did not have diabetic macular edema at the time of enrollment. The results of these trials showed that intravitreal VEGF inhibition with aflibercept was safe and effective, and it decreased the risk for vision-threatening complications.

What does this mean? In the sham treatment arm, if you were observed over the 2-year period, you had a 50% risk of developing a vision-threatening complication such as diabetic macular edema or progression to proliferative diabetic eye disease. On the other hand, if you were randomized to aflibercept, this risk was dramatically decreased to less than 15%. It shows that prophylactic proactive treatment with VEGF inhibition could decrease the risk of vision loss over time. This is exciting for the field, and we can see that practice patterns are beginning to change and retina specialists are thinking and treating patients earlier in their disease state.

What’s the most important data point from these studies? PANORAMA was a study where the primary outcome was a 2-step progression in diabetic retinopathy. That was the primary outcome. We’ve been programmed to pay attention to primary outcome data in level 1 trials. Is that the most important data point, or are some of the secondary data points—such as vision-threatening complications—more relevant to us in clinical practice?

 The reduction in vision-threatening complications is the most clinically meaningful for us and for the patients. As you said, the primary end point was looking at severity scale of their diabetic eye disease and the reduction, and these studies met those primary end points. But when we’re talking to patients and we’re understanding how we can preserve their vision, vision-threatening complications is where the money is. That’s where we can help patients preserve their central and peripheral vision.

Diana, we observed these reductions in diabetic retinopathy severity when we were all involved in the clinical trials evaluating anti-VEGF agents for DME. We saw similar reduction rates, slightly less, reduction rates in patients treated for DME. Can you talk about the data we saw in RISE and RIDE, as well as VISTA DME and VIVID-DME that informed these primary treatment of retinopathy clinical trials?

: If you recall, when we first used VEGF inhibitors in diabetic eye disease, it was for vision-threatening diabetic macular edema. When we were treating these patients every month or every 2 months, investigators also noticed that there was an additional benefit because these agents also improved the diabetic retinopathy severity score in these eyes. Because of this evidence, additional clinical trials were launched, specifically looking at eyes who had moderately severe to severe nonproliferative disease at baseline in the absence of diabetic macular edema. The key point with these new clinical trials is that the treatment burden for treating eyes with nonproliferative diabetic retinopathy is less. We don’t have to treat them intensively every month or 2. We saw that aflibercept in these clinical trials could be given every 4 months and still have a beneficial effect.

A panel of experts reviews data on nonproliferative diabetic retinopathy treatments from the PANORAMA, Protocol W, RISE, and RIDE studies.

A Review of Clinical Trial Data in Non-Proliferative Diabetic Retinopathy

How about questions about goals of therapy? The treatment goals in DME [diabetic macular edema] are straightforward, we’re looking for dry retinas and great vision. What are our goals of treatment and care for patients with nonproliferative diabetic retinopathy [NPDR]? Are we still in a surveillance mode? Is that standard of care changing? Is there a role for active intervention in NPDR?

 Lloyd, this is something, I’ve changed the way I look at NPDR for the past several years. When I had that patient who was lost to follow-up with severe disease, and she came back with a tractional retinal detachment, she was supposed to have come back in 3 to 4 months, and she came back in 9 months. And now, she has to go to surgery, and she’s hand motion. I always wondered if I would have started therapy early, would it have made a difference in her life? That’s the patient I always have in my mind when I see these individuals. My treatment goal is always to preserve vision when I can, and obviously at this level of disease, trying to prevent any worsening. What’s the kicker for me is the worsening of their retinopathy. If I’m seeing someone, and they’ve gone from mild, moderate to severe, or they’ve gone from severe to very severe, even when they don’t have any sight-threatening problems, I’m talking about a treatment. And I start talking about it before I probably do the injection because most of these patients, they’re very hands-off when it comes to therapy because they see really well. But I’m showing them the fluorescein angiograms, I’m showing them the differences and the changes in their eyes. For me, that’s been the biggest tool to help sell that point of why I wanted to give them an injection at such an early age.

We have such powerful data now; PANORAMA just came out. Depending on your level of severity of disease, if you have very severe NPDR, you can improve someone’s diabetic retinopathy severity score by up to 60% in some of these eyes. And by turning back the hands of time and treating them early, there’s no reason why patients need to lose vision. There’s no reason we need to wait until vision is lost. Now, this is something I normally don’t instill in every single patient. Obviously, I take a lot of things into consideration. I take what’s going on in other parts of their body. If they have heart problems, if they have kidney problems, if they have hypertension, these people are much sicker. When you have diabetic eye disease, and particularly diabetic edema, these individuals typically are seeing 4 to 6 doctors. It’s also true when you get to the more advancing forms of diabetic retinopathy. They may not have the edema yet, but you know it’s coming. But if you could just, again, save the vision, prevent them from progressing, you can decrease their level of vision loss over time.

The last thing I would say, and we hit on this, but COVID-19 has taught me a lot of things about my patients. We had a big reset in terms of how many patients were coming into the office, and I had more time to have discussions with patients. I’ve been talking to them more about their social determinants, where they come from, how is life where they live, what their social life is like, why do they miss their appointments? We always think that when patients miss appointments, they’re not compliant. But they can miss their appointment because they had an appointment with their kidney doctor. It helps me to figure out their follow-up. If I know Mrs. Jones needs to come in, in 2 months for a maintenance injection for her severe NPDR, and she has something going on in 2 months, I’m more likely to give her an appointment that she can adhere to. I have these discussions with patients early on because I know that to have an impact on their life, you need to have good communication.

I think being noncompliant has to do with the communication you have with your patients. And most patients will tell you that they already have a fear of the institution where they’re coming in, sometimes they have a fear of doctors. They have a fear of the way they’ve been treated sometimes. So you need to break down those walls and talk about what they want to get out of things and make sure that they feel like they have been listened to. When it comes to someone who has good vision, you have to do more selling, so to speak, and let them know what their goals are. Once you have those parameters set, you’ll be amazed at how well patients do long term, and you’ll have very few people missing their appointments.

Dr Joseph M. Coney provides insight into the goals of therapy for patients with nonproliferative diabetic retinopathy.

Diana V. Do, MD

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