 Viewpoints, “Updates in Diabetic Retinopathy and Diabetic Macular Edema.”

I am Dr Rishi Singh from the Cleveland Clinic in Cleveland, Ohio. It’s my pleasure to have the following panelists joining me today for the program. First, Dr Anat Loewenstein, professor of ophthalmology from Tel Aviv University in Tel Aviv, Israel; Dr Paul Chous, an optometrist specializing in diabetes eye care from Tacoma, Washington; and Dr Steven Ferrucci, chief of optometry at Sepulveda VA [United States Department of Veterans Affairs] Hospital in North Hills, California.

Today we are going to discuss a number of topics pertaining to diabetic eye disease, including diagnosis, clinical manifestations, some of the traditional treatment options, and some of the new potential emerging areas on the horizon.

Let’s get started for our first topic. In this segment, we’re going to provide an overview of diabetic eye disease. Diabetic eye disease is the leading cause of blindness in working-age adults. We want to hear from our panelists about what diabetic eye disease is and what diabetic retinopathy is in particular. We’ll start off with Dr Steve Ferrucci. Steve, can you help us understand better for the laymen, and for even the clinician, what is diabetic eye disease? How does it happen? How does diabetic macular edema form?

Diabetic retinopathy is damage to the blood vessels that line the inside of the eye, and you essentially experience loss on the pericytes that line the vessel wall. That can lead to problems such as ischemia, leakage, and the accumulation of fluid.

Paul, one of the real controversies in our field is how to perform a diabetic eye examination correctly. Can you discuss that in a bit more detail with regards to what the patient should expect, as well as the clinician? What is the standard of care for a diabetes eye examination?

An eye examination for any patient has many of the same components, but when it comes to a patient with diabetes, it’s imperative to get a good dilated stereoscopic view of the inside of the eye. Imaging is useful, especially at a baseline examination so you have something to compare. For me, the most important thing is a good case history about glucose control, blood pressure control, and lipids. I like to ask my patients not just about what their A1C [glycated hemoglobin] is today but what their A1C has been over time, because we know there is this phenomenon of metabolic memory. If I have a good sense of where they’ve been in the previous years before I’ve seen them, that’s helpful. It helps me give them better advice about the frequency of examination and what the odds are for them maintaining good vision throughout their lives.

Overview of diabetic eye disease

Dr Chous, you briefly mentioned the idea of imaging. What is the typical imaging pattern you’d end up choosing for some of the patients [such as] this?

Fundus photography is helpful, particularly widefield or ultra-widefield 

imaging….Some findings suggest that patients who have more peripheral diabetic retinopathy lesions are dramatically more likely to progress by 2 steps on the ETDRS [Early Treatment Diabetic Retinopathy Study] scale or ultimately develop proliferative disease. I’m also a fan of OCT [optical coherence tomography] imaging. I like to do OCT imaging every time I see a patient because I have a number of patients I’ve seen over the last 10 years who have subclinical diabetic macular edema [DME] that I simply didn’t detect with my normal fundus examination at the slit lamp.

Dr Loewenstein, can you talk a bit about OCT-A [optical coherence tomography angiography] and the idea of using widefield angiograms in these patients? What have they led to as far as understanding these patients?

Yes. It is more important to examine the posterior part and the midperiphery of these patients. I’m not against doing widefield imaging, but for diabetic patients most of the pathology is found in the midperiphery. Especially for screening purposes, widefield photography is fine, and I’m not doing widefield angiography on all the patients. I try to do angiography on any patient at baseline if they have some diabetic retinopathy. If they don’t have any diabetic retinopathy, I don’t do a fluorescein angiography at baseline even though they might have some nonperfusion and even though it might allude to the fact that they may have later progression on the diabetic retinopathy severity scale. At least for screening purposes, the most important things are the clinical examination and the OCT. I don’t trust myself [to not miss] mild cases of diabetic retinopathy.

What is a good clue is this: if a patient does not have diabetic retinopathy at all or if it’s only mild, the chances of them having diabetic macular edema are small. It is only if you have moderate NPDR [nonproliferative diabetic retinopathy] that you have higher chances to have macular edema. I am also doing OCT imaging on all my patients at baseline to make sure that I’m not missing something. This is what I am doing, but I’m not doing OCT-A imaging as a routine in every patient for baseline. If everything is fine, I’m not doing OCT-A imaging, mainly because of reimbursement issues. If every patient can have all the tests in the world, then I don’t mind doing OCT-A imaging, but the yield is not high in patients who don’t have clinical disease. I do OCT-A imaging if something is not clear to me during the follow-up of the patient or during the management while we are treating them.

Your points are well taken, but I wonder about the value of OCT imaging in a patient with good vision. For a patient who has 20/20 vision or 20/25 vision, I’ve stopped getting OCT imaging for them because of some of the data we may talk about in our later sessions. We may talk about why the treatment indication isn’t there for that patient. I suspect it’s good for baseline testing, as you recommended, as well.

Yes, I agree. For a patient with good vision acuity, according to the protocol of the DRCR [Diabetic Retinopathy Clinical Research] Network, you wouldn’t treat even if they have mild edema because it’s the same visual acuity results if you wait until they develop more severe edema. That’s only if you follow up with the patient. You’re absolutely right: it’s just for establishing a baseline.

 I would add that the patients who do have mild DME have good visual acuity even though they’re not going to be treated. The data say that those patients are much more likely to progress on to DME that does affect their visual acuity. It’s a marker for the eye care professional to monitor that patient more closely.

That’s a great point. Can you talk a bit about widefield angiography, Anat? OCT imaging is non–dye-based, but you’re talking about dye-based angiography. What have you found from the widefield imaging studies that you’ve done in patients?

 I don’t do widefield angiography as a routine. I don’t think it changes the way I will treat a specific patient. What is right about it was said before: if you have severe nonperfusion in the periphery, you might want to follow up on the patients more closely. However, it will not change your treatment at this point at all, so it is not in my routine to perform it. According to older studies, [such as] the ETDRS and other studies, nonperfusion in the periphery is not an indication for treatment. It is only the case if you have neovascularization. I also am not in the European group that believes that you improve the macular edema if you do laser therapy to areas of nonperfusion in the periphery. There is enough data to show that it does not do that, so to me, it is not routine to do widefield angiography. If I don’t understand something, then I might do it.

Imaging for diabetic retinopathy

Steve, we talked a little bit about OCT-A [optical coherence tomography angiography] imaging, so I want you to describe it for people who may not be familiar with OCT-A. How does it work? It’s non–dye-based in comparison with the fluorescein angiography we discussed before. Tell us and the watchers at home what it is and why it may be beneficial.

The way that OCT-A imaging works, in a simplified way, is this: OCT-A imaging can scan so quickly with so many scans per second that it can scan over a blood vessel and tell whether there’s any flow in that blood vessel over a certain period of time. By doing that, it can extrapolate whether that’s a patent blood vessel that has blood flowing through it or if it’s a blood vessel that doesn’t have any blood, which would be an ischemic blood vessel. It can use that technology without dye to figure out blood flow, blood patterns, and that sort of thing.

Tell me about the clinical situations in which OCT-A has been useful to you.

I agree that, for all of our diabetic patients, it would be a nice idea to do it, but we don’t. The times I find it helpful is when you have a patient with diabetes who has unexplained vision loss. Their vision is poorer than you think it should be, but they don’t seem to have edema. We’ve used OCT [optical coherence tomography] imaging, and we’ll find some macular ischemia in those patients. It does a good job of looking for macular ischemia in those types of patients.

Another area that I’ve found is sometimes a red herring is when you see a patient who is diabetic and has pretty much no retinopathy but they have some temporal microaneurysms in the eye. You may realize that they have JXT [juxtafoveal telangiectasia] or some other masquerade syndrome that might look like it, so I find that OCT-A imaging is helpful in those kinds of cases.

That’s correct. I agree. If something is not clear, then I would go to OCT-A imaging.

Yes, but why hasn’t OCT-A imaging become the standard of care? Should it become the standard of care? This may be for everyone on the panel, so I’ll start with Paul. Should OCT-A imaging be the standard of care? What are the barriers from OCT-A adoption at this point?

Cost is certainly a barrier to any technology that’s introduced into the marketplace. The argument has been made that you can pick up on DR [diabetic retinopathy] lesions much earlier with OCT-A imaging than you can with traditional examination techniques. You can see microaneurysms that wouldn’t be visible otherwise.

My question is this: does that really change the treatment the patient is going to receive? It certainly gives you an opportunity to counsel that patient about better metabolic control, and we’re going to watch that patient a bit more closely. There are some patients for whom I’ve used OCT-A imaging where I’ve discovered something I didn’t see on clinical examination, and it freaks them out a bit. They get more concerned than they may have been otherwise, so I have to reassure them that these are early changes. The reality is that adaptive optics shows patients have diabetic retinopathy within 6 months of diagnosis, but the question is this: what does that portend for the future?

 First of all, OCT-A imaging takes longer…than structural OCT. Then I think the interpretation is not that useful. It also takes time to interpret that imaging. It’s not like a structural OCT that the clinician is doing without getting instructions and getting results. If the segmentation is not done in the proper way in OCT-A imaging, then you will not get what you are looking for. For example, if we are talking about patients with diabetes, and 1 of the uses of OCT-A is for patients with diabetes, if you want to see if what is on the retina is MGE [medical ganglionic eminence progenitor cell] or not, you can do the slabs on the anterior surface of the retina, and then you will see them. If you are not doing the slabs in the right place, then you will not see it. This is something that not everyone is aware of, and you are sometimes just doing an OCT-A imaging test, but you are not getting what you are looking for because you didn’t look in the right place. It’s a bit of a barrier. Then, of course, there is also cost as well as the time that it takes to perform the imaging and interpret it. These are all barriers.

I would also add that, even though some of the newer ones allow us to see [farther] out, we’re still not getting to the periphery. There are still some limits there that make fluorescein, especially widefield fluorescein, very valuable still.

You’re right: OCT-A imaging has limitations in the line scans thus far compared with widefield angiography, so you still can’t get out as far. One of the other things that I can tell you about OCT-A imaging is that reviewing the images is not easy, as Dr Loewenstein pointed out. I find that I spend a lot more time reviewing the images and looking at the slabs. I like the idea of following neovascularization, and I do follow neovascularization on the disc with the OCT-A to see response. We can be fooled into thinking that there is a response to therapy when there truly is not, so it gives you a bit more of a quantitative look at that neovascularization in a patient you might have with that.

It has a lot of potential in this regard in diabetes especially now that we are talking about treating patients with PDR [proliferative diabetic retinopathy] with anti-VEGF therapy as compared with PRP [panretinal photocoagulation]. You do need to make sure that you don’t have active blood vessels as opposed to PRP, for which you do the PRP and that was practically it. We are now sometimes giving injections, and we are following up with the patients. I personally don’t trust myself to see all these MGEs. I’m not saying that I also have time to do OCT-A imaging all over the retina and make sure that there is no MGE anywhere, but maybe in the future, using the AI [artificial intelligence] or machine learning, we will have a score for that, and it can potentially be helpful in this regard in the future.

I want to talk to Dr Loewenstein about the concept of home OCT imaging. What are the pros and cons? How is this technology going to be helpful to screen or assist in diabetes care?

Theoretically, home OCT imaging can be beneficial. We use the home OCT imaging in patients with diabetes even though most of our studies [at Tel Aviv University] are on patients with AMD [age-related macular degeneration]. All of our longitudinal studies that follow the patients at home over a month’s time were with patients with AMD, but it’s OCT imaging, so you can see the thickness. We also worked on it with our artificial intelligence interpretation system, the NOA [Notal OCT Analyzer] that shows where the intraretinal fluid is and where the subretinal fluid is to know the response to treatment. We don’t have as many studies about the home OCT imaging for patients with diabetes as we do for patients with AMD. Theoretically, it can be beneficial for that, as well. The pace of things that happen in diabetic retinopathy does not necessitate daily OCT imaging, and the main advantage of home OCT imaging is to have the daily examination. It’s more for patients with AMD, but it does have potential for patients with diabetes.

Use of OCT-A for patients with diabetes

We’re going to discuss the successful partnership between our optometrists and our medical doctors in taking care of patients with diabetes. Let’s start off with our first question….What education can the optometrist provide a patient with diabetes to help optimize their health?

Talking about the asymptomatic nature of diabetic retinopathy and diabetic macular edema until they progress is an important thing. We need to get patients to understand that good vision on an eye chart or in the real world doesn’t necessarily mean that their eyes are healthy. The other thing that is important to educate patients about is metabolic memory, which is the idea that higher blood glucose controlled early has a protective effect 20, 30 years down the line, according to various studies. There was an interesting trial

 that looked at patients in 36 countries, and it said that these are all patients with Type 2 diabetes, and only about 18% of people 5 years after diagnosis had a glycated hemoglobin [A1C] under 7%, which is ideal, and less than half had a glycated hemoglobin under 8%. We need to harp early on, when diabetes is diagnosed, about the importance of good metabolic control.

The other thing I would stress may be outside of the purview of eye doctors, but I talk about it on a daily basis: if a patient has preexisting cardiovascular disease, we have diabetes medications now that dramatically lower their risk of having a fatal event, such as an MI [myocardial infarction] or a stroke. For patients who have known heart disease, it’s a good idea to talk to them about talking with their PCP [primary care physician] or endocrinologist about these new medications. I’m referring to the GLP-1 [glucagon-like peptide 1] analogues such as Victoza, [liraglutide], Byetta, [exenatide], and the SGLT2 [sodium-glucose cotransporter 2] inhibitors, which are the drugs that end in –flozin, such as Jardiance [empagliflozin] or Farxiga [dapagliflozin].

Dr Ferrucci, I have the same question for you. Talk more about this idea of metabolic control. It’s a wide field, right? It could be blood sugar or blood pressure. What do we mean by metabolic control that’s ideal?

A lot of studies show us that with better blood sugar control you’re less likely to get diabetic retinopathy. Hopefully, if you have diabetic retinopathy, then you are less likely to have it progress if you have good hemoglobin control. Most places use hemoglobin A1Cas a measure of blood glucose levels. In a perfect world, we want our patients with diabetes at 7% or less. There is some new research going on about different types of parameters that we can use, but I’ve found that it’s helpful to ask our patients if they know what their hemoglobin A1C is because it has been shown in many studies to be a risk factor for development of diabetic retinopathy.

We have patients who come into our clinics with various levels of diabetic retinopathy and diabetic macular edema, for that matter. Dr Ferrucci, at what point should an optometrist feel comfortable referring a patient with diabetic retinopathy or diabetic macular edema?

That’s an excellent question. First and foremost, it all depends on your own personal situation. I tend to see a lot of patients with diabetes in my practice, so I’m comfortable with patients with diabetes. We all have different levels of comfort, and there’s never a wrong time to get a second opinion if you’re not comfortable. If you look at the American Optometric Association Guidelines that were put out fairly recently, they seem to recommend that we refer over to retinal specialists at the earliest signs of severe nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema, especially center-involved diabetic macular edema. It makes sense when you start to see those types of patients. Those are patients who could benefit from a referral to a retinal specialist to discuss whether some treatment options are a good option at that time.

Dr Loewenstein, I’ll get an international perspective from you. When do you want to see patients from other providers who have diabetic macular edema or diabetic retinopathy? Is it the beginning mild retinopathy or is it much more severe?

No, in Israel, the situation is really different. An optometrist would usually refer a patient for diabetic retinopathy screening if the patient doesn’t have 20/20 vision and if they see something going on in the fundus examination. The patient will be referred early in the course of their disease. I’m comfortable because I work with optometrists all the time. I get a lot of referrals, and I am referring to optometrists, as well, sometimes because of the visual acuity. I’m not as big an expert as the optometrists are on maximal visual acuity. It’s also important sometimes to know what level of visual acuity we have with the patients for the treatment decisions. Even though most of the treatment decisions are based on OCT [optical coherence tomography] imaging, visual acuity may also be an answer to that. I usually get the referral early in the course of the disease in the health system in Israel.

Optimizing diabetes health management

Dr Ferrucci, what are the keys to getting successful communication to our providers? What do you send in that referral letter? What information do you think is helpful to them?

There are a couple of things. Number 1, it is often the case that the patients we see as optometrists may have been seen in our practice for many years. It may be a patient with type 2 diabetes who we’ve seen for many years, and we’re now seeing their vision take a turn for the worse. When I send the patient to a retina specialist, I give a brief background and tell them what my concern is and why I’m concerned. I highlight the main concern without a lot of extraneous information. You should get down to the meat and bones of why the patient is being sent over, what you want them to look at, and what you would like their opinion on.

Dr Chous, how does the primary care provider [PCP] fit into this discussion in that case?

It’s important that we’re giving consistent messages to patients. Regardless of whether a patient has diabetic retinopathy [DR], it’s imperative that all of us in primary eye care send a note to the PCP letting them know that, if the patient has developed any DR, they need referral to a retina specialist. The other important thing is what the surveillance interval is. When does the patient need to be seen by us again to monitor their disease if they have any diabetic retinal disease? It’s a great opportunity for collaboration with PCPs. We know that DR in particular is linked to many other comorbidities of diabetes, so it represents an opportunity to collaborate not only with PCPs but a variety of subspecialists, as well.

I want to add to that that the role of the optometrist is crucial. It doesn’t matter in which country you live because the patients often don’t even go to an ophthalmologist. They are often going just to change their glasses. They would then go to optometrists all over the world, and…that’s a chance to catch the patient, examine them, and decide whether to send them to a specialist. It’s a crucial role.

What do you look for, Dr Loewenstein, in your referrals? What are you hoping to hear from your optometrist or any other eye care provider when they’re sending a patient to you? What do you want to hear from them about the diabetes?

It is exactly what Paul and Steve said. I want to know that they have had good visual acuity until now, and they have now seen the visual acuity deteriorate. I want to know that they followed up with them for many years and didn’t see any diabetic retinopathy and that this is something for which the patient now doesn’t get maximal visual acuity.

Yes, and I always send a letter to the primary care provider because they usually have concurrent disease otherwise, and there might need to be some modification of therapy for those diseases that can develop. Patients are obviously at a higher risk for cardiovascular morbidities and mortality, and obviously for kidney disease, as well as neuropathy. I always send a letter to the primary care doctor. Dr Loewenstein, what do you send to the primary care doctor, and what do you tell them about the disease?

I tell them that the patient has diabetic retinopathy and that they should be monitored for their diabetic glucose levels, hemoglobin A1C [glycated hemoglobin]. I know that they know that the patient needs to be monitored and that they need to have their blood pressure and lipid situation monitored in these situations.

The communication with the primary care physicians is really important, especially because of the DRCR [Diabetic Retinopathy Clinical Research] Network trials looking at the importance of education done by ophthalmologists. Surprisingly, it was found that the ophthalmologist’s education of the patients was not important. It didn’t change anything. The way the ophthalmologists educate the patients does not change the final visual acuity outcome. It’s quite surprising for me because I make it my business to tell the patients that they need to have their blood glucose and blood pressure controlled.

I’m curious. How many of the rest of the panelists get letters back from the primary care physician about recommended glycemic goals for a patient?

Yes. Patients who have had diabetes for 30 years with comorbidities, the A1C target may be 8%, not 7%, so it’s important that we give messages that are complementary to those given by the PCP.

I’d like to get more letters than I do.

Diabetes management: Communication between ODs and MDs

What we just discussed sounds easy enough, but Dr Ferrucci or Dr Chous, do you want to talk about the common challenges that providers face when treating patients with this condition?

Yes, there are obviously a lot of challenges. One of the biggest challenges we sometimes have is something Paul alluded to earlier, which is asymptomatic disease. A lot of people seem to think, “If I see well, then my eyes must be healthy.” I’m sure that we have all seen patients with significant diabetic retinopathy who have perfect 20/20 or near 20/20 vision. It’s an important message to convey to our patients that even if they have good vision, they still need to get their eyes checked on a routine basis. I explain to them that, if there is a problem, I want to know about it as soon as possible because we then have more options for treatment vs waiting too late and then our hands are somewhat tied.

Dr Chous, would you like to comment on that?

Patients have a lot of physician visits when they have diabetes. On average, it is something like 15 per year, so patients get overwhelmed. We need to stress the importance of eye care, but a lot of patients face financial, food insecurity, and transportation barriers. There is also a phenomena associated with retinopathy called diabetic encephalopathy where cognitive function declines, especially in patients over the long term. Chronic hyperglycemia not only damages the retina, it damages the brain. This is something for which it is often helpful in my practice to have family members in with the patient when I’m discussing when the patient needs to be seen again or why they need to be referred to a retina specialist.

Dr Loewenstein, we’ll finish with you on this topic of patients who don’t come back. How do you ensure that they’ll come back to you? Are there mechanisms you’ve found or are there best practices you could share with us about how to have a patient not be lost to follow-up and return to us for treatment?

Unfortunately, both in my private clinic and in the division that I’m leading in the public hospital, we don’t have a system for that. The only thing is that, in Israel, there is a very good system with primary care physicians such that they’re being quality controlled by the percentage of patients they refer to ophthalmologists. This solved a lot of these follow-up issues because it is the primary care physicians who make sure that the patients are seeing us. For them, it’s a good parameter by which we measure the quality of their work.

That’s great. Thank you for that discussion.

Challenges to diabetes management

In this section, we’ll be discussing treatment options for diabetic retinopathy [DR] and diabetic macular edema [DME]. We’ll start off with Dr Ferrucci, and we’ll ask what the recommended treatment guidelines are. When is observation appropriate for the patient with DME or diabetic retinopathy?

As an optometrist, when we have a patient with mild or moderate nonproliferative diabetic retinopathy, I’d feel that we can safely see those patients. Once the retinopathy starts to get a bit worse rather than moderate, it makes sense to consider a referral. For diabetic macular edema, if the patient’s vision is reduced from the diabetic macular edema, then that’s a clear-cut time to get a referral to a retinal specialist. The patients who have diabetic macular edema with great or perfect vision are a bit more complicated. I will usually get a second opinion for those patients. I realize that they might not always be treated, but it makes sense to at least get a second opinion.

Dr Chous, we have all these guidelines from the ADA [American Diabetes Association] with regard to follow-up in these patients. Tell us about how you use them. Do you go by the book on all of them as far as 6 months for a mild nonproliferative to a patient with moderate nonproliferative disease? How do you practically use those guidelines from the ADA?

The ADA says it should be 1 to 2 years if the patient has no or minimal DR and good metabolic control. They amorphously say good metabolic control. I’m looking at that, and what is more important than A1C [glycated hemoglobin], which is what the new endocrine research is showing, is what percentage of the patient’s life are they within a normal glucose range, which is called the glucose time in range. It’s independently predictive of DR and vision loss outside of hemoglobin A1C.

My general strategy if a patient has mild or no disease is to perform an annual examination. It could be done less often to save money, which I get from an economic standpoint, but there is value in habituation for the patient, which means getting used to having annual dilated exams. As optometrists, we see this all the time. We tell patients, “Throw your contact lenses away every 2 weeks or every month,” and sure enough, when they come back, we learn that they’re throwing them away every 6 months. There’s value in getting patients acclimatized to coming in more often.

ADA guidelines for DR/DME management

Dr Loewenstein, we’ve had a plethora of data in the past years about how to treat these patients with DME [diabetic macular edema]. Can you talk a bit about the data that now help guide your treatment algorithm for patients with DME?

I can talk about this for hours, but I’ll try to summarize it. First of all, we have the data from the Protocol V trial that says exactly what Steven said: If a patient has good visual acuity, according to Protocol V, you don’t need to treat them up front if you follow up on them. If it’s a patient who will not come to follow-up visits, then I would even treat a patient with good visual acuity. Once the visual acuity is not perfect, if the edema is not in the center, then I might also follow up with the patient.

If I have central macular edema, I will usually treat the patient. If the patient has good visual acuity, then according to Protocol V, all 3 treatments that we have available for us nowadays, which are bevacizumab, ranibizumab, and aflibercept, are all good treatments. They are the same, but if the patient has less than optimal visual acuity, 20/50 or worse, then there is an advantage to one drug over the other. I’m not saying that the difference is huge. The difference is mainly toward bevacizumab, but I try to switch as fast as I can to one of the registered drugs. This is one aspect of the clinical trials.

Another aspect of the clinical trials is the issue that we can treat peripheral disease with anti-VEGF therapy, and we have that from the Protocol S trial from the DRCR.net [Diabetic Retinopathy Clinical Research Network] as well as from the CLARITY trial. That is another trial outside of the DRCR.net. For me, these are the most important trials that show how to treat patients with diabetic macular edema and diabetic retinopathy. There are many other trials, as well as trials that show that it’s not usually helpful enough to use anti-VEGF treatment in patients with NPDR [nonproliferative diabetic retinopathy] to lower the chances of developing [proliferative diabetic retinopathy]. That is probably not needed at this point, according to the knowledge we have from the newer trials.

When you look at the treatment options, what about the safety data that you see? Are all these drugs considered safe at this point for diabetic macular edema? Is there any concern about the systemic or local adverse effect profiles of these drugs?

From the drugs that we have in our armamentarium nowadays, the 3 main drugs don’t have significant local safety issues. We have new drugs that came out that showed an inflammatory response, some of which includes occlusive vasculitis with closure of blood vessels. Blood vessel closure, even with larger blood vessels, raises an ocular safety concern. With the 3 main drugs that we are using recently, there is still a question about whether there is a systemic adverse effect issue. There have been multiple meta-analyses, one of which said that yes, there is an issue there. The researchers said that the studies are not powered to show an issue, so I’m not sure if there is an issue, but I do have it in the back of my mind.

If I have a patient who just had a stroke or an MI [myocardial infarction], I will probably refrain from giving an anti-VEGF agent in the first month or two even though it’s not 100% proven that I’m right by doing so. In many of these cases, I will use a steroid as the primary therapy, with all the caveats that they have. We can also use intravitreal steroids by way of long-lasting implant of dexamethasone, and I use it as primary treatment mostly for patients who cannot come for monthly treatment, but they can measure the pressure, or I use it for patients who just had a stroke or an MI.

Treatment options for DR/DME

Let’s talk about COVID-19 [coronavirus disease 2019] and its impact on caring for some of these patients. Steven, lead off and tell us how COVID-19 has affected your patient clinics [with the Sepulveda VA Hospital].

It’s been difficult because, for a while, we were shut down and tried to perform only urgent and emergent examinations. It unfortunately pushed back some exams for patients with diabetes, especially routine exams, yearly exams, and 6- or 9-month follow-ups. It’s been a challenge with those patients because some of them got delayed treatment or at least delayed exams. We now seem to getting around the corner, and we seem to be doing a bit better, at least with getting our patients back in.

Dr Chous, would you like to comment on how COVID-19 affected your practice [at Chous Eye Care Associates]?

Yes, it slowed things down dramatically for a while, and I’m now back to seeing a lot of patients who are 80 or 90 years old who have had type 2 diabetes for 30 or 40 years. The most important message we can give is that these patients are at dramatically increased risk for bad outcomes if they end up in the hospital for COVID-19, and it’s directly related to their glycemic control. If you have poor blood sugar control, you’re 5 to 10 times more likely to suffer a fatality. That’s the first thing I stress to my patients when I see them. We need to assure patients that they can safely come to our offices and that we’re taking proper protocols to disinfect the office. My advice to my colleagues is to minimize face-to-face exam time because the patient’s risk is higher the longer they’re in an enclosed room. That’s sound advice for anybody in this time.

Dr Loewenstein, I have the same question. How has COVID-19 affected your practice [at Tel Aviv University] with regard to volume of patients, and what’s now happening when the patients return?

Yes. First, at the peak of the pandemic, we had to slow down. We also worked in capsules, so we had only one-third of the staff come to the hospital every day, and two-thirds of the staff were free. What we did was this: we reached out to the patients. We opened with 3 optional solutions. First, we tried to provide the safe environment in our hospital, but for the patients who did not want to come, we also opened a remote clinic outside of the hospital. We got a donation from WeWork in Israel, and we did an injection clinic there. We did OCT [optical coherence tomography] imaging with a clinical examination and treated the patients. That was wonderful.

We did another thing. Since I had a lot of physicians who were not in the capsule working, I sent people to patients’ homes to inject. Physicians were going to patients’ homes. For example, for patients who were in loading phases, or for whom you knew treatments were needed on a fixed regimen, we injected in patients’ homes. Nowadays, everyone is in to work. We don’t work in capsules anymore, so I don’t have the resources to do that. I need the physicians in the hospital. We’re trying to provide exactly what was said here. We’re trying to give a safe environment. We’re keeping social distance. We’re trying to not admit patients into the clinic until they’re going to be seen by physicians. We’re sending them a text message that we are ready to see them. If patients are worried and don’t want to have the time spent in the clinic, I agree that the shorter the visit that we do, the better the patients are. If the patient doesn’t want to have an OCT, I sometimes move to a fixed regimen.

There have been a lot of rumors that we may not need to do visual acuity examinations so often. I’m talking about the physicians. Some people say we should only do OCT imaging and treat the patient, that’s it; the visual acuity examination does not make such a big difference, at least not by the physician at every visit. Rather, the patient can go to the optometrist and have this done. Also for the OCT, if they don’t need an injection, it may be a safer environment than the hospital.

Impact of COVID-19 on management of DR/DME

We have a variety of different treatment options available to us, and there are some that are coming out. We can discuss limitations with the current treatment options and then talk about the newer agents that are here. Obviously, our limitations are that the frequency is high and that the burden is high. It is socioeconomically almost impossible for patients to get a full bevy of treatments, and we do the best we can, but there are other drugs that are becoming available. Dr Loewenstein, can you comment on faricimab as a start?

First of all, I want to say a word about the burden. The burden is not only for the patient. Of course, for patients with diabetes, the burden is terrible because they have many other things that they need to do. They need to go to the podiatrist, they need to go to the cardiologist, and they need to go to other specialists. The burden on them, on the system, and of course on their caregivers is terrible, so we need to lower the burden somehow.

Faricimab is one of the most promising drugs. It is a drug that is bispecific. It is anti-ANG2 [angiopoietin 2]. ANG2 is a trigger in the Tie2 pathway to cause destabilization of the blood vessels. The drug also enhances the activity of VEGF. If you have a molecule that has elements of being both anti-ANG2 as well as anti-VEGF, it theoretically and pharmacologically has the potential to be a good option for our patients. We have preliminary studies, both on AMD [age-related macular degeneration] and on DME [diabetic macular edema] showing that the drug is effective. For DME, the efficacy was better than with the comparator. In AMD, the efficacy was similar. Regarding the duration in both phase 2 trials, when we looked at the second phase of the trial and looked the durability and the survival curve, when did the patient need another treatment, it had great potential when compared to the comparator.

Another important thing about faricimab is that, because it is anti-ANG2, it’s also anti-inflammatory. We know that it’s not the end, but at least in the studies, there wasn’t any issue with inflammatory response. With other drugs that are coming, such as brolucizumab, we have results from phase 3 trials on AMD in the form of the HAWK and HARRIER trials that showed a great benefit. Unfortunately, both in the trials and in the post-marketing surveillance, it has been established that about 4% of the patients developed an inflammatory reaction. In 1% of the patients, it can cause a significant abrupt decrease in visual acuity, and that’s for AMD.

For DME, we have the results for the KITE trial. I didn’t see the readout of the KESTREL trial yet, but I looked at the results for DME, and it again seems to be a promising drug. I’m worried about the inflammatory response. I know that the company is looking into it and trying to find the reason, the root cause, the risk factors, and the management options. Until then, it’s a bit problematic to use this drug.

Regarding KSI-301 and gene therapy, the data are promising, but it is not yet close to clinical use on a large scale. I’m not saying that it will not be. I hope that it will, but I’m not seeing it coming up that soon. Another option that I see coming up is the slow-release device, like the PDS [port delivery system]. We know that it’s now only being studied for diabetes, but for AMD we have pretty good results. There is a small issue of safety. We have to look into the cases of endophthalmitis there, but the rates will probably come down as we go through the learning curve, obviously. We have a lot of things coming up. We have to weigh the risks and the longer durability that we see coming up. I see faricimab as the most promising drug for the future.

Dr Ferrucci and Dr Chous, you could speak about on the optometry side. If you had to look forward, thinking about some devices or technologies, what would make it much easier for you to do your work and help patients achieve the best possible outcomes for diabetic eye disease?

That’s a tough question. I don’t know. I’m not sure I can think of anything right now. Paul?

Something that I’ve been interested in is the retinal flavoproteins. It’s not specific to diabetes, but it’s the earliest marker of photoreceptor oxidative stress in diabetes, AMD, and in glaucoma they’ve even shown. I’m interested in that as an early marker in improving glucose control and improving those markers to keep the patients from needing to see the retina specialist. In optometry, my goal is to keep the patient from needing an injection in the eye or needing photocoagulation, if I possibly can. If there is anything with which I can detect disease earlier that’s easy to do and cost-effective, it appeals to me.

Steve, do you have anything to add to that?

I would mention that there be more OCT [optical coherence tomography] imaging out there. With more accessibility to OCT imaging, that would be a great way to help monitor for diabetic macular edema. More affordability in OCT moving forward will help more optometrists have access to them, which should help take better care of patients and look for diabetic macular edema.

I want to thank my panelists for today’s discussion, and thank you to the viewing audience for listening to the program. We hope you found this 

 program to be rich and informative. We hope to see you soon.

Updates in diabetic macular edema, diabetic retinopathy