I'm Charles Wykoff, a medical and surgical retina specialist based in Houston, Texas, that the privilege to be here to talk about diabetic eye disease? This is part of M. C L C M E. A part of a multi modular Siri's looking at diabetic eye disease. Today we'll be talking about optimizing management and treatment strategies. My disclosures are listed. I'm gonna go through four different chapters today. Here's our outline. Epidemiology and risk factors for diabetic retinopathy and DME screening at the physiology and imaging and treatment. When we look globally, it's pretty clear that diabetes is a growing global tsunami. But if you look back in the late 19 nineties, approximately 2.8 of the global adult population had diabetes. You can see year over year dramatic increases in these numbers to the most recent World Health Organization, or W H O assessment of the prevalence of diabetes around the world in 2016 at 8% that means about one in 12 or one in 13 adults on our planet have diabetes. This is truly a global problem, and of course, within the context of diabetes, multiple different organ systems can be affected and have a major impact on patients, life and their quality of life. The one that we're going to. Of course, focus on here is diabetic retinopathy. And I want you to think about this number for a second. Because if I tell patients that they have a 28.5% chance of developing diabetic retinopathy, right, that's that's that number there on the top left where it says 28.5% of adults with diabetes over 40 have diabetic retinopathy. What do you think most patients were gonna think? Well, the natural human tendency if you're told that there's a 28.5% chance of something, is to think that you're gonna be one of the people in the other percentage, you're gonna be in the 70 plus percent patients that don't get diabetic retinopathy. So the reason I pointed out that way a slightly different way of saying it then you've heard before is that I think these crocks, factional numbers on the epidemiology of diabetic retinopathy prevalence on DME are dangerous. That I think that the better answer to the question that I phrase here, I'm going to tell you on the next slide because this is the key question that patients have. Doc, what are the chances that I'm going to get diabetic retinopathy? What are the chances that diabetes is going to affect my aunt? What's the chances that I'm going to lose vision? And if you tell them a low number, they are automatically going to think that they are not going to get it. And the low numbers are are dangerously misleading. Overstate that just a little bit. And I wanna make this clear. Rather, I think the best answer to that question and the point that we need to make repeatedly tow our patients with diabetes is that diabetic retinopathy is a win problem, not an if problem. In other words, if patients live long enough with diabetes, unfortunately, they're living longer than long longer than ever because of so many excellent medical interventions systemically to keep these patients alive and keep their kidneys working well for many more years than they used thio. If they live long enough, they are going to develop diabetic retinopathy. The immediate make that point more clearly to our patients lost the spectrum of diabetes around the world. Some key points here diabetic retinopathy is, of course, the leading cause of blindness for adults age 22 74. Across the United States and in many developed countries around the world, that means that this causes more blindness than everything else. I mean, it's a it's a It's a bold statement in the true one, but one that we often gloss over. We just kind of say that. But when you see blindness face to face, which ophthalmologists and rent a specialist see every day from this disease, it's it is. It is heart wrenching because these patients do not need to go blind. There are many diseases that caused blindness that air untreatable. This is very treatable, and we'll get into that. That's why this number bothers me so much. If patients live 20 years with diabetes and they have Type one diabetes, they haven't over 90% chance of developing diabetic retinopathy and that they have Type two diabetes and over 80% chance of developing diabetes. And the key point here is that available treatments for diabetic retinopathy are exceptionally effective. Over 90% of patients do not need to go blind. They receive the treatments that they should to remember 500. Not but the is a when. Problem not a gift problem, but more granular. Lee. What are the risk factors for developing diabetic retinopathy? Well, there's some modifiable risk factors that are obvious, right? Blood sugar, blood pressure, cholesterol. We must always encourage our patients to optimize their control, but there's other that we often gloss over. Smoking is an accelerator of diabetic retinopathy. We must encourage smoking cessation. Wait. Um, being overweight is a major risk factor for this. We must encourage weight reduction and exercise. Sleep apnea is an underappreciated risk factor for diabetic retinopathy. Pregnancy, of course, can lead toe rapid acceleration of diabetic retinopathy. Be careful of any patient with either type one or Type two diabetes. Who gets pregnant, make sure they're getting examination every trimester and then kidney dysfunction. All of these are potentially modifiable risk factors for diabetic in apathy. Let's talk about the vascular complications of diabetes, and again we're going to focus on the I. And the other question that I think of from a patient perspective is Doctor, how much of a distance does it really make? If I control my blood sugar, my blood pressure I mean, I feel fine. I don't really care if my A one c is nine or eight or seven or 10. Does it really make a difference? Show me the data. And the simple answer here is that even small improvements in blood, sugar and blood pressure control and have a huge impact on decreasing the risk of developments and decreasing the speed at which diabetic retinopathy progress. So, for example, every 1% absolute change in a one C is correlated with a 50% decrease in production in progression of diabetic retinopathy. In other words, if a patient comes in with terrible blood sugar control in their A one. C is 10 right. If they go down to a nine, they decrease their risk of progression by 50%. And nine is still terrible blood sugar control. But you still get 50% decrease in progression of diabetic retinopathy with that 1% change. Similarly, if someone comes in with a 7.5 a one C, which is pretty good and they get down to a 6.5, they again have dropped their risk by 50% so we don't need patients to be perfect. We just need them to constantly be getting better to decrease their risk over time. Other numbers to think about here are that with optimizing blood sugar and blood pressure control, you can decrease your risk of developing any diabetic retinopathy by 76% and decrease the risk of progression of diabetic retinopathy when it's already formed by 54%. So blood sugar and blood pressure go hand in hand. Modifiable risk factors. What are the screening guidelines? Well, the point that I would start with is unfortunately, probably 50% of patients are not receiving the appropriate I care that they need and that they deserve. And 50% of patients who come in for screening don't follow up as needed. Simply, we're not doing a very good job of this, but this is follow without data. This is amazing data from the United Kingdom. What the United Kingdom has been successful at doing is unbelievable and needs to be transplanted across the Atlantic here in the United States. What they did was by instituting a national screening program where everybody got behind it and we and they said, we're going to screen every diabetic for diabetic retinopathy. They were able to for the first time, basically in recorded history. Take diabetic retinopathy from the number one cause of blindness down the number two cause of blindness, which is a big deal because now in the United Kingdom, actually hereditary retinal disorders are the number one cause of severe visual impairment, not diabetic retinopathy. Because of the success of screening, the screening really does work to prevent blindness. We have this now United Kingdom we have from Iceland we have from some of the Scandinavian countries. This has been reproduced in multiple systems around the world. So when should patients be seen for diabetic retinopathy screening? Well, the simple thing to remember here is that every one with diabetes should probably have annual screenings for diabetic rent map. Don't make it more complicated than that. Don't ever think it's okay to go more than a year. You're saying anybody with diabetes they should get an annual check for diabetic retinopathy and, of course, more frequently if they have any substantial pathology, Um, and some of the details related to the level of pathology correlating with the frequency of follow ups has listed here. Remember the outer limit here is once a year, and if we look at it from a patient perspective again, we are not doing as well as we could. I think our greatest challenges that patients are waiting until they have visual symptoms to come in for diabetic retinopathy screening. The whole point of screening is to capture these patients before they have symptoms. And only 29% of patients currently based on this survey of over 4000 patients are actually coming in for screening before they have visual problems. We need to educate patients and also broadly providers from primary care positions and technologist optometrists, ophthalmologists. But, hey, if you're seeing the patient with diabetes and they're not symptomatic, that's exactly the right time to screen. Don't wait until they have. Simple. So how does diabetes affect the retina? What's the underlying path? A Physiology of diabetic retinopathy? The core problem here is damage to the small blood vessels in the back of the eye. Actually, the back of the eye probably receives mawr blood flow for unit area than any other tissue in the body. It is incredibly densely filled with blood vessels from the core oId up to the retina and one of the focal places where diabetic retinopathy damages is those small blood vessels in particular the parasites, either the cells that nurture and support the endothelial cells which line the blood vessels themselves. The earliest manifestation of diabetic retinopathy are micro aneurysms shown on this flourishing angiogram. At the bottom here, you can see the little bright dots. These are changes in the blood vessel walls. Because of those damaged capital Aries damaged blood vessels. You see a little bit of stagnation of the blood and therefore these pin 10 point more pro florescent spots on angiography. There's a very typical I with non proliferated diabetic retinopathy. You can see now you have more than the micro aneurysms. Now you have dot plot hemorrhages again, Member. The core pathology here is damage to the small blood vessels. You eventually get breakdown of the blood vessels and hemorrhage into the retina itself. If you quantify the number of hemorrhages and other changes associate with diabetic retinopathy, your ableto have a quantitative scale which measures the severity of diabetic retinopathy. This is known as the e t d r s d r S s, which stands for the early treatment. Diabetic retinopathy Study. Diabetic retinopathy. Severity scale kind of a mouse full. But the point here is that there are least 12 different step of visible diabetic retinopathy from minimal on the top, left here to blindness on the bottom right. But the two core pathologies of diabetic retinopathy that caused blindness and vision loss are DME, represented at the top and proliferated. Diabetic retinopathy. Bottom again. DME stands for diabetic macular oedema, where you have thickening of the retina. At the top, E G. R is proliferated. Diabetic retinopathy When you have scar tissue that causes fractional forces on the retina, ultimately retinal detached. There's a case for you that I wanna walk through today. This is a mid forties year old woman with Type two diabetes with minimal symptoms. She has mild floaters in both eyes that air getting worse over the last couple of months, but she's very high functioning 2025 in the right eye in 2020 and the left. You can see our color funded photographs at the top and hero C T scans at the bottom. You see, there's no meaningful diabetic macular oedema here, and truthfully, these funds for photographs. What kind of benign? You don't see many hemorrhages. You see some mid cripple hemorrhages in both eyes, but not a lot of vitreous hemorrhage. No traction. But what's actually going on here? Well, one diagnostic tests that we use a lot when screening for the severity of diabetic grandma. Apathy among patients that we believe have advanced stages is illustrated here. This is called a white field for a scene angiogram, where you look at the blood flow through the back of the eye and there's a few things to point out here. There's a whole lot more pathology visible on angiography than there was on the funders photography. This is why screening by by eye care professionals that know what they're looking at with diabetic retinopathy is still important. Because if we just be kind of a bland color funders photograph like I showed you in the previous slide, people might just grants over that you say they're fine, but when you actually take a closer look, you can see this patient has high risk proliferated diabetic retinopathy with a very high risk of progression to severe vision loss and the B word again blindness If they do not get treated. You see multifocal areas of need, a vast authorization that these are these bright spots down here on the lower part of the field with some vitreous hemorrhage making this high risk lift the diabetic retinopathy. And this disease process, in many cases, is driven by up regulation of veg f. When I show on the top right here, vet Geoff fan for vascular endothelial growth factor, it's produced by the cells that are basically oxygen starved when they're not getting enough oxygen and become hypoxic. Remember, the core problem and diabetic retinopathy is breakdown of those normal blood vessels. And subsequently you get a decrease in the oxygen delivery to those parts of the retina, those cells, and send off more veg F, which is a def usable Sadiq Khan and signaling molecule, which then leads to both DME and ER in this case. So we are definitely going to intervene and manage this patient and treat them interventional e, even though their color funded photographs didn't look that bad. Welcome back to this patient. A few slides. So how do we treat diabetic retinopathy? This is end stage, diabetic retinopathy. This is the B word. This is blindness that you're looking at right here and again. I want to make this point again because it is so important. If we effectively treat people the way that they deserve to be treated, we can prevent probably 90% or greater all the blindness related to diabetic retinopathy. And there's two major cornerstones. The treatment lasers is shown on the bottom left here, an example of a physician putting in laser or injections and medications into the I show on the bottom. Right principal, with both of these treatment modalities is that overall earlier treatment leads to better outcomes. So if you're comfortable screening for diabetic retinopathy, fantastic screen these patients. And then if you're not comfortable treating for diabetic retinopathy. If you see I would say at this stage really any meaningful number of hemorrhages in the retina. Even if there's no DME, I would recommend that patients see a physician that is comfortable treating diabetic retinopathy, just in case they've crossed over that threshold where there need tohave intervention. So how do we treat diabetic retinopathy? We'll just toe Echo would have already said systemic medical management particularly important, But then let's talk specifically about the ocular specific treatments. There are laser options there, actually many laser options. But the two big categories are peripheral pan retinal folk regulation of PRP or more targeted laser into the post. Your poll, called Macular Laser pharmacologic therapy, involves two categories and medications currently anti that Jeff Pharmaceuticals and corticosteroids, all of which we inject inside the eye. All of these on the right, are examples of medications that can be injected into the eye through the forest. Plena in a needle passes across the eye wall really should not hurt For patients to receive these injections, there's always a risk. With these injections, the risk is small. The patients need to be aware of those risks, the biggest one being an infection, which probably occurred approximately one out of every 2 to 1 out of every 10,000. I'm injections. So what are our thresholds for initiation of treatment for diabetic retinopathy Will. Some are obvious and well accepted. These include center involved, the immediate with vision lost and I risk proliferated, diabetic retinopathy shown on the left and right here, respectively. But this is actually a very nuanced space. And here is a recent um Tpp or preferred practice pattern discussion from the American Academy of Ophthalmology. The authors were shown on the left here. From the right, you can see that the different treatment options are variable, depending on the stage and severity of the diabetic right now. But this is again a nuanced space where the patients in between those with moderate NPD are and severe NPD are with and without DME. You see a lot of these words sometimes on here. In other words, there's a lot of individual options here, depending on every individual patients, circumstances exactly what might be the best options. This is why it's so important that patients, when they're anywhere close with threshold that might need treatment, are able to see a retina specialist. Or at least someone that's come for terrible managing diabetic retinopathy, so that these important discussions about what is the appropriate treatment here can be had with patients before they begin to lose vision. So let's look at another case. This is a 2080 patients in their left I. They were late fifties with Type two diabetes in humans live in a one C of eight on the left. Here they had marked vision loss with extensive diabetic macular oedema. They got multiple intra vitriol anti V Jeff injections over the course of about three years and you see two things on the image of the right. First of all, you see that functionally, they are much improved. Their 2032. We don't always see this dramatic visual improvement right into virtual injections are highly effective that stabilizing disease, improving disease, but they're exceptionally good at preventing progression of disease. That's why earlier treatment leads to better outcomes overall. But in this case, we got a home run. The patient did great, much better visual acuity. The second finding on the right are the fact that anatomically they're much improved. Do you see that the extent of hemorrhages and the funnest photography here the hard exit dates have all dramatically improved, and the diabetic macular oedema has resolved in the faux beall region. You do. You do see some residual temporal macular oedema here, but the central fluid is essentially resolved. The benefit here is that the medications work. They're highly effective. The biggest challenge and one of the biggest challenges to compliance is it takes many injections. That's why I put up this image of Atlas here holding up the world. It's a significant burden for patients, and we all must appreciate that this is a big burden so that we can be with the patients both physically and emotionally. Through this journey. It's a lot to get multiple injections into your eye over the course of many years again. These really should not hurt, but it is a lot. Patients need to come in for frequent visits. We must courage compliance with this treatment option when patients needed. Here's another example from the Rod and Rise Phase three clinical trial program at Baseline. The patient had vision loss and again high risk lifted diabetic retinopathy on the left and you could see three years later, after regular and consistent anti that Jeff dozing you can see mark an atomic improvement that again, in this, this case was correlated with dramatic visual improvement. So I'm gonna come back now. The patient that I started telling you about before with the proliferated diabetic retinopathy, and I'll tell you a story about what happened to this patient. I described to them initially the options for treatment laser versus injections of anti veg of agents in the eye and the patient shows to do laser in there, right? I So that's what we did. I put in panda in the photo coagulation. You could see these dark spots are the laser marks, and immediately the patient noticed visual symptoms that they did not like. They noticed that their contrast sensitivity had decreased. They felt their color vision was worse. They felt their night vision was worse. They felt that their visual field was worse, and my initial plan was to put in P. R. P in both eyes. But after I put it in one eye, the patient said, I don't want that laser, my other eye. And so we actually have been injecting the left eye here with anti Veg F agents every 4 to 8 weeks now for multiple years, and the patient is much happier with their visual function in the left eye. It is a big burden for the patients to receive these regular injections, but the patient, it's well worth it because they could maintain their vision. The deeper point that I would bring out about this case. This is the same. I now this is the baseline on the left. Why? I feel florist angiogram and, um, four years follow up on the right. This is with every 1 to 2 month anti veg F injections. In this case, I'm using a liver ship, and the point I would make is first of all, their post your poll. There. Macula looks pretty good. They have good perfusion and immaculate. That's why they're high functioning from a visual function perspective. But if you look in the periphery, they have large areas of retinal, non perfusion member. That's the core underlying EPA physiology of diabetic retinopathy and what's become clear over multiple analyses of the last few years that are anti veg of agents in most cases do not revert those areas of vascular damage. There are some examples where there is some reversal, but in the majority of cases, we do not see widespread improvement in retinal non profusion. In fact, we actually see progressive retinal, non perfusion, even in patients receiving treatment. That's what these red circles or highlighting their showing areas that had some degree of profusion that is decreasing for five years later. But the point I would make is that the way I interpret the data over multiple clinical trials is that repeated injections of our anti V Jeff agents are able to slow the worsening of that damage to the vasculature. In other words, if you're not treating this patient, they're going to get worse, much more rapidly than if you are treating them. Treating them dramatically slows down the process of vascular lost. It takes regular treatments to achieve that benefit. But I do think that's one of the core benefits of regular, consistent, ongoing anti veg F dozing in the context of diabetic retinopathy. So what are the agents that we use to treat diabetic retinopathy? From a pharmacologic perspective, what we have to FDA approved on label agents ran a busy map. There is FDA approved for diabetic retinopathy, independent of DNA status in 2017 and a flipper set, which was approved in 2019 for the same thing. Here are two examples from my clinics showing extensive diabetic retinopathy on the left here, without center involved DME, who were treated with regular anti veg up injections over two years with marked improvement in their extent of hemorrhages. Um, you can see on the funded photography on the right. But what's the data that we have toe actually support intervention at the stage of non proliferate diabetic retinopathy without DME? The only prospective trial with public data at this point in the anti V Jeff era is the Panorama Phase three trial. This is a double mast random. My study of the efficacy and safety of a flipper step in patients with what I call high risk NPR, that is moderately severe to severe NPD are the RSS levels 47 53. On that quantified scale, I showed you that E t dear SDRs s 402 patients were randomized toe one of three arms, either sham injections or a flipper step dozing every four months for every two months after four and five loading doses, respectively. And the primary outcome data is shown on this slide basically in purple and blue. What you're seeing is that a majority of patients are experiencing meaningful diabetic retinopathy severity improvement with regular anti. That Jeff dozing every four month injections is three injections a year, and these patients maintain their improvements from 1 to 2 years. On the left, you see the control on the sham population, with only a very small proportion of patients demonstrating thes meaningful diabetic retinopathy improvements. But the concept that comes up a lot is Do we really care about the data shown on this slide? This data actually drove FDA approval of our two on label anti Veg F agents and I believe is highly relevant and very meaningful. But from a clinical perspective, this data isn't necessarily what patients want to see. Right. Remember, the patients enrolled in this clinical trial did not have DMI, so their vision was quite good at base one. On average, they were 2022 2025 and therefore, it's hard to make patients like that Steve Better. But what is it? The patients in that category once they don't really necessarily care how maney hemorrhages they have in their retina, which is what's driving these improvements and diabetic retinopathy. What they care about is actually the risk of developing a bad outcome. And that's what summarized on this slide. This trial was designed specifically toe look at the development of those bad outcomes here we're calling them vtcs, or vision threatening complications, which was basically the development of proliferated diabetic retinopathy or anti or segment of vascular ization or center involved DME. And when you look at that cumulatively through the end of the try a week, 100 or almost two years you see that 57.7% of the sham eyes developed. One of these bad outcomes compared toa 18 to 21% of the flipper Sepp treated isles, which is a 75 to 79% risk reduction. The likelihood of developing these events over this two year time horizon that is a meaningful, highly clinically meaningful reduction of development of P R or D. M. And I think highly clinically relevant when we discuss the opportunity for intervention of the NPD are stage without DME with our Asian. And so what the Panorama trialing has really set up is a theoretical debate which I lay out in this in this flied and that is for positions and interventional specialists that see this data as paradigm shifting. And we really should be intervening earlier for these patients to decrease the chances of them developing political disease, or DME. But then there's another camp that sort of sees this data is really important and moving the field forward but incomplete, and that close clinical observation of these eyes is still warranted. I think the simple answer to this right I set this up is a theoretical debate. But the simple answer is, is that this needs to be an individualized answer, right? There is no one. Shoe size fits all for this particular stage of diabetic retinopathy. Again, it goes back to the thresholds discussion that we had. There are certain patients with diabetic retinopathy, the with vision loss or high risk character category of Clifford disease that all of us would agree need intervention. But in this stage, without center involved DME, this is where the data is important to communicate with patients. It's important to review the images with patients and really find out their goals and their objectives with their long term care. They like to initiate earlier to decrease the chance of developing, um, a unwanted outcome. Or would they? Would they? Would they rather wait at this stage until they develop one of them or high risk characteristics? The discussion needs to be had with every patient, but I'd like to put forward a few arguments that I think sort of tip the balance overall towards recommending earlier intervention for many patients. Not all patients but many. This is the discussion I have with patients. First of all, treating earlier significantly decreased the probability of developing PDR or DME, the day that we just looked at, and neither thresholds that traditionally have been used to initiate therapy. Second, it's worth considering other extradited retinal diseases at this point, because for many expletive retinal diseases, including me, a vascular M D center involved DME with vision loss. Retinal vein occlusion is the second most common rental vascular disease. After diving or friend apathy, there's fairly robust data that the earlier one intervenes. Overall, the better long term outcomes can be achieved. Third, this is a passion of mine and one that I spoke to when we looked at that patient case a few slides ago. Anti veg F treatment can slow the development and progression of retinal non profusion, which is the core vascular pathology of diabetic retinopathy. Fourth, there's a body of literature that suggests that among patients with diabetic retinopathy, even without DNA that the worst the level of retinopathy, the worst, the any IBF Q scores. What does that mean what basically means that is diabetic, but not that the severity worsens there. The correlation with reduced visual function and quality of life one of most validated measure the quality of life from a visual function perspective is a thing called the any IBK, which was a questionnaire developed by the any I to study visual function on a questionnaire on what you see on this graph is that once you get beyond just mild to moderate NPR in both eyes, once you're down in the level 47 or 53 remember, this is where Panorama enrolled patients. You are well down on the visual function questionnaire across a population of patients, and one of the things that's driving this the blue trajectory is actually the driving difficulty score where patients will, on average, notice a decline in their ability to drive safely as their diet have been. Apathy. Severity worsen. At this point, I would make was a powerful Irish registry analysis that we did looking at patients preventing in the anti V Jeff era. So this is in the era of having access to our anti V Jeff medications. On we look the patients that presented with good visual acuity, and then we stratified them based on their severity of diabetic retinopathy. On what we saw is that that those patients with severe NPR remember that that's basically this category that I call high risk NPD are. They have a similar probability of developing sustained blindness as patients with proliferated diabetic retinopathy over 4 to 5 years of follow up and specifically two years after a diagnosis. The diabetic retinopathy I've with baseline severe, nonpolitical diabetic retinopathy and PDR had 3.6 toe four times the likelihood of developing sustained blindness compared toa eyes with more milder forms of NPR. Be careful. These eyes really are high risk. Ais. Even in the absence of DME before they developed PDR and the last point, I would make a two final slides here. So look at what what our retina specialists doing. Are they treating these eyes earlier with NPR without being mean? There's a survey called the PATH Survey, which is the preferences and friends of retina specialists across America run by the American Society reading Specialist. From what we've learned is that these numbers are slowly increasing, so currently almost a quarter of retina specialists are using anti veg F therapies for NPR without DME percentage that could 10 years to increase year over year. And secondly, this is looking specifically at the role of Panorama impacting how physicians consider managing eyes with non political diabetic retinopathy. And we saw here that 39% of retina specialists that their practice patterns were impacted by Panorama, suggesting that data that helps guide us in the management of patients with earlier stages of diabetic retinopathy before they have these end stage manifestations of proliferated disease and center involved. DME really do have the power toe, the change practice patterns moving forward. With that, I appreciate your attention. That's been a privilege to be able to talk to you about optimizing management and treatment strategies for diabetic eye disease as part of this multi series.