Hello and thank you for this invitation to speak at this forum looking at the advances we've had in mitigating the progression of diabetic eye disease. And I'm going to cover in my talk today the prompt referral of patients for retin. Ologists to take care of these patients as well as to initiate therapy. A lot has changed in the past few years with regards to how you manage these patients. And I'm going to cover that as part of my talk today. So my focus dig and is on the focus of prevention of DM related blindness in patients with diabetes. My name is Rishi Singh from Cleveland clinic. Cleveland Ohio. It's my pleasure to give you this talk today. In this talk, I'm going to talk about the prevalence of DMI and our populations and I'll describe the treatment approaches to dems as well and the underlying pathogenesis and we'll evaluate some of the newest evidence with regards to the clinical studies which have guided our treatment decisions. And again, many of this has changed in the past 10 years. We've really been able to tailor therapy to the patient's vision, there, retinal thickness, there are certain biomarkers that are present in order for us to maximize visual gains in a population that's at risk, Diabetes is a growing worldwide epidemic. And before the pandemic of the coronavirus, this is really our epidemic in our populations. We've seen a 51% potential increase in our diabetic populations from 2019 to 2045 with a huge economic impact that follows us as well. And so were also well aware that diabetes has many, many different effects on both micro vascular And macro vascular structures. One of the concerns that many patients have really is around I disease and in fact, that's the primary concern of most of the patients, that the loss of vision is the most feared complication of diabetes, with 50% of respondents saying that the vision or vision loss is a significant concern for them and the complications of this disease really are sometimes quite silent. Sometimes people may not notice they have this disease until really late in the stage. And again, patients awareness is not necessarily correlated with the potential for this progression as well. We know that 63% of patients actually knew that the problems of diabetes may affect them in the future, but the risk really seemed remote. 25% were devastated when they found that they might develop complications And 9% actually walked around and said they weren't really that concerned about developing over time. So clearly there is a population here are patients who either doesn't understand their progression rates or they don't understand necessarily that they are at risk for developing these complications over time. Now again, as I mentioned to this increase in diabetic adults means there's going to be an increase in the level of diabetic retinopathy we plan to see in this population as well and we know that the 27% of patients have any level of diabetic retinopathy, 25% of non political disease. 4% of these patients will have diabetic macular oedema or center involving disease of this, of this category, where the swelling and distortion of the central vision And 1.4% will have the most advanced forms of diabetic retinopathy, which again, 1.4% might not seem like a lot. But we look at the numbers and especially the growth. That could be a huge number of patients with the most active proliferated form of diabetes where you develop new blood vessel growth and certainly high risk of legal blindness in this population. Over time now we know that diabetic retinopathy and diabetic macular oedema are complications of diabetes that can cause vision loss. And so it's important to understand the stages of diabetic retinopathy to better understand when these occur. So first you have the non proliferated form of the disease, which is typically asymptomatic where blood vessels start to begin leaking as I tell the patient due to the loss of parasites and supportive vascular and a filial cells. And this causes distortion swelling of the retina where this fluid in the retina. This causes it exhibits to form in the retina and in addition it starts to form a hypoxic conditions which then lead to potentially a lower level of oxygenation, which then sets up the stage for the second stage, which is the proliferated form of the disease. In the proliferated forum. This is when it becomes vision threatening, when you could potentially have an increase in the blood vessels that form and these blood vessels form neo vascular franz, which can form on the disc or in the retina and cause hemorrhages and loss of vision due to the formation of glaucoma as a result of this as well. This is the vision threatening form of the disease with a high risk of progression to again legal blindness. In this population, it's estimated to be about 50% of patients with proliferated disease untreated will become legally blind within a two-year period. And finally you have diabetic macular edema which can occur at any stage of the the nonproliferation proliferate disease where their blood vessels in the macula or the red and in the central part of the vision which well and leak. And this is again vision threatening but again, can cause loss of vision due to this distortion swallowing over time. Now, we know again that there is obviously an increased risk of patients progressing based upon their stage. 50% of patients with very severe, non prolific disease will progress to proliferated disease. Within a year's time, 25% of patients with will have a lucrative diabetes after a 15 year duration. And again, DME can occur at any stage of the disease. And so that's an important thing to remember that it can occur on the time of diagnosis of diabetes, but it can occur even later in the disease after the patients develop proliferated the proliferated state for many years later. Now, we're also aware that DME is a chronic vision threatening condition that can cause blurred or vision or blindness over time and again, I talked to you a little bit about the stages, but you have essentially leakage of fluid from blood vessels which caused the local hypoxic estate state. And that can then cause significant blurring and vision loss and risk of blinds due to macular oedema, which is diabetic macular oedema swelling of the central division or retinal, neo vascular ization or proliferated disease. And again, the typical age of these patients of the population characteristics are that these are working age adults like you and I. They have family lives. They have work lives. They are very, very difficult to make all of their appointments. They usually have hypertension as well. They typically will have poor glycemic control and diabetes, again of significant duration, usually at least 15 years of duration before they have this condition. Now it's important to understand that obviously when we we treat patients with diabetic macular oedema, we only treat uh the eye, but we're treating the body. And when we talk about microvascular damage we're seeing in the retina, you can imagine this is present everywhere. You're seeing natural apathy and neuropathy in these same individuals. So that's why I always send a letter back to the primary care doctor to let them know that this patient is presented with diabetic retinopathy or diabetic macular oedema because usually there are other risk factors associated with this condition such as high blood pressure, high hemoglobin, a one C levels and increase in total serum cholesterol. Which can be again accommodating for this progression in those patients obviously with the duration diseases, not much we can do. But then this leads to an increased prevalence, especially in those with various levels of stages of diabetic retinopathy here. You can see the stages on the bottom and the risk of progression to macular oedema. Diabetic macular oedema in particular is higher, especially as the diabetic severity goes on. And so that's an important factor I think to remember in these patients is that there are some risk factors that you, as Diabate ologists can control, that would help out all of their other systemic issues. And sometimes as ophthalmologist were the first people to diagnose them with diabetes. So that can be an important finding and again, important for the patient to get in to see people like you who take care of diabetes and can manage their condition. Now I touched already on how diabetic macular oedema and diabetic ralphie. It's really a multifactorial path of physiology and it really is an interplay between the neurodegenerative pathways, the vascular pathways and inflammatory pathways in patients with this condition. And again, the accepted sort of state of the way we see the progression is that these osmotic or inflammatory changes due to hyperglycemia cause damage to the retinal blood vessels, which leads to micro vascular damage, localized hypoxia and Jeff production or vascular endothelial growth factor production and finally need of accusation and then vision loss. In addition, V Jeff can be a mediator or a downstream effect of leakage of the micro vasculature, which then can lead to macular oedema as well. And that in itself can lead to vision loss over time. And essentially what we're talking about here is that hyperglycemia state can lead to a disruption of the blood retinal barrier and unfortunately loss of vision due to this state over time. Now, many of the central studies that were done on this actually looked at both Aquarius and vitreous levels of that Jeff to determine if that Jeff was a mediator in these patients and what you can see on the left side is a patient population when they looked at the vitreous levels in various disease states. The basketball AMG retinal vein occlusion, diabetic macular edema and found elevated levels of the Jeff in all of these states. And again, if you look at the far right side with various stages of diabetic macular oedema, you can see as the stage worsens the obviously the amount of that Jeff increases as well. So this gives you a sense of the downstream effect of those. The conditions due to hyperglycemia which caused elevated levels of the Jeff and is a key mediator in the other effects that we see that increases vascular permeability, increases cardiovascular ization and causes disruption of homeostasis further for these patients as a result of being present. Now we know that diabetic macular oedema is actually a presence of macular fluid accumulation and I've shown you a schematic on the left side here with just a cartoon showing you where diabetic macular edema can occur. And this is on the far right side and O. C. T. Or optical coherence tomography image. We take a cross section almost like a histological section of the patient's retina as produced by light. And in this case we can see with spectral domain which is a typical, typical type of using clinic. Again this is a non dye based test but we can see clearly that there is a swelling and architectural change in the retina due to diabetic macular oedema which is associated with this breakdown of the bullet riddled barrier and again mediated by V. Jeff that we're aware of and the fluid accumulation can cause damage to the photoreceptors and other structures in the retina and cause irreparable visual loss over time. So let's talk about the clinical management of DME because this has really changed over the past few years with the advent of anti V. Jeff drugs and we know that the optimization of patients with diabetic macular oedema and even diabetic retinopathy is all about these three pillars. First, early diagnosis, making sure that we can find patients in their earliest physiological state where they might not have as much damage. Second initiating treatment and patients with especially good vision a vision that is not too far gone because they can have the best possible vision gain an outcome. And lastly, in patients who have good follow up and that's something that we all talk to our patients about, which is that we need to have good follow up in order and share care. But the vast majority of patients, unfortunately diabetic retinopathy and diabetic Nakajima have pretty horrible follow up, to be quite honest with you. We see in some studies at almost 25% of patients who are receiving anti VHF to a diabetic MacLeod Imo will have at least one or two missed appointments within a year's time. So really again these three pillars and followed well can preserve a patient's vision long term. It's only when you don't have these three pillars being adhered to that you have patients who lose vision and our current state of affairs with the wonderful transformative therapies that we have. Now. Now we use a lot of tools in clinic that your patients are probably going to tell you about to stage their level of diabetic neuropathy. We use spectral domain O. C. T. Which is again the cross section histological scan of the retina. We use optical coherence tomography angiography which is a non dialysis based test to look at the microvascular of the retina as you can see in the middle photograph. And we use florentine angiography on the far right side, which allows us to look at the micro vascular structures in the retina allows us to determine if there's any leakage or damage blood vessels or even neo vascular station by the use of a die, which is a transit based dye that we inject into the cubicle vein and follow over time to see those changes over time. And patients can have various levels or kind of various presentations on the OECD test. Here's just a couple of different examples from multiple patients with either fluid in the retina assist, sub retinal fluid disruption of the photoreceptors layers, all various different pictures you can see in patients as a result of having diabetic micro. So this is a really nice, easy non invasive way of determining both the diagnosis but also the treatment response. We use this quantitatively to follow patients over time so patients can have really really different pictures on presentation. So what do we do in clinical practice? Well first we do a dilated eye examinations. We put drops in their eyes and we dilate their pupils in order to do an indirect and direct optimus capi examination. And if vision is bad 2050 or worse in clinic we really consider adding on additional testing such as funders photography to show some pictures to the patient a baseline to kind of let them know how they're written off these doing and how it's how it's progressing. We show them the O. C. T. To really rule out or confirm diabetic macular oedema. We use the flourishing angiography or the dye based test to look at concerns of patients who might have severe retinopathy. To the point we might want to diagnose if they have proliferate disease. And we used to and causes of decreased vision in the absence of a fluorescent angiogram to look to see if the capillary bed is remodeled or damaged in the center of the vision. These patients with diabetic retinopathy. So these are the kind of the, you know, our go to test for a lot of these conditions. Again, only when really vision is compromised, efficient is good. 2020 or 2025. We tend not to get these pictures at least just not all of them may be funded photographs at baseline, but for patients who have an impacted vision. We do get these tests to help us with the diagnosis and management of these patients. Over time Now again, we've had a huge evolution and the way we've taken care of patients over the past few years. We started off again about 20 years 2030 years ago with really no treatment for diabetic MacLeod Emma. And eventually laser photo coagulation was developed where they can actually coagulate micro aneurysms and put in what they call grid photo coagulation laser, which really prevents the retina from swelling by creating artificial retinal scarring. So this is sort of vision threatening potentially because you are causing scarring the retina but it also doesn't necessarily improve vision. I'll show you what I mean by that in a few moments when I show you some of the data from the studies, steroids have been around for many years. The problem with steroids that they cause called coma and cataracts reforms. So they're not for every patient. But yet it's a very effective way of treating patients with diabetic macular edema as well. And finally we're into the realm of antibiotic therapy which is really improved and optimized visual outcomes by tailoring therapy to the patient based upon their need for these antibiotic drugs to be given. And usually that's based upon diabetic or not the severity or the presence of macro Dema on their O. C. T. Which helps us derive what treatment we're going to give them. Now. We know that laser has been has had limited proven visual acuity and here's some of the studies that have looked at all of these kind of protocols laser photo calculation may stable vision and reduce the vision risk of further vision loss but again rarely restores improves substantial vision in patients. And in the right side you can see an arrow with all these laser burns in the patient and the macular the center of the part of the vision where you can see that it can cause visual detriment or decline when it's really extensive like it is here and they can develop focal areas of scarring and significant loss of vision as a result of the laser treatment is done. And this is thermal laser, right? So this is uh sometimes can be quite aggressive when you're doing the center part of the vision. We also know that steroids are very effective options for trade changing patients, especially patients with diabetic macular oedema without a history of glaucoma. These drugs can be quite effective and we have studies on both crime scene alone, dexamethasone, even flu season alone for the treatment of diabetic macular oedema, each associated with some sort of unfortunate risk profile which that all steroids cause cataracts and potentially could cause glaucoma and certainly there needs to be checked each and every time these drugs are delivered now we have a bunch of therapies we use currently in practice and I'll talk about the ones that are on label first we have rented is a mob or we have a flavor cept. Secondarily we have an off label drug which is about this is a man And there's some key differences here that show how they are working or acting. Business is a member. Is one of the larger of the drugs that we use. Its 140 and killed all the size. Random is a map is a very very small fragment of the fab fragment 48 km in size currently. And again that's where their differences with regards to this association constant with regards to their size of the molecule what they what they retinol penetration might be. There's really differences in these molecules and I don't think people really understand that. And I'll show you some data in clinic from protocol T which is really validated that there are differences in these drugs as well. And we also have some really emerging need therapies. Were hoping to see on the horizon. First is the paralysis map drug, which again received some really positive outcomes from its kite and kestral data. It's not ready for primetime yet. It's going to be probably filed and rolled out by next year hopefully. And first map is another by specific and a body which focuses on a target called and two along with Jeff and has had two phase three's readout. Now with really positive results again, we hope to see these drugs within a quarter one of 2022 to see how they will affect how we treat patients in practice right now and again, a wealth of evidence supports the use of antiviral agents for diabetic macular edema. And here's some of the studies on the left side that have shown that because he studies really have shown that antibiotic therapy can improve visual acuity over time and again, really result in an individualist approach by tailoring the need for additional injections as the patient responds to therapy and seeing what they need from that standpoint of things. And we treat them in a variety of different ways. And I'll show you what I mean by that. By this showing the slide, we can choose to treat them in a fixed fashion where we give them an injection every month or every two months. We can choose to treat them as needed format where we see them every month but then inject only when needed. Or we can do what's called the treaty extent format, which is a popular format amongst many retina specialist where we decrease the burden of injections of clinic visits by basically getting to a dry retina and injecting them until they continue on in that fashion over time. Which I think again is an important finding to think about with regards to how we validate these studies. There's only one study really supports treating extent in the diabetic academia population. The rest of studies are either appearing or fixed dose and regimen for these patients over time. Now we have a lot of international guidelines that recommend the use of O. C. T. To assess and monitor a diabetic macular edema and here's just some of them here. But basically what I'm what I'm coming to with this slide essentially is that it is the best way to detect and quantitative uh center involved me in the patient populations and again thickness of these patients over time is something we follow as a biomarker to see treatment response. So that's a very, very important one to remember, as it does predict how we do with our patients. Protocol V was an interesting study compared a flip receptor To laser and a flipper cept as needed to observation patients with really good vision patients actually had a visual cuties, letter score of 2025 or better. So really great visual cutie. And the goal here was to see the proportion of eyes that lost five letters at two years to see if any one of these factors or any. One of these treatment paradigms resulted in more patients losing vision as a result when they started off with such a good vision in their eyes to begin with. So this led to some really um interesting results which showed us that really observation was as good as initial treatment of those patients. And so now we have a really good paradigm to explain how we should manage our patients with DME and it's really visual acuity driven. So if you have good vision 2025 or better on the eye chart really don't recommend treatment at this point. We can follow you and see how your disease progresses over time and see if you need additional therapy. If you have bad vision. 2025 to 2045 we should start with any anti Geoff because the protocol T. Study, which was another study denied the R. C. R. Compared all three drugs that are currently available and found really no difference at 2045 better. However, at 2015 worse a flipper cept has been shown to be superior with regards to its gains individual acuity as well as its ability to cause a two step right now with the improvement. So that is an important finding. And again those patients who can receive a flipper set for 2050 or worse vision are going to get it as part of Protocol T And again for all patients we administer these drugs released 3-6 months to see if there's a treatment response before giving up and potentially doing an inter class which or even considering a steroid implant at that point in time. So let's talk about a case that might hit this sort of home for you all and might give you a sense of what this is like in real practice. This is a patient who actually was 45 years old, 25 years of duration. Remember I told you before that 15 years was considered quite significant. Their hemoglobin a one C was elevated at 8.5%. They are an insulin. And then early in there for empathy but not on dialysis. And when you see this in the chart, your mind should really go well. If you have neuropathy you must have retinopathy in this patient. And this is actually what the patient presented as you can see on the pictures and the far top left here. Multiple micro aneurysms present, hemorrhages present and four quadrants. You can see some whitish areas which might be old or new. Exit. It's hard to say again the floor a scene showing you that multiple microns is present in the mid and far periphery here but again without any of accusation. Present and here. You can see that worked with a large amount of subregional fluid and internal fluid present as a result of diabetic micro Dema. So after one injection of an anti Geoff their visual acuity is now improved 2080 in both eyes. You can see that morphology improvement. The plan was to another injection here And we did another one again with a nice improving both pictures here again, 2015 vision in both eyes. And now we give another one to see if they get any better. And here now there are 2040 and the right 27 left. So they are getting better. It's just taking a long time. And again, the diabetic academia is not returning at all despite giving these injections over time, which is fantastic to see. And this is month four, month five. Again, when you see continual improvement of the contour, much of the fluid is going away further and further. Again, the same thing in the left eye, you see that fluid pocket that's there is not as prominent, prominent as it was before. And finally in month seven you're going to continue to give them out to Jeff therapy. But there's been a little bit of laps in the left eye of the visual acuity albeit that the O. C. T. Looks pretty good and the right I obviously has a visual cue to 2030. Now in the left eye you can clearly see there's some exhibits here that have conglomerate in the center of the vision. I wouldn't be worried about that. We gave him other injection here. You can see what happens to the exit. It's actually reabsorbed And now we're at the point where we have 2030 vision the right in 2016 and left. So really a nice outcome for this patient with continued anti TNF therapy over time. So in the last few minutes of talk I thought I would focus on some of the unmet needs and diabetic macular oedema. And again there's lots of different perspectives to consider here. First is the patient perspective. Again, the multiple comorbidities and it's difficult for them to schedule his visits at a high rate of non compliance. From the physician's perspective, we need better agents that have faster fluid drying. The reduced number of injections over time would be great. And again, sustaining vision gains is an important finding, I think, for these patients as well. Um, and from the health care perspective, again, high rates of non compliance and lost to follow up and make it difficult to manage patients when they return and increase in health care. Resource utilization is a reality. Unfortunately, with this condition and we don't have any good solutions for that at this given time. Just a quick recap from my talk today, chronic hyperglycemia induces VHF up, regulation the results in the breakdown of the blood retinal barrier and increases in vascular permeability. Rational fluid accumulation is an important marker of this activity and um, and persistent maximum food results in irreversible neural retinal damage and vision loss. And in routine clinical practice, a high treatment burden results in poor compliance and non adherence, leading to under treatment and poor visual outcomes over time. And finally, early intensive and individualized treatment that provides a rapid fluid fluctuation and maximum via gains that are sustained over time, is obviously the most ideal way of treating these patients over time. So I want to thank you all for your attention during this program and I really appreciate all of what you do. You are the frontline caregivers for a lot of our diabetic patients. So it gives me great pleasure to give this talk today and I hope you learned something that you can take back to your patients next week. Thank you very much.