so welcome to this program on preventing the inevitable blindness and a diabetic patient and evidence based clinical success and referral roadmap for 2021. My name is Rishi Single Cleaving Clinic in Cleveland, Ohio, and I'm going to talk about some of these recent strategies for managing diabetic eye disease alongside some cases which will illustrate how we manage diabetes in this current Erin. Here's the overview of the program today. This is CMI and CE certified webinar, jointly provided by the University of Massachusetts Medical School and CMI Education and Resources LLC. It's supported by an unrestricted independent educational grant for Regeneron Pharmaceuticals, and this activity may include discussions of off label or under produces of specific agents to receive CMI or C E credit. At the end of this program, click on the link below this video to access the online evaluation form. We are all aware that diabetic retinopathy is one of the more important causes of blindness in working age populations, and there are certain risk factors which could note a higher risk of developing this condition over time. Those include things that are listed here, such as hyperglycemia, hypertension, high polyp anemia and smoking cessation, obviously things that are modifiable in this category, or things like weight and exercise and some of the other items I mentioned to you before and on the far right side, you can see the picture of what you're trying to prevent in a patient with advanced diabetic retinopathy. Here in this picture, you can see a patient with proliferated diabetic retinopathy with the new formation of blood vessels, which are not normal blood vessels, which would leak and cause damage to the eye. In addition, you can see it some detriment of the central site to detraction and folding of this, the vitreous jelly in the eye again, a stage of proliferated diabetes causing this condition. And alongside this you have vision loss from ischemia, loss of vision due to poor blood flow in these patients due to the advancement of their diabetic eye disease. We know that a lot of these patients also have cardiovascular risk factors which go hand in hand with this diabetic eye disease. And there are variety different trials that have been looking at systemic control and glycemic control as a way of reducing the progression, just as if they reduced cardiovascular risk factors and renal risk factors for development of natural apathy. The same is true of diabetic eye disease, and these studies, including the D. C. C T. The edict study in the UK PDS are just some of the trials that have validated the systemic control matters within this condition. There's a variety of vascular complications of diabetes, and we're all aware of some of the more systemic causes, including Notre pithy neuropathy and large vessel diseases like cardiac issues and cerebral issues as well. But how much difference does it make if blood sugar and blood pressure are role controlled at preventing some of the ocular complications from this condition? And we realized that for every from the UK PDS study that every 1% decrease in the hemoglobin a one C, can lead to a 50% reduction in the level of progression of retinopathy in these patients over time and this is a rubric. I use a lot of my patients because this is true of many other complications related to diabetes. And so I do when I talk to patients, talk about reducing their hemoglobin a one C as a way of controlling their diabetic or not the progression and advancement to legal blindness. As part of this condition, let's talk about the screening guidelines for diabetic retinopathy, and they've changed recently, and I want to highlight some of those changes. Recently, the American Beauty Ophthalmology and the American Diabetic Association have come up with these screening recommendations for patients with disease. And I would point out the most recent change has been around the standpoint of patients without any history or while the presence of diabetic retinopathy and good hemoglobin a one c the American ophthalmology has now recommended. Those patients can be seen every two years. In fact, for annual visits with I practitioner, either an optometrist or an ophthalmologist for evaluation and management in patients who have mild, moderate or severe disease, you can see that the re examination and schedule is much more closer to schedule to the previous appointment. And again, referral might be necessary at various stages of retinopathy who are retina specialists like myself, who has done advanced trading and treating both I diseases related to diabetic retinopathy, as well as age related macular degeneration and other conditions that do both medical and surgical retina. In addition, a patient with diabetic macular oedema should be referred if they have sent her involving Dems promptly to a retina specialist for evaluation and management. And I think the paradigm of this is being evaluated a little bit further in the upcoming years. You're going to hear more about patients in this severe, proliferated, non proliferated and the proliferated category being managed with anti vascular endothelial growth factor injections and without receiving surgery at those time periods. And I think that that's where we're going to hear more about how we might get those patients earlier rather than later. As this scale might indicate. Now, one of the big problems has always been if you look at claims databases and M R studies of patients who have diabetic diabetes and they have I related issues is that 50% of those patients don't receive appropriate I care, meaning that they don't receive uh, they're appropriate evaluation with a dilated eye examination where they put the dilating drops to dilate. The people look at the back of the retina, either with photography or with clinical examination to score the level of retinopathy, and 50% of patients don't follow up as needed. and this has become an epidemic, and it crosses all socioeconomic statuses as well as racial and racial disparities as well. We are realizing that that patients are not coming in with an evaluation and management on a timely fashion, and especially highlighting this unfortunate during the Covid 19 pandemic when routine I Care was sort of paused for a moment that also led to a lot of detriment to patients realizing they needed to come in for I related visits and evaluations. Let's talk for a moment about the path of physiology of diabetic retinopathy, and this has been well studied and well known now, and it starts off with micro aneurysms, which are the earliest observable lesions within diabetic retinopathy. They can be seen on this electro microgram microscopy photograph on the far right where you see a dilation of the retinal vasculature, which causes, uh, leakage into the extra vascular space. These these points of micro aneurysm developed because of the loss of parasites in parasites, are the supportive cells of the retina, vascular and ethereum, and they cause weakness of the Kapler wall, and thus you get these microorganisms that forum. In addition, you can see the angiogram down below, where there is a significant amount of Micro Anderson's presence shown in this florist an angiogram as bright spots within an angiogram, as well as around the faux viel capillary bed in the center there, where you can see that there is definitely capillary remodeling. And change is related to both ischemia and the closure blood vessels. That's why the phobia vascular one is slightly larger in this patient than normal patients. And in addition, the micro aneurysms that are forming in around the phobia are important because they might lead to diabetic macular edema or the swelling of the center portion of their vision. We've had a variety of important improvements in retinal imaging over the past few years, and we start off with Optical Coherence tomography, which went from Time domain two Spectral domain to O. C. T. Angiography, which is a dye based, dye list based evaluation of the retinal vasculature. Without any dye that's placed in the patient's systemic circulation, you can now visualize the retinal vasculature with an act, and finally, we're going to hear more and more about swept source based OC T platforms, and those might be the next stage of development within O. C. T. But in addition, we've seen a variety of different improvements and just traditional funders photography, which has gone from Adriatic non Madrid IQ to seven standard fields and montage capabilities. And finally, to alter a wide field options, which are important because they allow us to look at the retinal periphery in a single picture without having to multiple photographs, as we did in the sandwich seven fields and without having to dilate the pupil as we did in the Mid Adriatic. Camera phases. It's just an example of what that photograph looks like just to get a sense of how large these images are. Here is just a standard fund this camera, which gives you a 45 degree field or 50 degree field, a few of the fungus, which is traditionally how many people image threatened in the past, but truly the gold standard disease. Seven Standard fields, which are encompasses not only the initial picture but some of the mid peripheral areas of the retina, because this was considered the gold standard for determining diabetic retinopathy in the populations that were studied during the diabetic retinopathy. These studies, but now we have ultra wide field options and you can see here with a single image taken, you can get all of these seven standard fields up to 200 degrees of field of the retinas evaluated, which is about 82% of the entire retinal surface. And that's led to some really important findings. And here's just one of those findings, which was published in diabetes. I Care Where they Compared non metastatic funders photography with ultra wide field photography. And what they found essentially was that the unbreakable rate, meaning the photographs that were not breakable, was lower in those with the ultra wide field image in comparison to the standard image. That was an important, I think, take away from this study and again is pretty close to what we see in clinical practice, because we do see that patients who have ultra right field images, even if there's a media capacity, were able to get a good, crisp image which we can read in those patients. Compared to a patient, a standard funders photography and in addition, there was a time savings here of almost three minutes per patient, using an ultra wide angle image in comparison to the seven Standard the traditional funds photograph that was used. This is another study that looked at this in the American Journal Ophthalmology and compared the concordance of patients who got the ultra wide field dimension comparison to the E TDRS photography. Again, the severe agreement was quite in line with each other, which is reassuring, and that the acquisition time was half of what was seen in the dilated eye examination, again showing you the true benefits from a workflow standpoint of evaluating patients with ultra wide field images. Now let's talk about some of our patients through a case, and maybe we'll hit some some of the points we just talked about with regards to evaluating patients with diabetic retinopathy. This is 46 year old Hispanic male with 2020 vision in both eyes. His most recent hemoglobin, a one C, was 11.2. He has a history of hypertension. He is obese, he's an active smoker, and he said diabetes for the past 10 years, and he's here for an evaluation. Here is his retinal image, which can see the beautiful ultra wide field images on both panes on the left side. You see the the right eye image. On the right side, you see the left eye damage and here you can see in the retinal, mid and far periphery. There's some hemorrhage is present in this patient again. This patient was 2020 which is quite common to see good vision patients with this sort of level of retinopathy. And again you see some exit its present within the focal center, indicating that he might have some Max Kadima here. This would be termed probably moderate, non proliferated diabetic retinopathy because it doesn't accommodate four quadrants of severity. And here is the angiogram just to confirm that there is no level of, um, proliferated disease seen by active Flores in leakage, which appears very white in the images. Instead, you see just the microorganisms present here indicating that he has non proliferate disease. And this is a CT again showing you a normal O C T, which is a normal phobia contour without any signs of a d. M. A president of this patient, which is important to see this is case to, uh, this is 64 year old Filipino female. She's 2020 and 2040 and her left eye. Her most recent hemoglobin, a one C, was 8.5 and her history again to see hypertension, hyper lipid anemia and diabetes for the past 15 years. And here is her images you can see here quite well. You see some hemorrhages present now within four quadrants of the eye, both superior, inferior nasal and temporal in both eyes. And so that's an indication this patient might have severe nonproliferation disease. And in this patient we have a very, very low threshold for getting a flourishing angiogram or determining if they have proliferate disease, either. By oc to as well. Here, you can see the optic nerves look a bit bit up to this patient. This patient might have preexisting glaucoma on top of this condition. And here is the Flores, an angiogram showing you the extent of the micro Anderson's present, as in the retinal mid and far periphery again indicating this patient has severe, non proliferated diabetic retinopathy. Here is their O. C. T. Again showing you good vision in both eyes. So the question is, why did this patient have 2040 vision in the left eye? Well, as I told you before, there's a significant amount of capital remodeling and ischemia that can form in some of these patients. And even though the might look structurally normal, the vasculature may not be normal in this patient, the left. And that's why they probably lost vision as a result. One of the reasons why I mentioned to you before why we're getting patients now seeing retina specialist with severe non proliferate disease or early proliferate disease before it becomes high risk proliferate disease is because of the Panorama study. This study evaluated patients treated with an anti V e g F drug, in this case a flavor cept at baseline comparison to sham injections over a one year period. And they actually follow these patients out for two years. In fact, the primary endpoint was at one year, but they followed them out for two years, and in this study they randomized patients to receiving either flip Aricept every eight weeks after a loading period or filter, except every 16 weeks after loading period to compare the durability, improving their diabetic retinopathy, scoring that which which is the primary endpoint in the trial, but also to see what effect it had on secondary ocular complications related to diabetes. And here you can see again the treatment experience through week 52 in the Panorama study again, those in the Q eight arm got a higher number of injections and those in the Q 16 arm after the loading period. Again, the sham patients were truly followed for their condition. And this is the proportion of two step improvements seen within the patients, with the trial showing you that there's an improvement and two step retinopathy scoring from Week 24 2 Week 52 in all of these patients that were treated with the flipper cept in comparison to the sham treatment patients who had moderate or small improvements in their D r severity improvement, maybe because of glycemic control or improvement during the course of the study. This Kaplan Meier curves shows you the time to first to step improvement. And this was a study that we did at the Cleveland Clinic in conjunction with the company. Uh, and what we did in this case was looked at the to determine when practitioners were treating these patients. When could they expect to see a two step improvement in retinopathy and what you can see here is in both of the flipper except arms. That occurs in 50% of patients within 85 days of treatment, which is quite early in their treatment cycle, in comparison to the sham treated patients who almost never achieve a two step improvement over to 50% of the population over time. This is Case three, which again illustrates I think, some of the points we talked about during this lecture today a 56 year old male Latino who has a one C of 9.5. They're employed a one C. I'm sorry. Their visual acuity was 2016, the right in 2014 the left. They have no prior history of any octopus surgeries or treatments, but they have Type two diabetes in the past five years hypertension and Hyperloop anemia. And here you can see the macula and a phobia in the right eye with some hemorrhage is present. There might be an epithelial membrane present here as well, and here you can see the angiogram in the early and late frames again showing you that there's just strictly micronesians President all quadrants of this patient. So this patient would begin classified as, uh, severe non disease and also the macular oedema present here could be in conjunction with either diabetic macular oedema, due to the fact he has diabetes and swelling with the central part of the vision. The central sub field thickness here is 406 microns, and he also has an epic battle membrane, which also can lead to some amount of oedema and distortion in the patient's vision. This is just a quick example of showing you where he was before because his patient was actually treated prior. I didn't tell you that before I showed you this case, but on the far left, as we're actually, he was treated when he first came to see us, where he showed that he had a significant amount of hemorrhages in four quadrants. And on the right side, you can see a significant improvement in the hemorrhages president all of those quadrants with the presence of that epi rental membrane now present there and available to see again, you see that the microorganisms are still present, but less so after treatment with the anti B e g f drug. And again, that was something that we saw in the panorama study where we saw significant improvements in the leakage of patients who are treated with the flipper cept in comparison to the sham treated patients. Over time. Uh, the event rate to developing proliferated disease was significantly blunted in those patients who received a flipper, except, in comparison, a sham injections. And this is the one that I think is the most important slide I'm going to present to you today, and it's the one that I think I talk to patients about the most. It's regarding the vision threatening retinopathy complications which accompany this disease, including neo vascular, glaucoma and vitreous hemorrhage. These can cause significant morbidity in our patients, and what you can see here is by having the flipper cept injections. Those numbers dropped drastically as a result of receiving those flipper cept injections comparison of sham control. Patients have a much higher level almost 3 to 400 fold higher level developing these ocular complications over time. So I think the paradigm shift now for us when we consider this is determining whether we should treat earlier and and potentially remove the ability for patients to progress. Who those vision threatening right? Not the complications and diabetic macular oedema over time. And that's where I think our field is evolving and where you're probably going to hear more of this. And why is that important? Well, because I realized that visual functional quality of life scales really drop off when you develop severe proliferated disease or early prolific disease in these patients. Here, you can see of Level 43 and and, uh, and above is where you really see start to see quality of life differences. But look at that level 53 beyond. That's really low quality of life, both for driving scores and NF any IVF Q 25 composite scores as well, and so that can indicate a different quality of life. And obviously, if we have the ability to treat them earlier, why not just ameliorate the disease state to prevent them from progressing? And here is just another example where you can see that from this day from Charlie White Cough that's been recently published in Did the journal Diabetes Care, which found actually that the patients who progress to proliferate a disease have a higher rate of legal blindness than those who do not, and that that rate of progression is quite significant over a four year period in comparison to those patients who had mild or unspecified or moderate disease again showing you that these patients who are well treated and do a good job controlling their blood sugar have a low rate of progression over time. Now, despite everything I've told you today, we still have a lot to, I think, educated This about, um, 82% of international retina specialist and 72% of US retina specialists still do not use anti by Jeff Therapy for a non prolific disease over the past year. And I think studies like Panorama and others are showing you why there's a benefit of treating these patients. Earlier in this condition and again here, you can see that while Panorama was a great study, it did have some impact with regards to changing practice patterns and habits. As a result, almost 40% of people were impacted by panorama as a result. So again, just to summarize the Panorama study, vision threatening complications were reduced by 82% to 85% compared with sham injections at week 52 the development of center involving diabetic Nakajima was reduced by a significant proportion almost 76% in one of the arms of the study. Compared to sham treated patients. Just to conclude anti bgf therapy has been increasing patient outcomes, including vision and retinopathy progression outcomes, and with the recent approval of a flipper cept and rent a basement for diabetic retinopathy. We now have other methods of managing these patients with retinopathy and retinopathy related complications. Finally, prompt referral to retina specialist for monitor Severe disease probably should occur now because as I've shown you from some of the studies, it can be quite silent. Number one and number two, we have drugs to ameliorate or slow the progression of this disease over time. Thank you very much for your attention.
