Andrew J. Barkmeier, M.D. discusses recent advances in glucose-lowering medications, including the systemic health benefits of GLP-1 RA medications in type 2 diabetes, potential risk factors for accelerated diabetic retinopathy progression and different categories of novel glucose-lowering medications for type 2 diabetes.
I'm gonna talk today, um, update on some of these newer diabetic, um, medications. I presented some work, uh, last year on this topic, and there's been some more papers since then and some, um, additional work since then, and we're gonna use that as a jumping off point to discuss in a little bit more depth and detail. Learning objectives, describe the systemic health benefits of GLP um medications and SGLT-2 medications, recognize potential risks for accelerated diabetic retinopathy progression, and also categorize, um, some of these glucose-lowering medications that we see on patients' charts increasingly. Multiple choice question, for patients with type 2 diabetes, GLP-1 receptor agonist medications reduce the risk of renal failure, myocardial infarction, stroke, or all of the above. So we're gonna start with um sort of setting the, the context of um the past, you know, 15+ years of, of research in these medications. In 2007, there's a meta-analysis of uh medicine, um, rusiglitazone, where, in which they found that there was an increased risk of myocardial infarction and um um CV death. I think they're gonna put it in the, in the chat, Amir. And then, as a result of that, um, previously, the approvals were all based on, uh, glycemic lowering for these diabetes medications. But in 2008, the FDA decided, um, based on those results that they actually, in order to get a new, uh, approval for a diabetic medication, they had, you had to have a cardiovascular outcome trial to show that these meds do not increase the cardiovascular risk. So these newer medications were all, all, all went through the testing and the FDA approval process in this era. SGLT-2 inhibitors um work on uh SGLT-2, which is transport protein located primarily in the nephron. And it's, but it's also located in the brain, heart, liver, thyroid, and the muscle. And this, this, um, specific receptor is responsible for about 90% of the renal glucose reabsorption. So as a result, when you block this, um, you end up with glucosuria. These are very powerful medications to lower blood glucose. They're contraindicated in type 1 diabetes. The patients can get DKA. And when you're looking on the chart for these medications, anything with the um suffix Flozin, F L O Z I N is uh SGLT2 medications. And these are all pills. You can see that um you'll see these on the charts, common, commonly, Invokana, Farxiga, Jardiance, Stellaro. But the, uh there are also a lot of combination medications. You actually have to look to see what the combination medicines is and look for a flows in there. When they looked at meta-analysis of the, the cardiovascular outcome trials for these medications, they've had a number of powerful findings. First of all, um, there's a 14% decrease in MACE, which is major adverse cardiovascular events, which is Three-point mace is typically um non-fatal myocardial infarction, stroke, and then cardiovascular death, and it's a composite outcome. So patients who had established atherosclerotic cardiovascular disease would have a 14% lower risk of MC. They also had significant improvements in CHF outcomes. So CHF hospitalizations plus cardiovascular death, that is a composite outcome, was 29% lower in patients who had a history of CHF and 21% lower in patients who had no history of CHF. So even patients without CHF um had a huge benefit. Renal outcomes, and this is a composite outcome as well of um decreased renal function, end-stage renal disease, or renal associated death. Patients with cardiovascular disease at a 29% lower risk and 21% lower risk if they just had risk factors for cardiovascular disease. So GLP-1 medications, um, as, as we all know, uh, are related to, um, it mimics an endogenous hormone that's res released whenever we eat. And this hormone stimulates insulin release. It suppresses glucagon, it slows gastric emptying, and that's why, uh, we have to ask patients about this now before surgery, and we have to hold these medications, um, particularly the, the longer medications. You can see here, um, that most of these medications are all injectables. In the earlier era of these meds, they were, um, once or twice a day injectables, but the more recent ones, um, are once a week injections. So that's why they have to be held for at least 1 week, um, for, for most ORs. There is one pill available for type 2 diabetes, this, uh, Rebelsus, which is a, a version of semaglutide. And these medications, if you just take a look at this chart, it's amazing. Between 2016 and 2022, 6 years, the percentage of people with type two diabetes, um, taking these medications went up from 4.3% to 19.4%. And as you know how large of a population of type two diabetes this is, and this has only risen since 2022. The important thing to note on these medications is they're not glycemic lowering meds alone. They're powerful, um, glucose-lowering medications, and they're very important for weight loss, etc. but these, uh, save lives. So a meta-analysis of these clinical trials showed a 13% reduced relative risk of all-cause death. And when you break it down, looking at some of the individual um consequences within those trials, there's a 16% reduction in renal failure. 13% reduction in CHF hospitalization. And uh 14% reduction in mace. So when you split out mace into some of its components, there's a 12% reduction in stroke, 13% reduction in non-fatal MI, and a 14% reduction in cardiovascular death. So, as a result, these medications in 2019 um changed the clinical guidelines dramatically such that they were no longer recommended just for glucose lowering. Any patient with type 2 diabetes and atherosclerotic cardiovascular disease was recommended to take one of these two medications by the ADA and the American College of Cardiology. And every year, Since then, the, the um standards of medical care by the, put out by the ADA have um expanded the indications quite dramatically. Um, so when it goes from 2024 to 2025, added another couple of indications. So the current indications are any patients with atherosclerotic cardiovascular disease or just risk factors for CBD You should be taking uh SGLT-2 and or GLP-1 medications. So they can, um, it's very reasonable to double up on these meds. Anyone with heart failure should be taking an SGLT-2 med. Chronic kidney disease should be taking one or the other, and there's some different cutoffs and criteria for that. Patients who are overweight should take one of the two. Both have weight-lowering effects. It's a little bit more powerful with the GLP-1 meds. And GLP-1 medications should be started before considering insulin in type 2 diabetes. So, one of the trials, one of the most important trials was the sustained 6 trial looking at semaglutide, and you can see these green boxes here. These are all the positive effects, you know, big-time effects, non-fatal stroke, revascularization, new or worsening um nephropathy, all improved, but the single red box here is um retinopathy outcomes. And um this was seen in the context of this rapid lowering of hemoglobin A1C. Within 4 months, on average, patients dropped from about 8.7 down to about 7 on these medications for an A1C. And you can see the um 67, 8% reduction of body weight over the first six months. And this early worsening of retinopathy has been seen in other studies. Anytime there's a rapid improvement of glycemic control, it was originally shown in the DCCT study in the 1990s where patients with type one diabetes given um intensive insulin dropped their A1C from about the same, about 8.7 down to about 7. And patients with no Retinopathy only had benefits. So 76% risk reduction of diabetic retinopathy progression over the course of the study, um, 6 to 8 years. But patients who already had retinopathy, there was a slight increase in the 1st 6 to 12 months of retinopathy changes that was associated with um higher baseline A1C and more rapid lowering of A1C. But in this study, as patients went on, they ultimately still had um significant improvement even if they had baseline retinopathy, um, and that switched after about 18 months. And furthermore, once the study ended 8 years later, patients had ongoing benefits, even as there's no difference in glycemic control for the next 10 years after that. The study ended. There are still benefits with respect to retinopathy, PDR, microalbuminuria, macroalbuminuria, CVD, and, uh, MC. So these meds are incredibly important. The US FDA said, well, even though that these retinopathy outcomes are, are noteworthy, it's clearly advantageous to lower A1C as quickly as possible. And the FDA approved the, the meds as we know. And the European Medicines Agency, which is the equivalent of the FDA said, yes, we'll approve this medication, but we need to do another trial. This focused trial is a five-year study looking at placebo compared to semaglutide. And it's gonna be a well-done study. Many of these cardiovascular outcome trial studies were not very well designed to look at retinopathy, but this one is exquisitely well designed. We're just not gonna have any results for another couple of years. Um, it, it, the earliest in late 2027. When we look at all those cardiovascular outcome trials with respect to diabetic retinopathy outcomes, again, these are a mixed bag of retinopathy signals. Some of them are just, are just clinic-based exams um in ophthalmology or optometry clinics, having, some of them have photos, some of them don't. They're short. There was no clear difference in this first meta-analysis in 2018, and the second meta-analysis in 2023 said, well, maybe there's an increased risk of early retinopathy, but maybe late risk was decreased. But they thought some of those changes were driven by one of the meds that we don't even use much anymore, the alba glutide. So, because these trials are not completely reliable, it's still unclear, uh, for a given patients what the um impact of retinopathy is, and these meds are very different. Their effects on the retinal vasculature, um, that are independent of the glucose lowering, and these different classes of medicines that are all available are all quite different. Now, I presented this, this study last year. Um, this is a study we did looking at comparative effectiveness of some of these different medications for patients with type 2 diabetes. And what we found was that there was, um, we looked at 370,000 patients starting treatment with one of these different medications. We found that the SG GLT-2 medications, um, patients initiating treatment with them actually had a slightly lower risk of developing slight site-threatening retinopathy with a risk reduction of 21 to 39%. And the GLP meds, uh, did not have an increased risk compared to some of the other commonly used historical medications, the DPP-4 and sulfonylurea medications. And there have been other studies now since then, um, that have been reported. That had somewhat similar findings. Um, this is a study using the TriNet X database, which is a federated EHR network. They also identified 231,000 patients. And you can see, look at these odds ratios going down the list. Um, um, in the top section, these are increased odds of, um, developing PDRDME and anti, uh, and requiring anti-VAGIF medications with GLP-1 meds compared to SGLT2. Meds. And this bottom portion is if they just look at the patients with um previously coded non-proliferative diabetic retinopathy. And all the caveats of coding for diabetic retinopathy levels are, are valid. However, there was a consistent um difference between these meds. Another study, um, those were kind of some database-based studies. This is a study that just did a chart review, um, single institutions, smaller numbers, but there were about 1000 patients who started one of these two medications, and they did a granular chart review of all these patients and And found similar rates of um clinical worsening in the 2.3 to 2.8% range. And there was no, they reported no significant interagent difference, or at least not a major signals that they were able to identify with these numbers. Um, the, the Taiwanese National Health Insurance Database also offers the opportunity to do some, um, coding-based population-based studies. And they, a couple of these studies looking at these meds showed, first of all, the SGLT-2 medications had a lower risk of site-threatening diabetic retinopathy. A second one looking at GLP meds. Um, versus non-users. These were, this is an active comparator trial showed, um, no, no difference. But you can see when they use the SGLT2 as an active comparator that the hazard is slightly higher but not statistically significant with GLP and it was favorable with the others. So, on balance, um, it was relatively stable. Now, Looking at individual medications, we know within the class of GLP-1 meds, there are substantial differences, um, differences in glucose lowering, substantial differences in weight loss. Um, semaglutide lowers lipids, other medications don't. They're very significant differences here. Furthermore, within the clinical trials, there are different outcomes. So we sought out to investigate whether the individual GLP-1 agents um differed with respect to the risk of developing site-threatening diabetic retinopathy. Uh, and this is focused on patients with type 2 diabetes at moderate risk. And we use the Optimum Labs database, which has a number of advantages. It's, um, it is a very Diverse population across the US, huge numbers. It's diverse with respect to age because it has Medicare Advantage and Medicare and fee for service and commercial plans, racial ethnic mix, income mix, geographic mix. It only is patients who have insurance though. And based on the timing of when these medications were out in practice. And the relative use in practice to avoid confounders. We had two separate studies, a three-way comparison between exenatide, dulaglutide, and lyric glutide in the earlier years. And then the, the latter years, just looking at semaglutide versus dagglutide, cause those are most commonly used in the latter years. The primary outcome for these medications was time to treatment for a composite of either diabetic macular edema or PDR. And when we looked at over 70,000 patients in this um three-way com um comparison, um, there was no difference between medications in either the primary outcome or any of the um subgroup analysis. And then looking at the semaglutide versus the daglutide, um, in the more recent years, the semaglutide actually had a slightly lower, um, slightly lower odds, uh, although it wasn't statistically significant. When we looked at the sort of the trends over time, um, in, in, in a graphical form, we see that the, in the initial comparison, um, for the doula versus enetide versus lyra glutide, there were no significant differences. The forest plot. On the, on the right-hand side is the same data here. And these had a mean follow-up of approximately 3 years and some of them out to um 6 or 7 years, which is much longer follow-up than what we had in any of the clinical trials. Looking at the more commonly currently used medications, there was no significant difference between the semaglutide and the daglutide. So the conclusions we had looking at these individual GLP-1 medications were that we found no difference in the risk of these site-threatening diabetic retinopathy outcomes between agents. And it supports choosing the most appropriate medication, really without consideration of diabetic retinopathy complications. And when we take a step back and look at all of these data, what does this mean? Well, we know that the GLP1 and SGLT-2 medications are really life-saving medications. They're critically important um to get patients who are never under glycemic control, under control, and to um benefit their cardiovascular and renal system. And there's no clear evidence supporting avoiding or delaying um GLP-1 meds out of concerns of increased diabetic retinopathy risk. Now, it is reasonable anytime you have a rapid improvement of glycemic control or just rapid change of um um systemic health in general, to have a little bit closer retintalal follow-up. Maybe, maybe shorten the time by half um over the first year or so, that would be reasonable. That's not specifically evidence-based, that's more clinical common sense-based. And this is a similar practice pattern to what we do for patients who are pregnant, who have bariatric surgery, intensive insulin therapy, or any rapid improvement in glycemic control. And our job as ophthalmologists, when people are reading, reaching out to us, um, whether it's patients, I get these questions all the time, or it's, um, the, the docs who are prescribing these meds, that it is OK. We just, we wanna stay aware of what patients are taking and perhaps tighten our surveillance a little bit. Thank you very much. This is our multiple choice question. And as we all know, the answer is D. I'm available for any questions if anyone has any questions or thoughts. Andy, this is John. Um, wonderful presentation. I think one of the hottest topics in neurophthalmology is this potential risk between GOP-1 agonists and NAION. It's gone so far that Europe says that if you have any eye in one eye, patient has to come off the GLP-1 agonist. And then, um, but again, the evidence is not great, um, you know, there's been no clinical trials even showing that risk. Unlike diabetic retinopathy, there's that potential early risk. Um, on Nanosnet, uh, you know, this listener for the neurophthalmologist, everyone keeps posting I've got a case of an AON they're on GLP-1. I've got a case of bilateral NA1, they're on GLP-1, and they think that that equals causative, and it's certainly not. Um, it's just a very interesting thing. Um, I just want to let the general ophthalmologist know that this is a hot topic, and I am a GOP-1 agonist, very, very, if there's an association, it's a very low association. And no evidence of causation, um, and that's important. Your intro slides, everything was just phenomenal here, and I loved how you kind of had the risks and the benefits, you know, that these are life-saving medications. And uh thank you so much, Andy. Yeah, and, and frankly, the, the diabetic retinopathy risk, I think over time as some of these studies have come out, I, I think some of the questions on that are going down as the NAION questions are ramping up. And um the, the clinical evidence that's out there, as you point out, is, it warrants very, very significant attention and um certainly, some of the recommendations do see, seem ahead of the Uh, of the evidence. I think this focused trial is interesting in the sense that it, it will really be the first trial that has very exquisitely documented longitudinal, um, ophthalmic data on patients vers um getting GLP meds versus placebo. Um, the data safety monitoring group is, is watching, um, those data and, um, Certainly, if there was something striking, um, they probably would've come out with that. But I, I think we look forward to that. That's one of the things that can inform, um, Our practice is on this really important question. So, yeah, thanks for bringing that up. And I'm looking forward to the results on that just to let people know in terms of where AAO is, in terms of this NAION business, it's essentially, uh, I think it's important for us to recognize that there's a potential association between NAON, um, just otherwise, the patient will hear about later and think that we're not competent doctors if we didn't bring it up. And AAO says that, um, essentially it's risks and benefits, and, you know, if it's actually helping a lot with the diabetes. It can be continued, but still discuss it because again, if patients hear about it after the fact and we didn't bring it up, they'll think that we're just um ignorant to it because some of the news. Has really painted an interesting way. Thank you very much. Uh, first off, uh, thank you, Dr. Barkmeyer for that excellent presentation, very pertinent. And, uh, good morning, everyone. Hope everyone's having a nice fall Monday morning. Uh, I'm Rachel Chapman. I'm a 4th-year medical student at University of Central Florida College of Medicine in Orlando, currently here on visiting rotation. And this morning, I'm going to be discussing the impetus for and some of the developments in the continuous telemetric IOP monitoring project that I've been assisting Dr. Sit with. So to start off with a few learning objectives, what I'm hoping will be the major takeaways from this presentation are an understanding of the importance of studying IOP fluctuations, as well as a framework for the many factors that contribute to fluctuations, including ocular rigidity, and then some insight into why we've been pursuing this research and how it's developing, particularly looking at the relationship between IOP fluctuations and ocular rigidity. Quick question to keep in mind during the course of this presentation. So scleral buckles decrease which of the following outflow facility, ocular rigidity, mean IOP or aqueous humor production, and we will come back to that at the end. So first, why study IOP fluctuations? Well, many studies have weighed in on the impact of IOP fluctuations on glaucoma development and progression, but I'm just going to highlight a couple of those studies here. So in 2008, this retrospective analysis of patients in the Advanced glaucoma Intervention Study was published and it revealed an increased risk of visual field progression in patients with greater IOP fluctuations across the board and more specifically a significantly increased risk in patients. With higher IOP variation in the low mean IOP group that was not seen in the high mean IOP group. So taking a look at this here, I'm just going to grab the laser pointer. So this was a study of 301 eyes from the Advanced glaucoma Intervention Study. They were divided into tersciles of 100 eyes, low mean IOP intermediate, and then the high mean IOP group. In the low mean IOP group, 22 eyes developed visual field progression. It was further subdivided into IOP variation based on the standard deviation in IOP, and those in the high variation group, 33 Is there, 10 of them developed visual field progression in comparison to 3 in the low variation group, and this same relationship was not seen in the high mean IOP group. So then in 2018, this retrospective analysis of the Los Angeles Latino Eye Study showed that among patients with lower mean IOPs, higher level of maximum standard deviation and range of IOP was associated with an increased risk of developing open angle glaucoma. Um, so interesting looking here. So they divided it. You can see there were patients with the red dot, the IOP less than 15 millimeters of mercury, and with the blue greater than or equal to 15 millimeters of mercury. For those in the lower mean IOP group, they had a higher odds ratio of developing open angle glaucoma for the maximum IOP, standard deviation and range, but not statistically significant for the mean IOP. Whereas in the higher mean IOP group, only maximum and mean were statistically significant. So interesting there as well. So those two studies really highlight how long term fluctuations in IOP over months to years appear to be associated with disease development and progression in patients with lower mean pressures. And since then, Other groups have also assessed IOP fluctuations over shorter intervals in both humans and animal models, um, finding significant variability in the short term, which is hours to days, and then also the ultra short term, which is seconds to minutes. And while I'd love to talk more about all of those studies, I also want to address some of the variables contributing to IOP fluctuations here, including some of the larger categories of aqueous production, outflow facility, head and body position, ocular rigidity, episcleral venous pressure, as well as the many like modifiable and non-modifiable factors that contribute to fluctuations, including blinks, caffeine consumption. Eye movements, accommodation, etc. So studies have shown that optic nerve head displaces with acute changes in intraocular pressure, and that follows with our larger question here, and that's, do these repetitive strains cause damage that ultimately lead to glaucoma? So now we're going to narrow in on um ocular rigidity and how it impacts intraocular pressure. So a population-based study, population-based cohort study performed here in Olmstead County had found that patients who underwent vitrioletinal surgery were 9 times more likely to develop glaucoma over the following 10 years than patients who did not. But interestingly, Amongst the groups who underwent vitrioretinal surgery, none of the patients who received a scleral buckle alone without vitrectomy developed glaucoma, and this provided some of the impetus for the study I've highlighted here, which looked at 9 patients with unilateral scleral buckles without vitrectomy. And so in these patients, IOP was measured in the seated and supine positions using pneumotonometry. And then outflow facility and ocular rigidity were calculated using weighted pneumotonography and the Friedenwald equation here. And the results here demonstrated that the scleral buckle reduced ocular rigidity with statistical significance shown here, without affecting outflow facility. And interestingly as well, the buckled eyes had a lower supine intraocular pressure in comparison to the fellow non-buckled eyes, which resulted in a decreased percentage IOP change when moving from seated to supine in these patients. So of course causality cannot be established from this singular study. However, this reduction of ocular rigidity and IOP change with body position may reflect a reduction in overall IOP fluctuations that contributes to that lower rate of glaucoma development in sclerobuccal patients compared to those who underwent other vitrioletinal surgeries. So how might sclero buckle surgery decrease ocular rigidity? Well, several theories have been put forward. However, the most convincing from my perspective is this first one listed here, which has to do with sort of compliance of the eye or the change in volume over the change in pressure. So the concept here being that a sclero buckle causes focal compression of the eye, resulting in a steady state, small reduction in ocular volume. And so when the eye needs to accommodate an expand a small expansion in volume, rather than needing to stretch the entire sclera to accommodate it, it really only needs to stretch that area compressed by the buckle, which should be easier than stretching the entire sclera. And so this results in a reduced ocular rigidity, therefore causing fewer fluctuations in pressure as a result of changes in volume and possibly a reduced risk of glaucoma in these patients. Now others have posed other theories, including a change to a more cylindrical shape of the eye, resulting in more equatorial stress. However, this is somewhat counterintuitive as an eye under more stress you would associate with an increase rather than a decrease in ocular rigidity. And similarly, some have reported that they believe it's due to a greater compliance of the silicone band versus the sclera. However, there's been a large amount of variation in measurements of scleral elasticity, so it's difficult to establish whether there's a significant difference in scleral compliance in comparison to medical grade silicone. Um, however, overall, these are very complex relationships that require further study, and these are just some theories that I've cited here. So now, having reviewed all of this, let's go on to some findings and developments in Dr. Set's rabbit pilot study. Um, so, as I had just discussed, past studies have primarily evaluated the long term and short term fluctuations. However, this study really aims to focus on the significance of ultra short term fluctuations over seconds to minutes by developing a model for continuous 24 hour IOP monitoring. And this is important because many of those factors that we just discussed contribute to fluctuations over seconds, not just days, weeks, months. So in 2023, presented Dr. Sit presented on the viability of the rabbit model for 24 hour telemetric IOP monitoring after previous research discussed the cost prohibitive nature of similar research in nonhuman primates and the inability to perform surgical interventions in rats and mice due to their size. So this study utilized the implantable telemetric pressure transducer system from TSE Systems to measure IOP from the AC of adult New Zealand white rabbits, and what it showed was frequent large magnitude IOP. Fluctuations, as well as a strong nhemeral pattern and increased fluctuations with animal movement, which correspond well to what we see in humans. As we know, humans also have a circadian IOP pattern and also have, um, IOP variation with body position. So, this established the rabbit model as a low-cost, large animal model for continuous IOP monitoring and subsequent intervention that was well suited to model fluctuations in humans. So the next step was then to establish an analysis protocol for quantifying the fluctuations in IOP captured through this continuous monitoring that could be used for comparison pre and post intervention. So previous studies, as some of that I had looked at here, used range of IOP. Maximum IOP and standard deviation over different timer intervals, though this was more appropriate to sort of the long term and short term fluctuations that didn't need to account for the circadian IOP component quite as much. Others had quantified area under the curve when looking at mean IOP and assessed peak measurements between two troughs to assess um. Some of the ultra short term fluctuations. However, given the strong circadian pattern in rabbits and humans, cosigner analysis presented a unique benefit here as it allowed for curve fitting to this pattern with the ability to measure amplitude. Which would account for the IOP difference between the resting and active hours in a 24 hour cycle, as well as fluctuations calculated as deviations from the curve rather than deviations from a mean IOP, which wouldn't account for the circadian pattern. So this first phase of the pilot study sought to assess the utility of cosigner analysis in quantifying ultra short term fluctuations in continuous 24 hour telemetric IOP data from rabbits. So for this first phase, continuous IOP measurements from two rabbits, one for 4 days and one for 7 days, was followed by quantification of mean daily amplitude and mean daily number of fluctuations more than 5 millimeters of mercury from the fitted curve. I assisted Dr. Sit by programming the data filtration using the No Acord software to correct artifact signal, as well as incorporate manometric calibration. And also developed templates for extraction of 62nd filtered pressure means that allowed for cosine curve fitting by least squares regression analysis that then allowed for calculation of the amplitude and fluctuations in each of the 24 hour files. So what we found here was significant variation between the two animals and some challenges with signal dropout and interference, particularly in animal one. Here you can see this sort of demonstrated by the difference in goodness of fit of the regression model to the rabbit 1 data versus the rabbit 2 data. So that was one challenge we faced here. Interestingly, we also saw this area where the fitted curve poorly approximated the data at the transition from light to dark, and this was actually consistent across the rabbit II files, sort of interesting there. When looking at the fluctuation quantification, we once again saw that significant variation between the two animals, which may have also reflected the signal dropout issues that we saw in rabbit 1, as you can particularly see here, there were far more deviations below the fitted curve. in rabbit 1 than in rabbit 2. However, like I showed in rabbit 2, we also had that area of poor approximation at the light to dark transition that might have accounted for there being a greater number of fluctuations, uh, calculated above the curve in comparison to below. Overall, though, a pretty modest number of fluctuations using the 62nd filtered pressure means. So then with attention to the signal dropout or interference issues previously seen, as well as the modest number of fluctuations seen with the 62nd filtered pressure means, a few adjustments were made in the next phase which sought to investigate the effect of scleral buckle surgery on ultra short term IOP fluctuations and circadian IOP amplitudes by assessing these variables pre and post intervention. So once again, two rabbits underwent IOP monitoring. However, some changes here with concerns for the implant battery life on that signal dropout. One rabbit underwent the same continuous measurement while the other underwent a 25% duty cycle with scheduled 32nd intervals of measurement every 2 minutes. And thus the mean IOP was calculated using 62nd intervals for the continuous data similar to the previous, and then 32nd intervals for the scheduled data. Additionally, given the rather modest number of fluctuations in the previous phase, we broke it down more granularly in this phase, including fluctuations greater than 12, and 5 millimeters of mercury from the fitted curve. Now sclero buckle surgery was performed 3 months after sensor implantation to allow for healing from the sensor implantation as well as The development of that circadian pattern that occurred within, you know, days after the implant, and then in terms of the data utilized, it was performed 1 month prior to sclero buckle and 1 month after sclero buckle. We looked at 1 week of continuous data for the continuous measurement rabbit and then 2 weeks of data for the scheduled data collection rabbit. And then paired T tests were used to compare the number of fluctuations and amplitudes pre and post sclero buckle here. So here's data from rabbit 3 looking at that curve amplitude 1 month pre and then 1 month post buckle, and what we saw was a 25% reduction in the amplitude post buckle when comparing those 24 hour IOP curves. Um, and this circadian IOP amplitude that we saw the significant decrease here in rabbit 3, there was a trend toward decrease in rabbit 4, but it did not reach statistical significance. And then we also found a reduction in fluctuations across all magnitudes one month post buckle in comparison to the one month pre-buckle, with the greatest reduction in large fluctuations, those fluctuations greater than 5 millimeters of mercury from the fitted curve. And similar results were obtained with the continuous and scheduled monitoring here. With a quick note, the asterisks represent p values less than 0.05. I will note here that when comparing the continuous and scheduled monitoring data, there were slightly more challenges with data analysis for the scheduled monitoring because the filtration program had to mark the start of each scheduled collection of data, and that could be thrown off by brief episodes of signal dropout. So some conclusions from this year. Thinking about the background data that I presented, IOP fluctuation is associated with glaucoma development and progression, especially in patients with low mean IOP. However, this does not confirm causation, so ongoing study of the pathophysiology, as here, is valuable. A cosigner analysis of continuous IOP data is a useful tool for analysis in rabbits, which exhibit that strong circadian rhythm similar to humans, though, as I said, signal dropout may interfere with some of the curve fitting. Sclero buckles reduce the frequency of ultra short term IOP fluctuations and the amplitude of circadian rhythm in rabbits consistent with that reduction of ocular rigidity. Like I said, less of an increase in pressure for changes in volume, and this may explain the protective effect of sclero buckle against development of open angle glaucoma seen in those background studies. Additionally, reducing ocular rigidity is a model for studying IOP fluctuations independent of mean IOP and may be a target for treatment in glaucoma patients to reduce the frequency and magnitude of fluctuations. I'd like to note here that ongoing studies are being conducted to look at ocular biomechanics of patients with untreated normal tension glaucoma, particularly the role of scleral and laminar properties, and continuous monitoring in humans is on the horizon with implantable centers like the iMate and InjectSense that may eventually provide the data needed to show whether or not IOP fluctuations are causative in glaucoma. So back to our question here, um, scleral buckles decrease which of the following? Hopefully everyone should know by now, we're pointing to ocular rigidity here. All right, huge thank you to Dr. Sit. It has been such a privilege to work on this project over the last 2.5 years, and I felt very fortunate also for their enormous contributions in coordinating and carrying out the project, Dr. Chris Gao, Kirsten Anderson, and Susan Shah. And I'm happy to take any questions now. Thank you so much. Great presentation. I enjoyed your explanation of why. Why do you have um OOP changes um in the scope, it's very difficult to explain that, and you did a great job there. Uh, the comment is about using rabbit, any of us, we use rabbit in, um, in the studies, we know that the scar is much thinner, it's about 0.2 0.25 millimeter compared to a human, it almost doubled. In thickness. And also there is a study about cross-linking of the rabbits that has shown that the rigidity there is less than humans, and that's something to have in mind when we are explaining and when we are trying to use rabbit model for explaining the score buckle in humans. Yeah, I think that that's a really important point, um, particularly when looking at, um, sort of the quantitative measurements. I think that it helps then to look at some of the relative measurements here as opposed to just the raw data itself. Absolutely. Very nicely done, Rachel. Um, I was kind of curious. There's lots of different kinds of buckles, you know, in the studies you highlighted, and then in your study, what were you, what band or uh element were you using? Um, so in the study here, I mean, I know that it was, um, Medical grade silicone as is typically used in patients. I know that in some of the background studies that I presented, they did note that there were differences in the the size of the band and slight differences in the procedure performed. I, of course, am not an expert in. Knowledge of sclero buckle procedure, but at least for our rabbits here, it was the, it was the same um silicone band size that was used in each of the rabbits for comparison's sake. But I don't have those exact measurements in front of me. I apologize. encircling bands. Yes, encircling sclero buckle surgery. Yes, correct. Yeah, and just to clarify, it's a Type 40 band. Thank you, Doctor. She I have a question. It was a really great study. Thank you for presenting. Um, When was the, could you refresh my memory, when were the measurements taken after the buckle was. Yes, so for each of the rabbits in the 2nd phase of the study, we looked at data from 1 month before and 1 month after the scleral buckle was performed. Now we were collecting data sort of continuously throughout that time. Those periods of continuous measurement or scheduled measurement were shown because sort of the time period. Necessary for healing from the initial implantation and having things returned to sort of their typical circadian pattern there and then also healing and sort of recovering from the stress of the sclero buckle surgery itself. So it was one month pre and post. Yeah, there, there, there's clearly the possibility that there's a small superciliary effusion associated with the procedure. Um, the, the other thing is, is that over the course of time, a fibrous capsule develops. I'm not quite sure that it's even there in a month, uh, uh, and that capsule, it, it definitely alters the mechanics of the eye, um, you know, it certainly alters the. Positional stability of the buckle in cases where in the old days when we would go back and revise a buckle. Um, you know, going back sooner was very, very different than going back later. Um, The other question I would have is, is, uh, have you considered looking at the relationship of the angle and the trabecular meshwork in the iris, you know, I'm wondering if there's any potential rotational mechanisms. You, you, you had mentioned that it wasn't altering, uh, trabecular outflow, but Um, I wonder if it's altering uveo scleral outflow or if there's any change in the anatomy of the anterior chamber. Yeah, I think those are both great points. I think on the first one, interestingly, in that study that I cited with the 9 patients who underwent unilateral sclero buckle surgery, they did note that there was a trend towards sort of slowly increasing. Ocular rigidity in the buckled eye over time postoperatively. So I think it is important to think about the how the buckle is impacted over longer periods of time, you know, rather than just months but actually years, and I think fibrosis is an important concept there. And then on your second point, yes, absolutely. So, based on the position of the scleral buckle, we don't see that it affects outflow facility in terms of like episclero venous pressure, that concept, but in terms of its impact on the angle, you know, I don't have data or information on how that might be impacted there, but I think it would be worth studying. And on the same note, um, when we do cryotherapy, cryo can impact the integrity of the spira. So that's one thing. And many times when we do cryo, it's very close to the ciliary body, so part of the ciliary body could be impacted by, by by our cryo treatment. Yeah, yeah. No, I think it's important to keep in mind on all of those sort of large category of factors that I put up at the beginning in terms of outflow facility, ocular rigidity, episcleral venous pressure, aqueous humor production. They can all contribute. And so this was taking a look at just one component to see whether it had significant impact, but that doesn't mean that it is the only factor contributing by any means. That's a really interesting point you bring up, Ron. I wonder if, if we could identify the same phenomenon of, of ILP, um, fluctuation lowering in patients that have undergone cryotherapy. Because, you know, sclero buckles have, have classically been associated with elevated intraocular pressure because of, believed to be because of co-compression of the uh emissary vessels, the, the, um. The vortex vessels are getting compressed in some cases. Um, but, but by, by, by performing cryotherapy, we're, we're bleeding very large areas of chloroid and retina pigment epithelium, and the retina overlying it is becoming thin. And so I'm wondering if in some way, because when we do buckles, we almost uniformly perform cryo except for the cases of buckle vitrectomy. I'm wondering if we're, if we're in some way improving uveo scleral alpha with cryotherapy. Ray, I, I, I think that's an interesting point, certainly for human patients. It's, it's just want to clarify though that in the rabbit model, we're not doing anything other than putting on the buckle. Yeah, I'm aware. I, I, I, I got that. I, I, I'm just wondering, you know, if, if the, if, if the treatment would be enhanced if cryotherapy were added to the, to the rabbit and or if we could study cryo in humans. Well, I think the question also the question also there would be, would that affect fluctuations in pressure or would it have a more sort of static effect on, you know, pressure, mean pressure overall in addition to any effect on fluctuations, whereas with the buckle here, we weren't seeing um a significant change in the mean intraocular pressure, but primarily in fluctuations. Certainly when we perform retinectomy. Large retinectomy, we, we wind up with an issue of possible hypoteny. OK, so, so by, by removing the retina itself, we, we can lower the pressure to the point where sometimes it's too low, um, and I've even done in, in one case a patch, an amniotic membrane patch to try to restore the barrier to uveoscleral outflow. Um, but it's a very interesting talk in, in, in line of research that you, you're pursuing here. Oh, thank you. Um, All right, I will stop my share here. Thanks everyone for listening. Thank you. Yeah, have a great day.
