Well, thank you very much and thank you, Dr. Bergenthall for the introduction and Dr. Wesham for your talk on dual glucose ketone monitoring and uh and the adult perspective. And now I'm going to shift a little bit and and focus on a new approach to pediatric diabetes with dual glucose ketone monitoring. And with the first question, it's why, why do we need this, and I think we've heard a little bit from Dr. Bergenthall and Dr. Weissman on this and hear, hear more from Dr. Lee Laanha, and I'm just going to start with a very basic slide here. As a pediatrician, we have books on the understanding diabetes or the Pink Panther book that are given out to newly diagnosed. Those patients and um just to emphasize the importance of education to our patients and to our families on how DKA can work, um, and here we see the Happy Pink Panther where insulin is being, is working as a bridge to get the sugar from the bloodstream into the cells of the body and also turning off internal sugar production by the liver, and of course there's no uh. Ketone production from fat, and what can happen in diabetes, as we know, is that without insulin, the cell gets hungry, um, the liver produces, um, excess sugar, um, we get increased sugar in the urine with polyuria, leading to polydipsia, uh, eventually breakdown of fat in the ketone bodies, and we see the unhappy pink panther here. So this is something we teach all of our patients and families at new diagnosis, um. And and try to help prevent this going forward after initial diagnosis. Now I'm going to try to give a little bit of a historical perspective in my talk, and this is a slide, a sketch from a patient who was seen at the Joslyn Center, and this is from a book called Bittersweet. which is a set of case histories of people with diabetes from, from the Joslyn Center since the discovery of insulin. And this was a gentleman who was seen there who also was a, was an artist and this was his understanding of what his care was like in the 30s, 40s, 50s, where Um, you see this elaborate chemistry experiment here in the background, of course, um, testing urine for glucose and, uh, and his conception of what delivery of insulin was like with this really long, torturous needle um and and the comment above. So we've come a long way in. Delivery of care, um, but we still have progress that we need to make. Now this is a paper that perhaps you've heard referenced before, and the title is The Answer is 17 Years, but what is the question? And, and the question is understanding time lags in translational research. And so the point that these authors make in this paper is that there is a gap going from discovery. With research until getting those discoveries into clinical practice and helping, helping our patients out. But how are we doing in type 1 diabetes? And let's look at the DCCT EIT study, and I'd like to thank Dr. Bergenthall for sharing this slide. And these are data from the diabetes Control and Complications Trial and the epidemiology of diabetes complications studies. These are over 40 years of follow-up data on the 1,441 DCCT and EDIT participants. And I'm sure that these data are familiar with, with, uh, everyone in the room, but just to review, um, at the start of the DCCT, uh, patients were randomized to getting conventional treatment, um, continuing with it, or getting intensive management, um. In in the DCCT and so at that time the patients were followed on average about 6 years, and there was a clear differentiation in hemoglobin A1c in these groups and some of the take home then as this trial then was stopped, published in 1993 definitively showed the benefit. Of intensive management on reducing eye, kidney, and nerve complications, and then later on, of course, showing that there were improvement also in cardiovascular disease and mortality, but at that time in 1993, it clearly shown that in addition to the benefits of intensive management, that with that lower A1c there was also an increase in hypoglycemia. And so we can see that then after the completion of the DCCT trial, as patients then were continued to be followed in the EDI observational study, that those who had been intensively managed weren't able to quite get that same, uh, same level of, of hemoglobin A1c without all of that extra support. that they were receiving in the DCC trial and then an edict that the patients who had been in the conventional arm adopted a lot of the practices of of the intensive arm, and you can see that over time there was a convergence and a pretty similar. A1c over 20 years post DCCT of about 8% and during this time hypoglycemia was really the biggest barrier to optimal A1c. So where are we then after 2030 years after the DCCT? Well, we have now the development of CGM um and also um with the standardization with the ambulatory glucose profile. Um, with that we saw concepts like time and range, time below range, and improvements in both of those, more time and range, less time below range. First approval of automated insulin delivery in 2017. And with that we, we start now to see some improvements over the last 1015 years with some improvement in, in A1c in this DCCT edict cohort, and again aiming for a time and range below 40, time below range less than 4% below 70, and less than 1% below 54. And so I think we can, we can clearly say that. The diabetes technology development has helped optimize glycemic management. Our next question then though is dual glucose ketone monitoring and will an innovation in technology help reduce the DKA risk. Now, interestingly, the DKA in this cohort of very highly selected patients and very well educated and dedicated patients that there were over the course of these 40 years about 488 episodes of DKA. So, um, DKA continues to be a problem and, um, and I think that's what we're here to talk about is, um, how can uh dual glucose ketone monitoring help prevent episodes of DKA or reduce them going forward. So I think it's clear to say that DKA remains a clinical problem. So just one older study already now, this is over 10 years ago, and this is a registry collaborative study that was, was done with the Type 1 diabetes exchange in the US, the DPV cohort in Austria and Germany, and then the NPDA, National Pediatric Diabetes Audit in England and Wales, and you can see. That at that time, and this was the early 2010s, that there was a range of frequency from about 5% in DPV up to about 7.1% in the T1D exchange, and in multivariable analyses, the odds were a little bit higher for decay if you were a female from minoritized groups and if you had an elevated hemoglobin A1c, which is not a surprise. So that's one already fairly old data and also, as I said, I'd like to talk a little bit about history. I'm going to show a picture from uh from uh Colorado, um, and this is Dr. Peter Chase on the right, um, who was one of my clinical mentors, and one thing that he, uh, he would do would, would be to take kids with type 1 diabetes from the Barbara Davis Center clinic up skiing in the mountains. If you're a kid in Colorado, one thing you want to do is to go ski like everyone else. And so this is pretty remarkable to think that he would, would take these, these kids up skiing, and this was before we had any sort of monitoring. Uh, other than perhaps very, very, uh, crude blood glucose monitoring, um, certainly didn't have continuous glucose monitors, and, um, and anyway, that was, uh, so we've come a long ways not only in, in ski technology and fashion, but, um, but also I think in diabetes management and Now I flash forward into the study that we performed in 2015 and ended up in a in a paper in diabetes care, and this was a collaboration with colleagues at the University of Virginia and in the Barbara Davis Center at the time where I was. And in this study we took a group. Of teenagers skiing in the mountains, and in addition to the fun that was had skiing, we also were doing a research study, and you can see that we had either patients on closed loop control or remote monitoring with sensor augmented pump, and that those who were on the closed loop control did better. At this time though, we were watching the data in real time on a, on a dashboard, on, on monitors at the ski lodge while groups of 3 or 4 kids were up skiing with having a good time, but also accompanied by not only ski counselors, camp counselors, but also then research team members to help. Shoot any issues that they were having. So these data contributed to the Control IQ development and and again just showing advances that we've made in diabetes technology and in ways to help children do what they want to do, which if you're, if you're a kid in Colorado is often to be able to go ski. All right, so we've, we've had advances in diabetes technology, but, uh, but A1C, A1cs are still higher than we would like. And so this is a 9, registry study. Um, this was in The Lancet Diabetes and Endocrinology, um. And this reports from 9 registries and over 100,000 children, and these are data from 2013 to 2022. So that's 30 years after the publication of 1993 of the DCCT, and you can see on this axis that we've got the range of A1cs. There may be some of you in the audience who are from many of these. Countries, the ADDN, Australia and New Zealand, we have the DPV data, Germany, Austria, Luxembourg, Switzerland, we have data from Sweden, Czech Republic, Norway, the SWIT International registry, and then also from Denmark, England, Wales, and the US. And you can see that in all of these different registries, there's been an improvement over time. Um, excuse me, um, unfortunately, um, for those of us in the US, um, we're still at the, at the higher end here in the T1D exchange, although I will note that there's been a pretty dramatic improvement in the last 5 to 6 years, which has continued. So the authors of this study attribute the improvement in A1c to increased use of technology, CGMs, pumps, automated insulin delivery, and that in parallel to these improvements in A1c, there was also a reduction in hemoglobin A1c. But what about DKA? So this is another, another slide figure from this paper again, the Zimmerman paper, and you can see over here that these are the rates of diabetes ketoacidosis, and this is pooling all of the different registries. Um, and you can see there certainly is some variation, but it really has stayed kind of between the 2.5 to 3 events per, per 100 person years in these registries. So if you look at this slope, um, And where we are in 2026, if we continue at that slope, we're just not making a whole lot of progress apparently in the last few years. So I think the question is, can we bend that slope? Can we be doing something to try to reduce the amount of diabetic ketoacidosis that we see in our pediatric patients, and can dual glucose ketone monitoring help us with this? So I'm going to show now an abstract from Paper that is being presented at the ADA this year and in this it was a a look at the burden of diabetic ketoacidosis among youth with diabetes, and this is a hospital claims analysis, so there are some limitations to this, but in this, the, the decay related hospitalizations in children with type 1 or type 2 were assessed and estimated the differences in mortality and the cost of the hospitalizations. Um, so some of the take-homes with this is that in 2022 there were 38,000 more pediatric hospitalizations with type 1 or type 2. 59% of those hospitalizations were associated with a DK diagnosis code. And, um, really disturbingly in my mind, um, that there were 49 deaths associated with, with DKA hospitalizations, um, and, and the length of stay was 2.4 to 7.3 days with costs, um, uh. Close to $10 to up to close to $40,000 per hospitalization. So I think a conclusion that these authors make is that there is a substantial burden of decay in terms of incidents, cost, and duration of admissions. So a few slides here on some of the ongoing issues facing people living with diabetes, and I'd like to thank my colleague Dr. Jennifer Scher at Yale for sharing some of these slides. I think it's important to remember that many people with diabetes still struggle to achieve glucose targets and that the acute complications of diabetes remain severe hypoglycemia and diabetic ketoacidosis, namely, and that the cognitive and emotional burden of daily management is significant. And also we've had the development of access to adjunctive to insulin agents, but that's limited for people with type 1 diabetes, and one of those concerns is euglycemic decay with SGLTs. So again with diabetic ketoacidosis, it's acute life threatening complication of diabetes occurring when there's insulin deficiency. We're all familiar with the signs and symptoms of elevated ketones, nausea, vomiting, abdominal pain, rapid breathing or difficulty in breathing, confusion and altered consciousness. And the advice is standard to measure ketones when glucose levels are elevated during illness, when symptoms of elevated ketones occur with prolonged fasting, and during specific situations where ketones could be elevated. Now we are, I'm sure all familiar with the different methods that we currently have either to measure in urine where acetoacetate is measured, and it's semi-quantitative, and I think we're all familiar with having taken calls from our patients asking what the color looks like. And, uh, and the different ranges that those are associated with. And then in contrast, we've got, um, beta hydroxybutyrate testing via point of care capillary test, which is more, uh, which is quantitative. Um, now some of the drawbacks to the current methods with urinary measures. It does not measure the predominant ketone body in DKA and, excuse me, with delayed clearance, it averages ketone readings since the last void. Also, the strips have a short half-life, and people with diabetes need to carry the strips and find a bathroom to perform a test if they're out of the house. Um, with capillary measures, um, and I wouldn't perhaps have said this 10 years ago, but it's potentially painful. A lot of people don't just don't poke their finger as much anymore. Um, it's relatively expensive. People need to carry their meter and their lancing device and also understand that a numerical value does not necessarily mean abnormal. So both methods though rely on the person with diabetes to initiate the test, and that's a key distinction. And I think these are sobering data from Dr. Albanese O'Neal, now with Breakthrough T1D, just on the frequency of monitoring and the take home that people with diabetes don't frequently check their ketones. And so what we see here is the percent of people who check always, most of the time, half the time, occasionally, rarely or never in the. Different age groups and you see that we're doing a little bit better here in, in pediatrics, um, likely, um, uh, parent involvement, and then that, that drops off fairly significantly, um, as age goes on, and that's with when there is vomiting and then um similar data um on the frequency of monitoring when glucose is above 300. So another, another slide here, another study, when people with diabetes were asked what glucose level would prompt ketone testing, and almost 2/3 said I simply do not test. So anything that we can do to reduce that burden to have data on, on ketones could be extremely beneficial in preventing DKA. So what happens in the real world? Well, here's a case. A 6-year-old on type 1 on an automated insulin delivery system. Overnight she begins having episodes of vomiting. Her parents were worried she'd developed a viral gastroenteritis, but the glucose was in range. They'd been administering small amounts of honey to keep glucose levels stable. After hours to do this, uh, doing this overnight, um, they contact the team at 6:30 for guidance, and the standard recommendation to check ketones came back mildly elevated there we see it 1.6 at 6:32 a.m. and also then with the realization that it wasn't a stomach bug, but it was, it was an infusion set failure. So let's talk a little bit about um issues with infusion sets and um. And that if you, if you look at the data on the right here, um, and this is from uh DTT, that, um, if you look at the various frequencies of this and pool the, um, greater than or equal to one infusion set failures per month, we've got 41. 4% of people who reported having some sort of infusion set failure monthly, so a pretty significant amount of infusion sets, and we can't underestimate the importance of education about this. Another point to make is that the rates of glucose and ketone changes don't consistently correlate. Here we've got a nice example with the blue of glucose going up over time and the purple ketones going up in step with them as well. And this is, these are data from an adult. Pump interruption study, but sometimes glucose rises faster than ketones. You can see here where the glucose rises and ketones stay relatively flat on the bottom, or ketones rise faster than glucose here, or ketones rise and glucose stays flat. So there can certainly be Some variability from what we commonly teach that they that they rise together. It's important to keep that in mind. So other things to be on the lookout for is that ISA guidelines will be coming out later this year with updates from the previous guidelines, and those are being led by Professor Nicole Glazer from Davis, who's a world expert on pediatric DKA. And also earlier this year, there was a Lancet diabetes and endocrinology paper that was sponsored by Breakthrough T1D that has provided guidelines and, and recommendations so that once dual glucose ketone monitoring is available, we will have um. Some, some expert recommendations to start with to help with our patients. Now I wanted to run through one case here and just to orient you. These are the glucose concentrations. These are the different times over 6 days. These red stars are when glucose was checked, and this is someone who You can see it has glucose readings, but then they're also on a blinded dual glucose ketone monitor. And so these lines in green are the ketone measurements, and you can see that on the axis here, the different levels with the hash mark here of ketones of 3 millimoles per liter, which I think we all agree is, is elevated. And so, um, again, this was a blinded meter, but this is the point at which, uh, the, the person would have received an alert, crossing over that 3.0 ketone level, um, and we see that then it was about 20 hours later, where the person was actually hospitalized for DKA, arguing that there would have been 20 hours in which something. Could have been done to prevent DKA and uh uh if, if not even more, um, to try to prevent that from happening and the ill consequences from, from diabetic ketoacidosis. Um, and then we can see that the, the glucose and ketones came down with treatment, um, and, uh, what happened after that. So this is from the. The Lancet paper, and I think we're all familiar with these different levels of ketones, 0.6 to 1.5 being elevated, high, 1.5 to 3.0, and then above 3, the urgent, urgent alert, and it has a nice list of the symptoms. Again, these could be helpful also then to have actions to be taken by the person with diabetes and hopefully this could be a useful. Um, schema for practical recommendations on what to do with continuous ketone monitoring thresholds. Also, um, the American Diabetes Association, um, has a paper and review at Diabetes Care, again, on a ketone monitoring and elevated ketone management, again, designed to help patients, um, and providers so that when these devices do come out, that there is, um, Some expert opinion and some patient facing materials as well as provider facing materials and Dr. Weisham showed this to us earlier, but just to emphasize that that this is a clinical algorithm for children, adolescents, and non-pregnant adults on what to do when you have ketones and if you're using CKM or no. and how to move through this depending on these different levels and also includes advice on what to do if you're using capillary or urine, urine ketones as well, and you can see, you know, once you measure the ketones and then advice on what to do as far as self-care or advising to Go to the emergency department as that's needed. So with that, I, we hope that this paper will be out soon and additional information in addition to that of The Lancet diabetes Endocrinology paper, and I think we are at an exciting time in In diabetes care, certainly in pediatric diabetes care where we have more options now to try to prevent one of our biggest concerns, which is that of diabetic ketoacidosis. So with that, I thank you for your attention and look forward to our next speaker. So thank you very much.
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