Hello everybody, my name is Kaitan Dattaria. I'm a diabetes doctor from Norwich in the UK and it's my pleasure for you to, for me to give you this presentation on dual CGM monitoring. Uh, let's get straight ahead and into the presentation. So these are my disclosures er for today's presentation. So let's go back to basic principles. So insulin does lots of different things, and it depends on the concentration that's in the blood, depends on what it actually does. And what this slide shows you is that if you are starving, essentially what happens is that you need, that you've got no carbohydrate coming in. If you've got no carbohydrate coming in, you've got no insulin secretion whatsoever. And insulin at the very, very, very lowest doses switches off ketosis and switches off ketone production, because that's the hormone that, uh, that's the substrate that your cells need when you are starving and when you don't have any carbohydrate coming in. But as the glucose concentrations rise, the first thing that insulin does is it switches off ketosis, so you can then start uh switch preserving fat because you need that for the long-term. If your glucose concentrations continue to rise, the next thing that it does is that it switches off hepatic gluconeogenesis, so it stops blood glucose from rising further. If your glucose concentrations rise even further, then what happens is you then start getting glucose uptake into the cells, which then helps you lower uh glucose concentrations. If glucose concentrations in the blood rise even further, then you get uh you get glycogen synthesis in the liver, in the muscles, and finally, at the very highest levels of insulin, you actually get, uh, it's an anabolic hormone where you lay down skeletal muscle. So insulin does lots of different things at different concentrations. So let's just talk about what happens in the physiology of ketosis. So if, as I mentioned before, you have absolutely no insulin on board because you've got no carbohydrate coming on board, for example, or if you've got type 1 diabetes and you've got no insulin at all. Or if you have some kind of intercurrent illness where your counter-regulatory hormone concentrations go up, and what that means is that the insulin to glucagon ratio changes such that you've got more counterregulatory hormones on board, raising blood glucose and antagonizing the effect of insulin. And what then happens is that you actually get uh uh that, as I mentioned, you get ketone production. How do you get ketone production? You've got no uh uh glucose going into the cells. Your cells require an alternative energy substrate, and those that substrate is going to be ketones. And as you see from this small diagram, what happens is the adipose tissue breaks down. Into free fatty acids and glycerol. The free fatty acids are taken up into the circulation where they are eventually taken up by the liver, and they are used by the mitochondria and condensed into acetyl-CA, which is further condensed into the two most common ketones that we know about acetyl acetate and beta hydroxybutyrate. Now those two ketones are, are both released back into the liver when they can be either taken to the lungs through the circulation where you can breathe off the aceto acetate, and you know that uh if you've met people with DKA you'll know that familiar fruity smell or, or nail varnish removal. And that's why, because they're ketoacids, and we want, if the rate is rising very quickly, you will then get that kusmal breathing. We all know that long, deep breaths and people trying to breathe off that acid to try and get respiratory compensation for that metabolic acidosis. But also what happens is that the ketones are taken into the blood where they're taken to the kidneys, where you then get ketonuria, you get glycosuria, of course, you then get an osmotic diuresis, and you get, uh, volume depletion. But of course, don't forget the aceto acetate is still taken up by the muscle because that's the alternative energy that they need. But from a physiological point of view, why are ketones important? So let's remember, if you are thinking about human beings 50,000 years ago wandering around the plains of Africa trying to find their wooly mammoth, what they have to do, it may be weeks and weeks before they find their wooly mammoth. And so in those few weeks before they. Catch their wooly mammoth, but what they're going to be doing is eating just a few seeds and nuts, fruit if it's in season, but not very much, so almost no carbohydrate. And of course, as I mentioned, they then need to, uh, use that ketone bodies to try and, uh, maintain their health and maintain their, uh, uh keep them alive. But what you need to remember is that actually ketones are really important because your brain and your heart prefer ketones as the energy substrate. And if I, if you are starving, of course this process takes place very, very slowly, and actually over a period of weeks, you can see from these data published in the 1970s that actually ketone concentrations can rise really very high, 67 or above mlimoes per liter. But because they are appearing so slowly in the circulation, we have more than enough time to compensate from a respiratory point of view, compensate from a renal point of view, so you don't get acid, you don't become acidotic. So that's why they are very healthy, and you can see from the bottom right, uh, part of this graph here that actually, uh, um, when you're starving, the brain prefers ketones as its energy substrate of choice. And there are lots of data from animals and for at all levels, and these are nematodes and mice and higher primates which show that actually if you starve an animal, you make it ketotic, it actually lives for longer. So there is an evolutionary advantage to being ketotic. We've got evolutionary adaptation to starvation which allows us to live longer, and that's actually fascinating. And these are data just published in the last couple of years, very complicated slide. I just want to just point out to you that actually what this shows is that if you give people who have heart failure, either hefpeth or hef ref, if you give them oral ketone esters just for a couple of weeks, all the markers of cardiac function improve, suggesting that your heart, uh, likes ketones, and indeed these data also show from these papers. That cardiac myocyte mitochondrial efficiency rises in the presence of ketones when you compare it to glucose. Many of you may have, many of you may have seen these published a couple of years ago, now, these are the uh new global consensus document on the management, on the diagnosis and management of hyperglycemic emergencies. And when we talk about DKA, there was a sea change for many people who use the old ADA guidance, and the, the, the emphasis really is on, if you diagnose DKA you must have the D. The K and the A and the D is a glucose above 200 mg per deciliter or 11.1 millimo per liter, and really the reason for that is, is because every single field of other, other field of diabetes. The diagnosis is made with a glucose above 200 or 11.1. Now, in the previous ADA guidance, you had to have a glucose above 250 for some reason, and we said, well, why, why, why can you not have, and what about you, glycemic DK? Uh, and the ADA agreed, and that's why the threshold was reduced. We keep that threshold for K, the ketones at 3 millimoles per liter or 2 pluses or more of ketones on, on urine sticks, and the A is a, uh, bicarbonate of less than 18 or a pH of less than 7.3. Now with these, and because a large proportion of the world has access to bedside ketone monitors, you do not necessarily need to do the anion gap, because you're measuring the actual thing that you're measuring, you know, that you need is the ketones. So if we're encouraging everybody to use bedside ketone monitoring, particularly in hospitals so that you can then monitor er progress appropriately and at the bedside, and that can help you make er clinical decisions. Why do we choose 3 millimoles per liter? Well, this is one of the small uh piece, uh, pieces of data that help us decide that, and these were published back in 2001, uh, showing that actually it's at a threshold of 3 millimoles per liter that actually people need to seek medical attention, and that's why, uh, we chose the 3 millimoles per liter. But as I mentioned, ketones are physiological. They are beneficial. But when does physiological, physiological become pathological? Really, it's dependent on the rate of appearance and the ability to renally and respiratorily compensate for that drop in pH. And uh, I and others have, uh, came up with a, a, a, a threshold saying, well, actually, if your rise of ketones is, uh, in particular beta hydroxybutyrate is greater than 0.2 millimoles per liter per hour, then that is probably going to be pathological. But there are no current uh uh um uh technologies that we have available to us that allow us to check what the rate of change is, apart from doing bedside uh finger prick testing, which you don't really want to do every half an hour or so, that's a bit mean to the patient. But until now, we've had nothing, and as you all know, if you've had bedside capillary glucose meters, if your glucose rises above 300, or if it rises above um uh uh 13.3 in the UK, sometimes it will say check for ketones. But there are some, there are some data to show that DKA, and we're talking about DKA of course today, is by far and away the most common hyperglycemic emergency in people that happens with people with diabetes. And it is by far and away the leading cause of death in people under the age of 58. So that's a tragedy and it's all preventable. And depending on the literature, depending on what you read in from which country, there's an annual prevalence of DK of anywhere between 1 and 13%. We're higher in those parts of the world where medic access to medical care is not as easy as you'd like it to be. And in the ADA and UK and uh other EASD global consensus documents, we say that up to 1/3 of people who present with DKA may have mixed HHS and DKA. But actually if you look at other data showing that 1 in 5 people with DKA actually have type 2 diabetes. And it's got a, it still has an appreciable mortality. So it's not a benign condition and must be treated with very, uh, with all seriousness because people can die. And of course the rate of death in people with type 2 diabetes is much higher than those people with type 1 diabetes, presumably because of the uh uh associated comorbidities. Um Having said all that, unfortunately. There is still a lot of unawareness about DKA out there in the community, even though I, as a, a diabetes doctor think to myself, actually, every time I meet somebody, every time I have face to face contact, every time I have some kind of, uh, interaction with the people I look after, I try and make sure they do know about DKA. There are data to suggest a large number of people are still not familiar even with the term DKA. And beyond that, almost half were unable to name even a single symptom of DKA. And finally. 2/3 of people did not test for ketones even when they should have been doing so. How do they self monitor? Well, most people don't even self monitor, they think that actually less, less than 1 in 5 people tested for ketones when their glucose concentrations were high. That's 16.7300 300 mg per deciliter. More than 1/3 didn't even check when they were sick or actually vomiting. That's when we'd assume that people would say, oh, I'm not very well, maybe I've got ketones. Almost half didn't check for ketones when they had a fever. When we think that people should be. Now, there are many, many barriers to why uh why decay prevention may not work. Of course, as I've just mentioned, it's a lack of knowledge as you see here. What is DK, when should I check for ketones, how to interpret those numbers that you get either on the urine dipstick or on a bedside capillary ketone meter? When to seek emergency help. We think we're giving that information to people, the people with diabetes, they don't really think about that. Some people go the other way, they think it's their condition, even though they've been given all the education, they've been told to seek for help, they think, well no, it's my condition, if I'm ill it must be my fault, and they get embarrassed and they're less likely to seek help from uh healthcare professionals. And other people, we know that, you know, everybody thinks they're indestructible, they're never, it's never gonna happen to them. And so they don't realize that when they do become ill, that may happen to them, and they may still need to ask for help. There's more things that prevent people from seeking help from diabetes. We know, we know, I think I do it all the time, and of course I've just shown you data that suggests that people may not be doing it, but every single patient contact is important, every time you contact, every time you have a conversation, just to remind them about when do you know when to check for ketones, do you know what DK is, and what can we do to prevent this potentially life threatening complication of this of this condition. We want to try and give them that information in a way that they actually understand and can retain, because it's easy for us to give them all the jargon, but if they don't understand the jargon, then they're not going to implement those instructions that we give them uh in the times of need. We want to try and involve everybody who knows that individual to make sure that they're also familiar that if they're unwell, to say, well, check for ketones just in case. Have you checked for ketones? And of course if you live in a place where you have to pay for your own care, of course being ill and having ketones and testing may incur major costs and maybe a disincentive for those individuals to seek help. I'm gonna change tackle a little bit now. These are data from uh Jen Schur in Yale, and what she did, this is a pump suspension study, so she got 20 people with type one diabetes, she brought them into her lab and she stopped their pump. And what she then did is she then recorded their glucose concentrations and ketone concentrations at the same time. To check what was going on. Now this is a fairly messy graph. I'm gonna show you, uh, some examples of what, uh, what was teased out from here. And these are 6 different kinds of variation. And you can see from these, now the light blue lines are glucose concentrations over the following 7 or 8 hours. The dark blue lines are ketone concentrations over that same period of time. Now, for many people, they would say, well actually as the glucose rises, the ketones rise, and that's the top left as you can see, so glucose and ketones rise simultaneously and at about the same rate. But actually, everything, every other variation happens. Now if you look at the, the middle 1, S18, you can see that glucose is rising faster than ketones. If you look at the top right hand corner, S8, the, the ketones. Excuse me, the ketones are rising faster than the glucose. Look at the bottom left, S20. The glucose rises, but the ketones stay absolutely flat. And similarly, look at S23, the bottom in the middle. The ketones are rising, but the glucose stays flat. So actually there is very little relationship in many people between what their glucose is doing and what their ketones are doing. So you can't always assume just because ketones are high that uh uh just because glucose is high, the ketones will be high. And similarly, you can't just assume just because glucose is low. That key chance would be low because we all know about this thing called euglycemic DKA in this day and age, particularly with the use of SGLT2 inhibitors. Well, there's something on the horizon that may help us all, and that's this. This is continuous ketone monitoring, and at the moment there's one being developed, we know there's one already on the market which is not licensed for people with uh with diabetes. Uh, but this is uh just on the horizon, it looks very similar to a Freestyle Libra uh uh glucose sensor. It's built into the same sensor that will check for glucose and ketones at the same time. Uh, the illustration there in the, on the what the phone shows, that's purely an illustration, that may not be anything what it shows at all, but you can see what's going on, similar to a CGM that ketones may be changing and at what rate they're changing. It goes into the cloud, it tells you that there's a problem and you, and it, you need to take some action. And ultimately, and it's not there yet, but it may be built into an algorithm for artificial insulin delivery system, but that's in the future. You may have seen this, this was published in January. I and my colleagues from all over the world, we came up with a consensus document on what the numbers actually mean. Now, if you remember back, say, 10 years ago when CGM was brand new. Nobody knew how to use it. Yes, there was some idea of what we needed to do. Yes, we knew, we, there were, you know, there was a new technology and we knew that we could look at things and look at glucose change rates of change and so on. But actually some of those more subtle glucose metrics really came along with the use of this CGM, and that's when now people are, you know, 10 years down the line, you've got a whole series, a whole enormous bank of things that we can do to try and ensure that the care for people using the devices is as good as it can be. But with continuous ketone monitoring, we are right at the beginning of that journey, we're still right at the beginning. So we don't know, because it's not available yet, we don't know what those numbers will mean, but we wanted to give people something that they could use immediately on day one that this technology became available, so we have some idea of what to do and what those numbers that we should be looking out for. And these are some of the suggested thresholds. So the ketone levels are on this bar, so at the very bottom, you know, 0 to 0.6, completely normal. We know in starvation if you were, if you had, if you had that, if you don't have diabetes, and I gave you nothing to eat or drink except for water until this time tomorrow, uh, we'd all have some ketones in our urine. But above 0.6 to 1.5, you can see their elevated ketones. What are the potential symptoms that somebody could develop and what are the actions, and you can see that. So just check your glucose a bit more regularly. Make sure if you're on an insulin pump that it's actually connected and it's working, it's actually doing what it's supposed to be doing, and take some insulin, take some fluids, take some carbohydrates, and maybe take some insulin just to switch off that ketosis, going back to what I said right at the beginning about the physiology of ketones and insulin. If, however, your ketone concentrations continue to rise between 1.5 and 3 millimoles per liter, that is high. You're likely to get more symptoms, and what should you be doing? So those are the suggested actions still on the screen that you can see there. But once somebody's ketones are greater than 3 millimoles per liter, they are likely to be symptomatic, and they probably need to seek urgent help, uh, from the medical profession to make sure they don't have overt DKA and they need to get treated if they do. And these are suggestive graphics that maybe are coming along with that, similar to the arrows that you see on a CGM on your mobile phone or whatever device you're reading. What is the change rate of change, and we've given some suggestions that this is what may be happening. So if your, if your ketones are rising up more than 0.4 millimol per liter per hour, then you'll see the up arrow similarly or the down arrow, they're coming down. So you know what to do and how urgently you should be seeking help, similar to what's going on with CGM. And then we have a whole series of what to do in various situations. So if your ketone concentrations are normal, but depending on your glucose concentrations, this is what I would describe as in the UK as sick day rules, what you should be doing when your ketone concentrations are so high or your glucose is so high, and You can see here, depending on whether you've got normal ketones, elevated, high elevated, or urgent high elevated ketones, and depending on what your glucose concentrations are, what you need to be doing in terms of taking carbohydrate, what you need to be doing in terms of taking extra insulin as well. So there are some suggestions which will, which are on that document which I suggested to you. You can see the reference on the slide there. What are the potentials for this technology? Well, there are loads, and hopefully you can see them. They're blindingly obvious to many people who are looking after people with type one diabetes who develop DK. So, you know, the ability to identify a rise in ketones and the implement allowing the implementation, the early implementation of sick day rules to prevent hospital admission, prevent it progressing to overt DKA. It tells you that your pump or your infusion set and something has gone wrong, so your ketones are rising. Again, this can happen without glucose rising immediately. It prevents er acute illness and hospital admission, and we all know that the most expensive part of somebody's career if they have diabetes is if they're admitted into hospital, and particularly if you are somebody who has to pay for your own care, that is something we want to avoid at all costs. Of course, if you've got the dual ketone and uh and glucose meter in one, it's fewer pieces of kit to carry around as you see, and eventually what we would hope is that it, the, the ketone concentrations can be inbuilt into the AID algorithm to allow glucose and insulin concentrations uh to be calculated with those ketone concentrations to make sure that people stay safe on that AID system. Who are the people who may benefit from this technology the most? Well, there are loads of people, you can see here, those people who we know are at greater risk of developing DK. So you can see people who are, uh, women who are pregnant, those people on SGLT-2 inhibitors. Now I'm not telling you in any way, shape or form that you should be using these technologies in people with type 1, and then that's safe to give them SGLT-2. They're not licensed. I'm not telling you that, please don't do that unless you absolutely know that that individual with type 1 diabetes knows what they're doing. Um, but it is an opportunity, potentially. People with CKD who are at risk of of repeated episodes of DK, you can see those people who choose to go onto low carbohydrate or ketogenic diets because they think they're healthier, of course. People who live a long way from healthcare, uh, facilities, so in rural populations, people who, uh, have mental health conditions, uh, pump users as I've already mentioned, the old and the frail or the very young who are at risk. But what about the challenges? Now, there are loads of challenges to this new technology, as there is with any, the introduction of any new technology. So what do the numbers mean? How do you, you have to educate the people using the device uh who are actually wearing the device. What do those numbers mean? But, and what about. Healthcare professionals, what do the numbers mean? They don't know, because it says on that table, you know, consider contacting your healthcare professionals. So if the healthcare contact is, is contacted and they go, I don't know what it means, that doesn't help. So we all need to have, uh, uh, some education on what to do when somebody has a higher than anticipated ketone concentrations. When does physiological become pathological? Yeah, we've said yes, that the rate of rise of more than 0.2 millimoles per liter per hour may be pathological, but we have to get the real world data to know that that is the case. Are there differences between, uh, blood and capillary and interstitial um ketone concentrations, just as we had to deal with that, uh, with the CGM for glucose, uh, capillary and interstitial glucose measurements, we have to do the same for, uh, ketones. Are the differences between those people with type 1 and type 2, and how do you manage your glycemic decay, so your glucose is completely normal, can remain less than 200 mg per deciliter, but your ketones can be really quite high, and of course, as I've mentioned, those people have to pay for the technology, how's that gonna work? Well, this is just a, a short case that I could show you. This is a chap who's 55, who's had diabetes since the age of 2. He's got no beta cell function, he's got he's got no measurable C peptide. He's on an AID system, so he's been given the best uh uh the technology that we have. He's got a total daily insulin dose of. 0.5 units per kilo per 24 hours. You can see he's got great timing range, 83%. I mean, it's fantastic. He's got a little bit of, and the rest of it is mainly time above range. His HbA1c, pretty good. I've, you know, if someone's had diabetes for 53 years, I'd say that's a pretty good HbA1c at 6.9%. And he didn't have a DK episode since he was a child, so for many years, you know, so people forget what was happening. But. His physician decided to give him a trial of dapagliflozin, and once again, I'm not saying that that's licensed or indicated, but you just need to be aware that if you do it, you need to make sure you've documented it and you've educated them, and you've documented that you've educated them. Well, he's been given this CKM system as part of a clinical trial. And it goes off at 1. What do you do? Well, the pump says, you can see here, suggest pump site's changed. He needs to rehydrate, give himself some extra insulin, using his pen, his emergency pen device just to make sure the pump is still working. But these are his ketone concentrations. It looks quite complicated. Let's talk, let's talk through it. You can see here that at 6:30, the CGM expired. That's the bottom line in the middle there. Uh, and you can see that he changed it. He said, look, I know my CGM is is gone. I need to change it. And 2 hours, it's a 2 hour warm up, so you've got 2 hours where you've got no CGM reading at all. But at 7 o'clock, so 45 minutes later, the ketone concentrations are 1. And that's where his alarm goes off because he's set it at a ketone concentration of 1. 15 minutes later, it's still going, it's now approaching 1.5, so within 15 minutes, it's gone up to 1.5. He gives himself an instant bolus through his pump. He wants to make sure it's going through, but half an hour later, you can see that his ketones are at 2, at 8 o'clock, it's now 2. So now we're talking a bit of a problem here. One hour later, it's greater than 3.1, it's alarming again, you know, it's telling you you need to go and seek urgent help or you need to do something about it. You need to check. Now, the CGM then kicks in because he's put it on a the previous one, he noted that the pump cannula site had become dislodged. So that was the key. He reinserts it, and then of course by midnight his ketones are falling, and he's, he understands what's going on, he's taken some action, noticed, and then did not need to be admitted for DKA. So in summary, ladies and gentlemen. I hope I've convinced you that ketones are an evolutionary adaptation to prolonged starvation. They are normal. They are normal physiology. However, their presence can be beneficial, as I've mentioned, or harmful, depending on the rate of appearance in the circulation. And with the advent of this new technology of continuous ketone monitoring, it would appear to be the next logical step in the management of people with type one diabetes and hopefully eventually be incorporated into AID systems to help prevent DKA in people using that technology. There are a number of challenges, but I hope you will agree with me that the potential for benefit is huge. With that, I'll say thank you very much for your attention. These are my contact details, thank you for listening.
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