Hello and good afternoon everybody. Thank you for attending this session. I'm Neda Rasouli. I'm endocrinologist from University of Colorado and I'm very excited to be the moderator of this session and this is one of the exciting topics and very relevant in clinical practice. We are very glad to have Dr. Rodolfo Galindo as our speaker. Dr. Galindo is associate professor of medicine in division of endocrinology at Emory University. He currently serves as a medical chair of the hospital diabetes task force of Emory Healthcare System. His research has been focused on areas of management of diabetes in the hospitalized patient and also in patient with chronic kidney disease. He's been continuously funded by NIH, NIDDK, Georgia Center for Diabetes Translational Research, PCORI and also served as a PI for investigator-initiated studies sponsored by Pharma. He's been the recipient of numerous awards from endocrine society. The FLARE award as an example which stands for Future Leaders in Advancing Research in Endocrinology. He's going to talk to us about management of type 2 diabetes in patients with advanced CKD and all the pitfalls of glycemic monitoring and management. So I will leave it to Dr. Galindo and thank you. Hi, good morning. Thank you Neda for the kind introduction. So we're going to be discussing today a topic that is a very big interest to me and it's how we manage patients with diabetes and advanced CKD, advanced chronic kidney disease. I'm going to be discussing about glucose monitoring and also some glucose lowering agents in this population. These are my disclosures and I'm a member of a couple of guidelines but we will not be discussing them today. So this is our agenda and we're going to be discussing what is the status of end-stage kidney disease and diabetes in the United States and some markers of glycemic control monitoring and also how we can adjust or which medications we can use in this population. So historically we have been focused on the prevention of the progression of CKD to advanced end-stage by reducing, by controlling glycemia and moderating and improving blood pressure and cholesterol. So all the risk factors and also working on smoking cessation. But recently there have been a paradigm shift in two main points. We have evidence and a strong evidence from all the studies that improvement of glycemic control can prevent progression of CKD but we have new agents that delay progression of CKD regardless of the hemoglobin or the glycemic control. And I'm not going to be focusing too much on that specific topic because you have an amazing lecture yesterday from Dr. Catherine Toto who is my mentor on this as well and then you will have another lecture on SGLT2s by Dr. Rasooli. So the focus today is how we manage in the clinic the patient with advanced CKD. And most of the data on this paradigm shift come from all those millions of studies that we have right now and hundreds of patients. So these studies are really big 10,000 patients, 15,000 patients and actually this slide is from 2020 and as you see there are more coming because what we learned as secondary outcomes now needs to be proved as primary outcomes and there are many studies ongoing. So in 2021 the way we look at this is similar, it's different. So for early CKD we know that there are new agents that delay progression and is not really respective of, it is respective of the glycemic of the A1C. And in fact one of the agencies already approved for CKD, for treatment of CKD because of the delay. So what do we do with patients with advanced CKD? A stage four which is defined by the GFR less than 30 and what do we do in patients on dialysis? And what do we do with patients on type 1 diabetes? So not too much data on that. Overall, so for early CKD we try to use agents and prevent this progression but for this population, the advanced CKD population, we try to do two things. One, we try to minimize hypoglycemia but we also try to avoid severe hyperglycemia and the excursions up and down because glycemic variability is important for many of our patients as well. So key points is control glucose, trying to minimize hypoglycemia because of the impact but also minimize the severe hyperglycemic excursions. And the question that I always get is does it matter to improve glycemia in patients with end-stage kidney disease since they already have end-stage kidney disease? Two ways to answer that. One is ethically. I don't know if there is a way to prove that we don't need to treat a patient because they have end-stage organ disease. The second is because they get other complications. So it's not the same of being on dialysis that being on dialysis and blind or being on dialysis blind with an amputation. So it is always important to control glycemia because of the control on the prevention of complications. And what about preventing mortality in this population as well? So something that we need to prove. This is data that we published recently and I don't have a cursor to show you. On the right is data on diabetes care that I published with my colleague Rosalina McCoy from Mayo Clinic and is severe hypoglycemia and severe hyperglycemia defined by ICD-9 or ICD-10 codes. And this is the data that we always see and later I'm going to show you different data. So overall what you can see on the vertical axis is the events per 1,000 years and the horizontal axis is all the years of the study. This is nationwide data from the United States using the USRDS. And basically what I'm trying to show you is that in red are the hypoglycemic events. So people requiring ER visits or hospitalization for a severe hypoglycemic event. So it's about 45 to 65 events per 1,000 years. And in blue is severe hyper which is DKA and hyperosmotic state defined by codes. So not getting into the limitations of that type of study. So as a comparison I have another slide next to it which is from the same methodology from Rosalina where she broke it down by different comorbidities and she's showing what are the rates for different comorbidities. And as you see they rarely bypass the 20 or 30. So the USRD population in that sample that is private insurance. It's only one percent and they are private insurance so most of them will be transferred to this study, the Medicare patients. So as you see patients on dialysis have about two to three times higher rates of severe hypoglycemia compared to people with other comorbidities. So the burden is really high. And then what about who is that group, the high risk group that is having the biggest burden? So it's actually the young population, those between 18 to 40 years of age in blue. I'm sorry I'm trying to use that. Anyway so right here on the right is the hypoglycemia rates. In blue is that young age group 18 to 44 that have a very high, extremely high. And then the point is who are these patients? Very complex young people with end-stage renal disease. They are struggling with being a young person, going to school, probably not having good insurance until they get on dialysis and so many other complications. And then the elderly is actually not bearing the high burden of disease, not on the hypoglycemia, not on the hyperglycemic crisis. So it's mostly the young group 18 to 44 that is having this big visit to the ER or getting hospitalized when they have, when they're on dialysis and they get hypos or hyper. So moving into hyper, this is a study that we did at Emory. We look at all the DKA admissions in patients on dialysis at Emory. And of course not a big sample but this is the largest sample that's been published so far. And then we look at many, many variables but I want to focus on a couple of them. And we compare end-stage renal disease, and the terminology has changed a little bit, to non-state renal disease. And as you see the average blood glucose in the first 48 hours is always a little bit higher in this population. And that has to do with the fact they don't have osmotic diuresis. So they don't have a kidney to get rid of that. So they always come with very high osmolality as well. And then the other point that I want to make is the time to correction of glucose. So how fast they drop. Because this is where, this is where they get most of the hypos. And this study used the protocol that we use for everybody. Whether you get renal failure or not, you get the same treatment. And that's the point that we're trying to make. Do we need to change that standard of care or treating everybody by the same standards, right? So basically, and of course I will show you what happened when you treat them with the same protocol. But anyways what I'm trying to show you is that the degree of glucose reduction is way higher in this group. During the first 24 hours and 48 hours. And of course you go down to hypoglycemia. They end up having way more hypoglycemia. So more patients will develop hypoglycemia. And it has to do because we're treating them without paying attention to the fact they have any stage kidney disease. So for those that make changes in the protocols at their hospitals, I will advise that we work on that. And so let's just move on to some parameters. So this is another study we have done and was published recently. So what happened on the emission parameters for DKA when they come and they have different rates, different stages of kidney function. So on the first column is any stage kidney disease defined by the year far less than 15. And then moderate renal failure and preserved renal failure. I'm just highlighting here the main points. Again they are coming with severe hypoglycemia, very high glucose levels. So keep that in mind. And then the beta-hydroxybutyrate is a little bit lower. And the anion gap is not that different. So keep that in mind. So they don't come with a lot of acidosis. They come with a lot of severe hypoglycemia. So they're really... And that has to do with what we need to do in management. So for this patient mostly is insulin replacement. Remember you cannot really do fluid replacement because they don't have weight unless you do dialysis right after. So it's mostly insulin for clearance of the ketosis. And why? So overall in kidney disease earlier stages we know that there is an increase in chronic inflammatory state and that has to do as that result in a little bit of increased insulin resistance. So there is tendency to hyperglycemia in this population. And less hypo and it has to do with many changes of different organs. As you progress in the disease and you move into severe hyperglycemia or advanced CKD. I'm sorry, excuse me, into advanced CKD with low GFR there is a shift. So there is a higher tendency of hypoglycemia compared to hyper. And it has to do with the fact that first you have decreased clearance of insulin, endogenous and exogenous insulin. You also have decreased production and decreased gluconeogenesis. And also this patient have a really poor nutritional status and the intake, the food intake is not really that steady. So it's very interesting what you can learn by talking to them. So let's move on into glycemic control markers. So these are all the players that are available. So fasting plasma glucose. So we have it for many years but it's only one point in the whole time frame. So it doesn't really give you a good picture. And then we have hemoglobin A1c all the way to the bottom. So it's the average glucose for the last two, three months. And then you have some intermediate markers which are glycated albumin and fructosamine. And I want to mention glycated albumin is being on the study for many years but it was not available in the United States until a couple of years ago. So now it's available in commercial labs. So we do have these markers available. And then here it's just showing you what is the average, what is the time that these markers will give you a picture of. So A1c again 8 to 12 weeks, glycated albumin and fructosamine, kind of like two weeks maximum. But just bear in mind that A1c is considered a standard of care but probably not in this population because as the GFR progresses and it decreases there is decreased accuracy of the A1c. And this is K-DIGO 2020. And it's going to be very similar to 2022. It's already under review. It's going to come out in the summer next year. So basically what they are saying is that the accuracy and the precision of A1c, it decreases as you progress and it may not be the best test. So these are the guidelines from K-DIGO. So just straight from the guideline, there is no way to simplify this. So they went and said well A1c is not reliable. Maybe GMI, glucose management indicator, is an alternative for those patients where A1c is not reliable and not concordant. The issue is that the data is very limited. So this is basically based on expert opinion and a couple of pilot studies. But it makes sense. So you can also use self-monitored blood glucose and we had that for many years. But the issue is that patients don't do it and you only get two or three values per day. Which is never enough to understand the glycemic excursions of a patient that goes to dialysis three times a week. And then you can also have the combination of both and try to use agents that have lower hypoglycemic risk. So very straightforward from the recommendations. They recommend timing range. So they are moving the field forward and saying maybe we need to start using this CGM metrics in interstate kidney disease. Again the data is not there. This is just basically based on expert opinion. This is just basically again from the KDGO. It's very simple. Early CKD you can use A1c. You should do it at least up to four times a year if you're changing the management. But if you have severe or advanced CKD, it may not be that reliable and then GMI may be useful. And look at the terminology for the GMI. Occasional, useful, likely, useful. So it's very, you know, very soft because of course they believe it's a good choice but the data needs to come and you don't have a strong data to support that. So overall the A1c targets is being determined by somat analysis and the magic number comes down to be between 6.5 to 8 percent. And of course you need to do some personalized assessment. One point that I want to make. Raising the A1c target is never the answer. So there are plenty of studies showing that you raise the A1c and the hypoglycemia still happen. So you can raise the glycemic target but you need to do something to avoid the hypoglycemia. So raising the bar to a higher A1c, it will not eliminate hypoglycemia if you don't do something to eliminate hypoglycemia, okay? So just keep in mind that the burden of disease is important and you need to do a personalized A1c assessment of these patients. The magic number of A1c, 6.5 to 8 percent come from this meta-analysis and a couple more. And it's just basically showing you that the hazard ratio for overall mortality goes up if the A1c by, you know, past the 8.5. But it also start coming up if you have an A1c less than 6.5. So that is where you get that 6.5 to 8. Again, this is before having CGM. This data is from like eight years ago. So this may be changing. So I think that K-DIGO is going to be changing a little bit as we move forward. So the new kid on the block in the United States is glycated albumin. It's been tested and studied extensively in Japan. It's part of the guidelines there. A Japanese physician developed the assay there, the one that is available here, so that's why. And this is just a study by Barry Friedman from Wake Forest. So this is a study of correlation of glucose and A1c on the first graph and glucose and glycated albumin. Not to be a scientist to understand it, it's just in plain terms. The first graph is showing a lot of dispersion and not really a good concordance. The second graph is showing that glycated albumin has a better correlation with glucose, mean glucose in this population. So we know this, right? So A1c is not reliable. It doesn't really correlate with the glucose. Glycated albumin has a much better correlation. But again, this is an old study. And what is the magic number? This is one of the critiques for glycated albumin. We don't know. So A1c, 6.5 to 8 percent is what is being considered as the standard based on meta-analysis. But what about, what is the number for glycated albumin? Some smaller studies coming up. This study was published in PLOS. Nice journal. They have some different way of doing the peer review. But the magic number comes down to be like 20 for some authors. But for some people it's 18. Because you get, you will get with an 18 of glycated albumin, you will get an approximate 6.5 A1c. I would say between 18 to 20, remember you need to also bear in mind the hyperglycemia and the burden of disease. This is a nice study. It's just still we need better confirmation and bigger. This is a smaller study. So what about using CGM? These are the four kids on the block that we're all very familiar. I just came back from Barcelona and I learned that what it was two would no longer be two, it would be three. And what it was six is going to be seven or one or ten. So technology is moving very fast. And what it was three is now going to be four. So this is data presented two weeks ago on Guardian with the MEC2780, Guardian 4. And then maybe by the time we do this lecture again it's going to be D20. So this is basically moving too fast. So we cannot keep up. But anyway, so let's just talk about this is data from one study that I'm doing at Emory. And then the study is basically intervention to see if we use real-time CGM data and prevent hypoglycemia in this population. Everybody needs to be treated with insulin and have type 2 diabetes. So this is baseline data, CGM Pro. As you see, timing range in the 60s, 30% high, not too much hypo and I will show you more detailed data about that. This is a very interesting finding. The hypothesis was that they get a lot of hypos based on the ICD-9 data that we have presented. But when you put a CGM you get a different picture. I will show you in a second. So then they're going to intervention, they use real-time data. And this is of course one patient, don't take this as the only answer because the data is going to be presented later. And when you remove the real-time, you put them to do finger sticks and adjust the insulin based on the standard of care, they go up and down again. It's still a little bit better, probably they'll learn a little bit of their patterns. This is a crossover study, so just stay tuned, more data to come. So this is from the same group of patients, insulin-treated, type 2 diabetes patients using CGM, just description of the statistic, of the CGM metrics. So the new finding is they do not get that many hypos. And this was really, I was very, oh wow, this is new to me. Well, all the data that we have on severe hypoglycemia or hypoglycemia in this population is based on claims data or databases or retrospective analysis or point-of-care glucose testing, which is one or two glucoses per day. You put a sensor, and if the sensor is better or not, that's a different discussion, I will show you in a minute, is you get more data, you get a better assessment of glycemic excursion, where you do 24 hours glucose assessment. So in summary, 40-something patients that we have so far, the mean A1C is like 7%, and 50% of them go to Monday, Wednesday, Friday to dialysis, the other one go Tuesday, and that matters because people tend to eat more on the weekends, so that's something that matters. So what I want to show you is that, look at the timing range for this population. So the mean glucose is 180, not that high for this type of population, right? Although I can claim that we can get better with CGM, right? So if we can prevent hypo, what are we gonna have then running in the 180s? Well, 52% of the timing range, not too much hypo, so 1%, or one point, almost 1.5%, but up to 40-something percent above 180, so they're always running high. And I have seen patients on dialysis popping candies. I have seen people drinking juice because they're actually fast. Before they come to dialysis, they fast. The nurse don't let them eat, and they are fasting a few hours, so they are waking up at 6 a.m. in the morning, and then the last meal was many hours ago, and then they take their insulin. So it's a very complex situation, but they are very afraid of the hypos, and avoiding the hypo, they're always running high. Overall, 100% of patients had at least one event more than 180, and based on CGM metric definitions, and 90% of them have events more than 250. This is what I'm saying. There is no ethical justification to have this population running more than 250. That is not appropriate care, right? And at least 70% of them have more than 5% of the time, more than 250. So this is running some time on the high ranges, so we need to do something for them. Let's talk about hypoglycemia, because that's what we have in our brains for 30 years, that they get a lot of hypos. They do, but an average of two events in 10 days. And then, actually, nocturnal is not that much. It's less than one event average per 10 days of assessment, and not too much nocturnal. And then, overall, as I say, they get hypos. It's severe, very dramatic. They get a lot of symptoms. It's very hard to recover, but fortunately, when you put a CGM in, not too much. The new finding is they're always running high, and we need to do something to prevent that. So this is some data that we published a couple of years ago. It's a summary of all the CGM studies, all technology, three, four days of data, one dialysis session. So very limited evaluation of what you can do. So this is newer data. I don't pretend to explain the whole table, because we cannot do an explanation of 20 studies. But what you can see is that more data is coming, and we have these new sensors that we use for everybody else but this population. So it's some emerging data, and we need to keep working on it. And I'm gonna discuss the last study that was published a couple of weeks ago. So not to get into the details, because it will be a full lecture, talking about accuracy of CGM in dialysis, or accuracy of CGM. This is a study done by the VGT, Virginia, Megan, good colleague. I knew about the result even before publication. So what I want to show you is what is highlighted. The MARD, all the way in the back there, is about 13% when compared to point-of-care capillary glucose, and about 14% when you compare it to venous blood glucose, acceptable. The limitation is this is only 20 patients. So, what is it, 12 patients with type two, right. 12 patients with type two, four with type one, and one with post-transplant diabetes. We need more data, there are three more studies coming out on accuracy of G6. One is from the UK, one is from UC Irvine, and one study that is supposed to come from me, but that data will come later. The point that I want to make is, remember my population have a timing ratio of about 50%. Well, their population have a timing ratio of 38%. So again, they saw the same. And if you look at timing hypo, 0%, and I cannot really use this. So basically, timing hypo is minimal. They spend most of the time running high, when we put 24-hour glucose monitoring on them. If you keep doing ICD-19 studies and keep publishing, they get a lot of severe hypos, but that's not the true life, right. That's not the real world. So this is another study, this is using Libre. They presented another study in ATTD last week. It was from the group of Stefano del Prato. They did a study, they did no work on accuracy, but it was also done on that. This is basically the GMI. Remember that the K-Digle went ahead in 2020 and say, we believe that GMI may be a better marker than A1C in this population. Well, it looks like that GMI that they're recommending needs to be adjusted for GFR function, because it's not the same. This is a study that you look at the difference between the discordance between A1C, measured A1C, and the glucose management indicator in patients with and without CKD. When the GMI was created, again, a regression line, it was done with people that didn't have CKD. And then I think that Viral Shah presented some data on that also. There is new data emerging that GMI, one for all doesn't fit. You need GMI adjusted for different situations, right? Anyways, let's just discuss this. The first graph is basically showing the difference between the A1C and the GMI after 90 days of Libre, and the proportion of patients in blue with CKD and in red, no CKD. And as you see, all the way to the end, so looking at the 1% difference, as you see, the non-CKD group has much less patient will have that significant difference, right? When you compare the expected GMI, and it's not supposed to be that terminology, it should not be called expected A1C, but the correlation of A1C with GMI, difference of 1% is way less common when you have non-renal failure compared to people with renal failure. And the second graph is just showing similar data. Overall, we need to use a different formula, and this is the formula that this study, this study was published a couple of weeks ago. It was on the work for some time. So basically, we need a new GMI formula for people with CKD. And this basically is that regression line showing that when you use the new formula, you get a better correlation compared to the one that was developed by Roy Beck and Rich Bergen style in the overall population. It's still not perfect. I didn't like the R too much, but anyway, so it's showing that we need to have better personalization on that market for this specific population. So let's move on into TwinBank. I have 20 minutes, so you guys are gonna learn how to do this in 20 minutes. So I'm gonna make it simple. Do not, do not, do not over-insulinize these patients because it is, it is not the safest plan. So simple. We over-insulinize them. Study, this is the study that I published a couple of years ago. 63% of them are treated with insulin. Many of them don't need any treatment, and that is a population, it's called burned out diabetes. Terminology to discuss this is appropriate or not. We plan to do some studies. And about 17% of them use something else that is not insulin, right? Well, when you compare insulin therapy to no therapy, insulin was associated with a higher risk of hypoglycemia and a higher risk of hyperglycemia. So it's not that we're doing better. The notion that insulin is the safest treatment in patients with severe CK or advanced CKD is not true anymore. We have safer agents, okay? And I'm gonna show you in a second. And don't, look at the risk of a DKA and hyperosmolar crisis bearing the limitations on the study. My own study has limitations like everybody else. So 72% lower risk when you use no treatment compared to insulin for DKA. What is that? So it's like, I was like, what is this? So this data, please don't take pictures, it's on the review, but it's just showing how we treat these patients in the country. This is 10 years data on how we, five years data, how we treat them. This is USRDS data, all patients on dialysis in the country. So on the right is different insulins. So I was glad to see that we're using more basal insulin and we're trying to decrease human insulin, but I was not really happy to see, on the other graph, the glucagon. And glucagon is one of those lines below the 3%. So these are patients with severe hypoglycemic events requiring ER visits or hospitalization and then got discharged and less than 5% of them had a glucagon prescription. So if you ever wonder what is the treatment for severe hypoglycemia, remind your colleagues that less than 5% we prescribe the glucagon, right? Especially if you're in dialysis. So anyways, on the other graph, a little bit more interesting. So we're using a little bit more DPP-4s, whether it's the right treatment or not, I will discuss in a minute. And then we're decreasing the sulfonylurea prescription. Good, right? So we have better agents nowadays. And then all the way at the bottom, less than 3% GLP-1s and all of that. And SGLT2s, of course, this is probably not the right treatment. So why do I do in my clinic? And this is basically expert opinion or clinician, because the data is very scarce. So my hyperglycemia, basal insulin with enagliptin or other DPP-4. The enagliptin just because you don't need to be adjusting the dose, but if you use enagliptin low dose, you don't need to adjust it either. So that would be a choice. And then I try to minimize over-basalization or over-insulinization, because again, it's not the right treatment based on the data. If they get a lot of meal-related hyperglycemia, and how do I know this? I put CGM on them. I'm sorry. So we have been pricking their fingers for so long, and the data is not good. And the A1C doesn't tell me the full picture. So I put CGM on them and I learn what is going on. So if they're having a lot of prosponding hyperglycemia, and it's mostly after dialysis, so they fast, come to dialysis, three, four hours fasting, and then after that, they're really hungry, and they're gonna eat. And then they spike. So it's the rollercoaster. So that's why I can really work a little bit better if you put CGM. I use repaglinin instead of short-acting just because first, when you tell a patient, I'm gonna get rid of the three injections per day of short-acting insulin, I'm gonna give you pills, they love you as a physician, right? But mostly because a lot of hypos when you over-insulinize them, right? They need to have still some better cell function if they don't make too much insulin and different discussion how I figured it out, but not getting into that. But I'm using a lot of GLP-1s, right? Why? Good agents, simplicity, and I'm gonna discuss some data that is gonna probably show you that it may be. So dulaglutide, semaglutide, those are weekly, and I show you they don't have any limitations based on the GFR. Dulaglutide is daily. Lixizenatide has some secondary outcome analysis showing that decreased albuminuria, but you cannot use it in this population. I'm just showing you for comprehensive evaluation. So this is K-DIGO. So if you need a reference to use GLP-1 in this population, K-DIGO guidelines, right? You can also go to the label, right? And we review these labels all the time. I have like two papers on the review and we review the labels all the time. So you do not need to do those adjustments for dulaglutide, liraglutide, and semaglutide in patient with GFR less than 15. You do not need to do those adjustments for those three agents. But there is a comma or a period in the label says limited data, right? And we all know why, because it's a very complex population. That doesn't mean we cannot do good for our patients, right? So not having data doesn't mean we cannot do good. So anyway, so this is what is there. You can cite it. This is a paper that was published less than a month ago. It's just some emerging data showing that GLP-1 may be a good choice for these patients. So this is comparison with GLP-1 versus DPP-4 in patient with advanced CKD at stage four, stage five. And what it's showing is that GLP-1 was associated with a lowered risk of events. And I'm just highlighting there mostly sepsis and infections related mortality. So these people get a lot of infections and acute infections and many of these complications and also lower mortality. So keep that in mind. And then when you adjust it, when you do some propensity score, that's the bottom analysis all the way to the end, there is a lower risk in this when you use GLP-1s. And this makes sense. We know this from other populations. So some data that is needed, flow trial and remodeled trials. So remember liraglutide and semaglutide show some benefits in CKD, but it was secondary outcome. So NOVA is doing these studies and hopefully it's gonna be done soon. Some data for liraglutide. This is the lirarenal trial. Not gonna get too much in detail because I want to discuss the next study. But basically this population have moderate renal failure. So it's extrapolation of the data to the dialysis population. There is not too much data on dialysis. So you get good A1C reduction. The first graph, label A. And you get more patients achieving that target. You get better reduction of fasting plasma glucose. And you also get some weight loss, not new. The issue is here. So basically if you compare liraglutide with placebo, you don't get any changes in the GFR if you have moderate renal failure. Again, flow trial and remodel will let us know if liraglutide or semaglutide is the right choice. But anyway, some data. So caution when you use GLP-1. More side effects, more nausea, more vomiting, at lower doses. That's fine. That's fine. You don't need to use the maximum dose if you're doing good, right? So you can use a lower dose. So this is a study that I really want to emphasize because it's probably one of the strongest data that we have for these agents. So dulaglutide versus basal insulin glargine in patients with moderate to severe CKD. Cut it in total. The first out of all is in Lancet. So 30% of this study had a GFR less than 30%. So not a big population, but so far good enough for me to make adjustments, to make good conclusions. So 30% of this sample have severe advanced CKD. Walking you through the slides. So A1C reduction on the vertical axis and then on the horizontal, 26 weeks and 52 weeks. The first line is dulaglutide high dose. Second, dulaglutide low dose. And third dose is basal insulin. As you see, there is a better A1C reduction. There is a better A1C reduction when you use dulaglutide. And what is really, really interesting is the second graph is basically you may then lose some weight. And you may wonder, well, these people are on dialysis. They're not supposed to be overweight. Well, unfortunately they are. So in our studies, 80% of this population have a BMI more than 28 and like up to 60% more than 30. So we're dealing with a population that have excess weight or excess adipose tissue, ABCD. So anyway, so dulaglutide, really good results. You get really good A1C reduction and you get some weight loss. And then this is basically GFR changes. So we already know that dulaglutide simplify less injections, less risk for hypoglycemia, better A1C reduction, some weight loss. Well, what about GFR? Well, if you treat them with glargine, with insulin, they get some decrease in the GFR. If you treat them with dulaglutide, you don't have that. So the 40% decline of progression to NSA kidney disease. So basically if you use dulaglutide, there is a 40% lower risk of progressing to NSA kidney disease. And then on the second graph is basically the GFR graph by all those. The first is dulaglutide high dose, second dulaglutide medium dose and the third is basal insulin. Basal insulin, you see there is a decrease in GFR of about three points, but the main point is that with dulaglutide, you don't get that. So I don't have any other studies comparing to, let's say deglutide or levimere or something. Everything is very preliminary, but I think this is good. So let's just move on to insulin therapy. I have some minutes. So overall, I said already, do not, do not, do not over-insulinize them. And I'm not gonna make more emphasis because you guys are gonna be mad at me. But basically we need to test if that glycemic control makes a difference. But again, we don't need to be strong like 3000 patients to just show that you do some benefits and all the complications. Start with low dose, so 0.25. There is a study on some CKD patients done in the hospital. They did that dose and it was associated with lower hypo. So I tried to combine basal insulin with non-insulin agents and try to minimize the amount of insulin. And do please avoid mixed insulin. It's very hard to adjust it. They go to dialysis three times. The other day that they don't go, you need to change the dose. If they go in the morning, they are fasting. Or if they go in the afternoon and they were not, it's not the right choice. I have people on it because I have no choice. Insurance sometime determine what we can do for our patients. But probably not the best choice. Very hard to adjust it. Very difficult to really get a good control. And basal blood is probably the last choice. It's just because too much hypoglycemia and too complex. All the study over like 20 years, but it shows how much insulin we need to decrease going all the way from GFR of 80 all the way to a GFR of 10%. So what percentage of insulin, what is the percentage of decrease in insulin requirements? On the top is type one, at the bottom is type two. And the table is just summarizing it for you. Just to make it simple. So when you have a patient with type two, the magic number is to reduce about 50% when they go to any stage kidney disease compared to when they were before going on dialysis. And for type one, about 38%. So there is some data also on CKDs, early CKDs. So I try to recommend lowering 20 to 30% of basal insulin. In early CKD, they start low dose and decrease 50% of the basal insulin for type twos when they go on dialysis. So they have a stage five. And then decrease also basal insulin the pre-dialysis date. This is based on some studies using CGM in the past. We won dialysis session, we're doing some analysis. I think that we may need to change that recommendation. But anyways, keep in mind that they have a big significant reduction in the amount of insulin they require. Not to say that there are closed loop studies. This is a study for Charlotte Bolton in UK. She just presented this data two weeks ago, but the data is already published a few years ago. This is control, no control IQ is a closed loop system they use in UK. They use Dexcom G6 with the University of Cambridge insulin pump. And then basically shows that in the closed loop is this salmon color. And then in the gray area is the control. So you have an improvement in glucose control. The big comment on this study is that regardless of closed loop, the mean glucose was in the 180 to 200. So maybe they could have been a little bit more aggressive, but I think that they were really very careful because it's new and they didn't know. Anyway, so don't, I would not recommend that everybody on dialysis need to be on closed loop. I think it's a lot of burden for the patients, but some people actually would do fine, especially type ones, different discussion to have. I do not have too much data on peritoneal dialysis on this presentation because it's a full lecture. It's a different population and they are really complex. But I'm gonna walk you through some cases. This is gonna be published very soon. This is a patient with 58 female on dialysis. She's on multiple daily injections from insulin. She was referred to us for hypoglycemia during dialysis. And she's checking two or three times a day. So she's really doing a lot of work. But when she goes to dialysis, she doesn't do it because she's in the dialysis center, everybody's watching her. Why am I going to be pricking my fingers? So the issue with her is that she was having prolonged hypos after, and I don't know if the answer was to change the treatment. I changed it, but I think the answer was to put a CGM on her and know what was going on. Very hard to assess how this goes. So we put a CGM, we learned that she was having prolonged hypos after dialysis, I stopped the bolus, put her on dulaglutide, low dose, and she's doing really good. And then the other point is that she learned that she needs to eat some proteins and some snacks before going to dialysis and when she's on the center, because going fasting for so many hours may not be the right choice, they don't have good gluconeogenesis to compensate. The second case is actually not from me, from Seattle, this is from Ian DeBoer, he's running a big study with 800 patients, he's putting CGM on them and see what is going on, so really a lot of data coming, it will take some time to recruit 800 patients on dialysis, but this is a study, 79 with type 2, she's a veteran with diabetes, and she's been on dialysis for five years. She goes midday, so she's not early dialysis, 6 a.m., she goes into the midday, it's usually 9 to 10 a.m., and that matters because they tend to eat breakfast. So she's using low dose of insulin every night and the A1C is 4.8. Don't be surprised. When we started doing our studies with CGM, we needed to modify the inclusion because A1C could be 10 or it could be 5 and it doesn't give you a reflection of the glycemic excursion, so it's actually not really a good marker. You can get an A1C of 5 and they are getting 300, you can have an A1C of 10 and they're getting hypos. So the most recent glucose was 128 and 147, when you see that, you actually believe that she doesn't need any therapy and you would probably stop the therapy in somebody with an A1C of 4.8, right? Well when you put a CGM, I don't think that that was the right thing because she's actually having hyperglycemic excursion, the timing range is only 44% and she's having a lot of hyperglycemia up to 30% more than 250 and I see this a lot. I see this a lot in our studies. So keep in mind that that burned out diabetes based on A1C less than 5.7 or less than 6.5, so stopping the medication is based on the wrong assessment of glycemic excursions, okay? So not the right tool. This is a type 1 patient, actually a patient very familiar to me. She's younger with type 1, she got many years of type 1 diabetes, she was progressing from CKD 3 to 4 and then she was referred to us because she was having severe hypos and severe hypers and what we see all the time, urgent referral to endocrinology because of roller coaster, right? So she was using a 670 but not really 670 because the sensor never really worked for her or she didn't like it or the pump, she didn't really and then I said let's just see what is going on. I put a sensor on her and as you see she had about 28% in hypo, so the reason is she didn't trust the bolus, she was bolusing herself because the kidney progression, the GFR was dropping, she was getting a lot of insulin stacking and getting a lot of hypos, so I made her wait, made her to come back in a week and then I decreased the basal insulin right away and I say we're going to let you run a little bit high, we're going to see how you're doing and then this is first week, just learning what was going on, family was very afraid, she got two kids and the family would not go in the car with her because when she goes hypo or she feels bad, she goes like bad, bad person, so the family, a lot of impact on the family dynamics and the quality of life. So a week later she's coming and then of course she's running a little bit better, she's running a little bit high but at least she doesn't have that much hypos anymore, so I start working on sensor with a predictive early loss soon, so she needs that, but she got Medicaid, so I needed to talk to the chief of pharmacy of Georgia Medicaid to get that approved because different lecture but I'm going to do one minute of that. So in Georgia to get a CGM you have Medicaid, you need to be seen by an endocrinologist that is registered with Medicaid and that end up being only 35 endocrinologists in the whole state and all of them are in the center of the state, so of course if you live outside the center, you don't get CGM if you have type 1, so different discussion, so talk to your Medicaid and try to get your patients the right technology. So anyway, so she was very afraid of the correctionals, we tried to help with the CGM, she was doing a little better, but she would not trust the pump, she would not trust that bolus wizard because she's very afraid she's going to go low, so a little bit of training, when she got the sensor, she got a Dexcom, she was put on Basal IQ back then, she started doing a little bit better, it still was not very friendly with the bolus, but learning and more she started gaining some trust, and of course she started doing better, and then I think that we transitioned her to control IQ and of course she's doing much better, and the only issue is that she's gaining weight, so she actually gained like 20 pounds, meaning she's really getting right insulinization by eating too much probably, so working on the carbs, that's a different lecture itself, so our nutritionist is always giving me advice. So a nice review by Cathy Tuttle, so make this comprehensive, this cannot be only endocrinologists or diabetologists, this is a very complex patient that needs integration with other specialists, you also need to work on the blood pressure, and also on the cholesterol, and then bear in mind that A1C may not be the right number, and the limitations of capillary glucose, CGM may have a role, data coming, and if we don't have studies that we can put strong recommendation, that doesn't mean we cannot do really good things for our patients in clinical practice. So in summary, we need a better way to assess glycemic excursions in this population, the finger sticks don't give you the full picture, GMI may be a really good choice, our studies need to be more studies, we need more studies, and of course we need a new formula for that GMI calculation, a boil over insulinization, and newer agents like DPP4 or GLP1 may give you a better choice to prevent those hypos. Of course we need to include this population on the studies, so I see many colleagues from different companies, so do please include this population, we need to do something, we need to do better for them. So we have like 12 minutes for questions, I was a little bit fast, I was told that there were many questions with Dr. Tuttle in these lectures, so I want to give you some time for that. Thank you, this is my email, happy to share, if you can go back, happy to share, if you can go back, they can get my email, alright, I cannot give you my email, but the purpose of the last slide was to give you. So this is my email, happy to share any articles, the presentation, whatever you need, always happy to share, and this is a picture from my daughter in Spain, telling me that, this is a very old mesquite in Cordoba, and he's just showing that light crossing those old doors, so new technology crossing old doors, so happy to take questions and Neda will be the moderator. Yeah, thank you Dr. Galindo, it was a great talk and a lot of information, yeah. For sure this is population that it's very challenging to take care of their blood sugar with all of the excursions, so I stop and I will start from this side, would you introduce yourself? Thank you, Dr. Sultan from Saudi Arabia, two questions, how safe is the ribaglinide in those dialysis patients? So a couple of studies, 10 patients here, 20 patients there, most of them are actually from Asia, there is one study from Europe, very small sample population, I don't know, I just know that bolus on time is not the right choice, so remember, there is prolonged time of that insulin action and then if they are fasting for 4 hours and they go on dialysis, the sensitivity gets better, and then they have different pharmacokinetics and pharmacodynamics after dialysis, so what are we doing with that bolus? So I do low dose of ribaglinide, I make them happy, I make them check the sugars, they're happy because they are not doing so many boluses, if it works, great, CGM will let you know, if it doesn't, then you need to put bolus, but the burden of treatment is important for these patients. So imagine doing 4 injections a day, 4 finger sticks, going to dialysis 3 times a week, fasting 3 times a week, going to cardiology, by the way, they don't see the endocrinologist, these people are busy doing that study, very poor diabetes care, very poor retinal screening, very bad other comorbidities of screening, so anyways, I just do it, low dose, see if it works, the CGM, if it makes sense, I increase it, if it doesn't make sense. Okay, what about the ultra short insulin? I don't know. Not yet? I don't know. I think that there was a study from Ulrich, from Europe, again, a pilot study in one of the clinics, but very limited data, very limited data, email me and then maybe we can find the information together, but I think that very limited data there. It would make sense, it would make sense. The issue again with bolus is hard to time their meal intake and their bolus administration. Sometimes they eat, sometimes they don't eat, sometimes they are fasting, so I try to use something that is a little bit safer. Thank you. Alright. We go to the next question, and if you don't mind repeating the question so everybody can hear what the question is. You say considering aspirin, other studies show decreased mortality with aspirin, because I think these patients have high risk of bleeding. You have considered aspirin. So that was the last slide. So not really the expert in cardiovascular prevention in this population, I was just citing the article. Yes, high risk population, but remember they have other indications for that aspirin, it's not basically diabetes and any stage, they have probably other cardiovascular disease, so I think that it's based on the overall assessment. You're right, so risk and benefits assessments, it's always that. But again, my feeling is that with these people on any stage kidney disease, the impression is they are really any stage. What are we bothering, right? So I feel that sometimes we minimize care by the fact they have an any stage organ damage, but the point is that they can get other comorbidities, right, and other complications. And again, it's not the same being on dialysis with, you know, carcass or heart surgery, right, or amputation. So we need to prevent the other complications as well. So basically risk-benefit assessment of the patient. But you don't remember any studies specifically with aspirin? Not that I can recall. And one more, cancer or cardiovascular disease, what is more? So your question is cancer, and... Or cardiovascular disease, what is higher prevalence or incidence? So, cancer or cardiovascular disease... Because these people die of cancer, cardiovascular disease, infection, three. So we're always concerned with the cardiovascular events and everything. I'm sorry, we always, for example, the early CKD population, we're very concerned with the cardiovascular events and everything, and that they don't go to dialysis. So actually, they get a lot of cardiovascular events even before they progress to dialysis. In dialysis, I think that the risk of cancer is a totally different lecture. So that will be based on many other factors. But they do have a very high risk for cardiovascular events. So and they also probably high prevalence as well. Imran from Pakistan. I would like to know that, what is the correlation between the A1C and the CKD one? And what should be the target levels of the A1C when the patient is on the dialysis? All right, so your first question is, what is the relationship? Correlation between the A1C and the GFR. So what we know, that the estimating of the A1C levels in the patient of the chronic kidney disease is not the worthwhile. Because all the time, the A1C level is changing with the dialysis. So estimation of the A1C all the time with the patient of the dialysis, in my sense, in my opinion, is not the good indicator of glycemic control. You're 100% correct. So he's saying that the A1C is not a right glycemic control indicator in patients on dialysis, and that is correct. And there are many factors. So they have anemia, they're getting iron treatment, so many other factors. So we do know that A1C is not the right glycemic control marker. Still, KDega says that that's what they have, and it's probably because they don't have other data. But maybe we're going to be moving away from that. And your second question was? What would be the targeted A1C level in the patient of the hemodialysis? So based on some meta-analysis of about 10,000, 20,000 patients, there is a J curve. So if the A1C is above 8.5, you start having a higher mortality risk. And if you also go below 6.5, so the recommended target is 6.5 to 8%. Thank you very much. Next question. Good morning. Thank you, doctor, for that talk. I am Maria Sanchez, internal medicine resident in St. Barnabas in New York. I just want to know your experience about using DPP-4 inhibitors, especially linacoliptin, in hospitalized patients with advanced CKD, trying to avoid hypoglycemia. I know you gave us information about outpatient setting. So I will split your question in two. So one is use of DPP-4 in hospitalized patients, and the second question is use of DPP-4 in dialysis patients. So Dr. Pascal is in the back. He's one of the experts in hospital diabetes. He just published a paper a few years ago in Lancet using the sitagliptin specifically in patients with type 2 diabetes. And yes, it makes sense. You just need to find the right population. So mild to moderate hyperglycemia on admission, less than 180, less than 200, you will probably control well a hospitalized patient with some basal and... I'm sorry, the experts in the audience, if you want to make a comment, you're welcome. So anyway, so you can use sitagliptin for the hospital. Our group has published that. We did not include dialysis patients in that study because it's very complex. But yes, it makes sense to use it. So I use a lot of DPP-4s. The problem is that sometimes they get severe hyperglycemia and the DPP-4 doesn't provide them with enough glycemic control that they need. So I always start with that, especially if they were having high pulse, super-insulinized, having high pulse. I try to transition away from there and use the lowest risk, right, and I use DPP-4s. But then I end up a few months later not getting good control. So that's why I was giving other choices. My hyperglycemia, doing a good job, it may do it, but most of the time you need more than that. And then I tend to use a lot of GLP-1s, weekly GLP-1, because of the simplicity and everything. Dulaglutide has some data. The other fact that I like about Dulaglutide is the pen. So you say, if you have poor dexterity or you're partially blind, as many patients in a lot of complications, you just turn it, it's green, push it, throw it away. So you don't get mistakes on the dose. I have tried all of them. And then sometimes you get the high dose, the low dose, they are confused, they don't see it, they don't understand it. So that one helped me in that sense, but insurance always dictates. But anyway, so DPP-4 will work. Not enough, most of the time. Okay. Thank you. Good. There is a question this side. Thank you, Dr. Galindo, for such a fascinating lecture. Rivka Shulman-Rosenbaum, Northwell Health. I have another inpatient-related question. So for the patients who are going to the dialysis unit, right, and they're missing their meals. Uh-oh, he's cringing. They're missing their meals, so they don't get their pre-meal insulin, their sugars are going up and down. Have you tried any interventions working with the dialysis units to make sure they get their insulin at the right times? Or have you tried using insulin regimens on different days of the week from the inpatient standpoint? So, Dr. Shulman, I had the privilege to train with her. So she's a former professor of mine, and you have Roma Janchandani in the front. She has published on this and she has reviewed the data on dialysis in the hospital, so more than one paper. So I do not have any experience. The reason is the dialysis unit is hard to work with. The nurses are always changing. The time is never on schedule, but I would think that it makes sense. So the point for these people is you need better personalized management. So on basal bolus, so we come from the rabbit trial house, and we are bringing new data saying that maybe basal bolus for everybody is not the right thing. So for the inpatient management of diabetes, you have another lecture. Maybe more personalization is the right way to go. For that population, Roma can explain, please. This is just a debate. We have just a few seconds left. Very quickly, Roma. So quickly, these patients do very well if you give them their long-acting insulin in the morning, because most of their hypoglycemia is in the morning before dialysis. They also do very well with linagliptin and basal insulin. And if you use repaglinide, actually, you can use it twice a day, breakfast and dinner. You don't need the lunch dose. It lasts for so long. So some of those are indications. And working with the dialysis unit is very, very difficult. Very difficult. So anyway, so it's very good to have colleagues and experts in the audience, so you don't need to take the question yourself. Yes. Thank you so much for an excellent lecture. Elizabeth Obiello from Texas, endocrinologist. My thoughts and my question is on the ratio of endocrinologists and patients in the state of Georgia. So I was wondering, have you tried e-consults, telehealth, video visits? So the question is that we don't have enough diabetologists to care for this population. And it's not just for this population, it's for the diabetes population in general, I guess. Yes. So unfortunately, we need to have a pandemic called COVID to learn that we can do remote patient monitoring. And then, I mean, we knew it, right? So we always knew what is right. So we're physicians, right? But insurance and everybody else, they were not really convinced. So COVID came, put a lot of people sick in the hospital, and then we learned that we can do remote patient monitoring. So the point is that we did it without data. Now we're doing the studies to prove that it's good. So yeah, we have done it. We do it a lot. And I know a few colleagues in Texas, actually, I can connect you with them, that are working with rural areas and doing remote patient monitoring specifically in this population. So most of these patients don't go to see the endocrinologist. Most of them don't have a PCP. Their PCP is a nephrologist, and diabetes is the 10th item on the plan. So it's always at the bottom. So I have a colleague in Texas who is actually doing work on this. It's also because it's a closed system with a, what should we call it, ACO. So it's insurance. And then they have an agreement so they can care for all the patients and do more. But yes, it would definitely be a good choice, a good approach. Thank you. That was a great closing statement, and we are out of time. If you have more questions, you're always welcome to come and ask Dr. Yalindo here. And thank you, everybody, and hope you enjoyed the session. I personally learned a lot. And thank you, Dr. Yalindo. Thank you.

type 2 diabetes

advanced chronic kidney disease

glycemic control

hypoglycemia

hyperglycemia

glucose monitoring

A1C

glycated albumin

fructosamine

individualized treatment plans