In this Grand Rounds presentation, Zachary T. Bloomgarden, MD, discusses glycemia and its impact on health outcomes, quantifying glycemic exposure, and glycemic variability.
All right, so we're gonna get started. I think people will continue to trickle in here. I dissolved in the case, So I have the honor of introducing someone that we all all know pretty darn well Zach Garden, who is going to be given, I'm sure a very, uh, elucidating talk of beyond. They would see him excited to hear about it, so everyone knows that. So I'm gonna give sort of a few a few lines. Here is an introduction, and I was intrigued to sort of see your background here, where you trained Princeton with a senior in a mathematics that was 45 pages and that with that line, it's time for his med school. He then did internship Montecristo stuff like you stay there for a period of time and then ventured out Commander Bill for his for his fellowship and then right back to New York. And you've been we're gonna try Thio, people who've been aside from the beginning of which, you know, for all of your your, you know, professional career. And that's everyone knows. Zac has had a very prolific, um career from not only a clinical perspective, but it's well from publication and interest perspective. He has been the lead on the head of the general diabetes. So for many years, which impacts for such matters. Um, you know, over time. And it's been very impressive. A couple of articles. You've given us a nice feedback on and always has a very nice to say about various areas of diabetes on we look forward to toe talk, Thio. Thanks, Carol. So this'll is. Actually, my computer died, and I thought I was gonna copy the file from my laptop. And so I e realized that I just gave you talking shame. Yeah, way. Actually, way could have I was able to find by email that said it. So it was Here s Oh, this is kind of extension of what Over talks about. I would tweet. Uh, that agency is I'm extraordinarily useful test that we all love. But there's a lot to and so we'll talk about another area a little bit. First, we'll go over a little bit of what girl talked about. Um, here is my multiplicity of interest. Eso we'll talk about, uh, different approaches to quantity. Places exposed her What a once he might mean But then I'm going to spend most of it talking about Chrissie the variability, what that means and what you should see variability, because variability. So, um, so glad to see me is clearly related. Out are four million studies show it. And here's one that was just published by these Kara with about 300,000 person years and follow up looking at fasting, blood glucose and hemoglobin a one c n showing that both women and in men um, cardiovascular outcomes, Greece, individuals, uh, either with higher fest glucose at higher would see. Interestingly, this analysis they also published just fasting glucose versus showing statement. So wait. So here the previous one was vastly goes. Here's fasting with those and they would see um So how do we quiet the exposure of a given individual too? Oh, group net fax. Crucial place off. And I've thought for a long time Yeah, it would see is often this leader see patients that you want to see, and I say it just doesn't exactly makes sense. Eso about 10 years of the on Derek Soviet TV Oh, Ellie carton. But melting. Who's here in Israel? I think. And it was common piece in diabetes, Ojea. Um And around that time, uh, article, uh, with Erica Patrick implosion on the same thing and I had a piece of care on it. And particularly, it annoys me that people use they want to see so Catholic literally for diagnosis of diabetes. And so and I'm 29. Oh, practice on the topic is that the data is just not that good. Um, so this is a review that Emily Gallagher and American Idol diversification, uh, this figured that Emily did totally e, uh, is kind of sums it all there are on this year, you see black Asian of hemoglobin off. And so that's the piece that however, the whatever the prevailing glucose level is, it attaches to the booth failure. Um, and that is proportional budget level. Although it also is affected by injury with th yeah, on. Then there is actually deep location is with site on. A lot of these probably have genetic control, a variety of factors. And then there is a red cell turnover. So with greater Aretha appoints this or with greater with science construction, you'll sleep, please. Different levels. They wouldn't say. Um so here's a study I did with people from divine really are where way took individual patient data from a number of trials hold of insulin penetration where we had three days of seven point profiles and they wouldn't see about this. And what this figure shows is that at each a one c grouping so greater than 9.5 8.5 to 9.57 point 58.5 and so on. If you they do a frequency history, graham, and then add it all up, you'll see that about 10 or 15% whatever curve you're on are well below. So here's the average. So indeed, um, if you're a one c is 7.5 April 5, you're a wouldn't see your mean plans with glucose. Is that eight levels? Police. So So that's this. A P H G concept they wouldn't see survived average glucose. But there are plenty of people on the lower end of their actual include post. And there are a lot of people who have a meat glucose and a one C is way better than they deserve sexually, if you will, Um, so this is part of the issue Um, here's A and nights of analysis that came out from a study where continues glucose monitor and was done. And in individuals not having diabetes or people with early type two and rather low a one scene or people with types of it, they want to see over 6.5. Here's a fairly substantial portion off the, but they would see that explained. That's explained by non classified factors, particularly though people don't have diabetes. So if you have you don't have diabetes, you happen to be highlight later. You may look like you're in the pre diabetes or even the diabetes training. It's not true. This is particularly point. This study was done in order to point relationship a onesie and being placing gods began, and so they excluded everyone. Everyone with everyone had anything wrong. So in a really population that we can take care of a one scene is not particularly a great chance. Um, so here's a wonderful article just came out of the A, C E N F. And Robert Cohn has been involved in this whole question off. What do you know? Why do they wouldn't see it because not always had for a long time of it. So I love this layer that I just gonna read part of it to you. So emphasis was not on those individuals who discrepancies because even moving off that everybody knows get a sickle cell disease agency slower, etcetera. But rather those with normal hematology who's a onesie include those missed each other by just enough. Not make sense exactly what we see his conditions. This is for continuous monitoring, etcetera. So he said, I'm asking fellow clinicians they're generally responses. A. I see at least one person a week with this issue, but I don't have time to think about. A lot of people would say or e sort of came from patients not reporting their fingers. Six properly or yes, repair irritable. Um, but actually they're studies going way back, which show that that they would see is sometimes Highland high plug, sometimes lower. But I think the one would expect, based on because tolerance test or or other measures. So, for example, definitely Americans happening here, higher blood nation than non Hispanic whites. Um, so here's a study, uh, looks at the association. They wouldn't see, uh, with good looks in diabetes prevention on in non Hispanic whites and African Americans. And these basically everyone was involved with certain high level productive. So we do. They're all about this, um, in their fasting glucose levels were one oh, seven. You know, a tow, our blood sugars. 65.64 but a one C 5.86 point two. So a 0.4% different. She's quite a big difference. So all the way on the right is a one C versus. Sorry, uh, continuous glucose monitoring mean glucose versus from toasty the middle is GM average versus quite hated album. And African American Hispanic worlds are on exactly the same line. No significant difference. But on the left is a one say versus CPM, me and the lines. So it really matters. Um, so that's one part of this. But the other part of this book is quite simply variability. So ask you think about it and worry about it. You you you know, he s finished constantly. Earth phase by but higher, lower. So here is unfold Our first issues of diabetes care, like John Services, Famous person clinic, way back when Andi he said here is an unstable diabetics. Here's a stable diabetic. Here's a normal person. Look at the tremendous variability. Leisure. So it's not like we just discovered it today. Um, and, um, any proposed a variety of different measures being glucose being amplitude of placing excursions? Age? Um, some people, an end value view, daily differences. What are these fitted over in our present on C G M analyses that we get either from text or from Apple? Um, so he's actually have important differences on this is an interesting study, which took a look at individuals with Type two on multiple daily insulin injections and said, What about the, uh, coefficient of variability off continuous glucose monitoring? And what is that related Thio. So here, as the C V off the glucose goes up, these were people with Type two diabetes, so there's a big range of C peptide, and those who have mawr endogenous insulin have less pricing variability. Those who have less have more guys inventory ability. That's clinically quite important because it translates into differences in frequency of type of icing in a very major way. Um, so we know about that. Are there other things that variability most is associated with. So this is kind of the interesting, important study that was published diabetes care with few months. Um, this took three individuals who were possibility with my, um he put on his trip, Um, so that were, you know, moderately sick. But they said, what are some of the factors that were associate ID with subsequent complications recurrent and my or stroke or, uh, cardiovascular death so higher. Carter Disease, smoking, cholesterol, LDL, less pain, triple a million factors, you know, various analysis, But in multi variant analysis, history of prayer, coronary organ, syntax score, which is so something drive from how bad the primary Andrew Grant is left ventricular ejection fraction less than 40%. One. It took all of the blood sugars that we've done during the whatever for thio undated. They looked at the quite civic variability off those bunch of so stated that we have in every hospitalized in theaters. And if the Istinic variability, however they measured, it was greater than 2.7 million. Its leader that those people were at higher risk off a. So look at that. All of this complicated pretty bastards and then our blood sugar on, but also attract with had a mission. Blood sugar, I mean, because we're with development type of places. So a lot of place stupid factors, okay, are extremely important for credit vaster outcomes. Hello. Um, here's another very similar study. Um, 200 people post semi on ivy into for hyper place e. Uh, and if you look at this syntax court or tile, those who were in the the worst syntax portrait, the hottest that's this job service Uh huh. That you're meaning amplitude question variability. Um, and what was associated with high fly civic variability? Sex, syntax, score? It would see a bunch of her racial diabetes, instant therapy. So a lot of the things that we worry about, but there is this issue that archaeologists say. Well, the book sugar. Okay, you take care of that. We're gonna worry that I couldn't stay. Not so simple in patients with diabetes. Um, so, um continues with a little bit of a digression. See, GM is modestly effective in are going to see in type one diabetes and in tattooed. I think so. We certainly are increased. Truly deciding this is a passive do. A lot of our patients. And one of the things that we can get from some is thes measures of my city variability. So this is a graph that looks pretty much like that John service graft. But this is from a much more reason our hero Perez here few months ago. And so you take the but seemed variability given individual. Here's over a 72 hour period and you get time in rain. Uh, yeah. Amplitude Replacing the variability a lot, uh, of factors can be calculated, which you're very useful in addition to just yeah, being glucose. Um, so here's from, uh, problem Rogowski, um who said look the time in range. It's just another way of would be placing variability. He is a very easy way of expressing this ocean off. That's the being pushed. Wouldn't see are not everything. So he has three different curves. Um, here's a patient who stays 100% with 70. Here is a person whose up and down and up down here, someone who's got less variability on point of this graph is that average these curves they have to be for yet we know they're not the same person. Oh, and, um we have all these measures of placing the variability, um, standard deviation of the media coast coefficient of variation of glucose, age, etcetera, etcetera. Um, And then we're going to talk about visit to visit. But there's also a loan terms quite similar variability, which is quite important. Um, so this is kind of similar to what we talked about before going to the variability off as another important factor off beyond mean glucose. So here's me look. 200 people with type two diabetes. Uh, this is from money. A on the older study looked at individuals with type two diabetes, no symptoms of hyperglycemia. And the question was asked when you do I think this was a three day see GM and you want to see how many people or 48 hours how maney hypoglycemia events. Yeah, who have in various groupings those who had the, um, the lower mean glucose and the greater degree of flexing variability. You're measured by the standard deviation. A bunch of group actually have the highest. We had a worsening events, which makes perfectly good sense with a one C. It's actually a little different that if you look at hemoglobin a one c versus hypoglycemia, and you look at the standard deviation. Those individuals with high standard deviation of blood sugar have, um, mawr hyperglycemia. But those who have low a one c have higher level of hyperglycemia yet, but also people who have high a Wednesday more absolute placing. This is kind of a factor that's very important in interpreting the court set where we brushed the emotion that wouldn't say associating adverse outcome. You don't worry, be able to see overly issue. But actually, it's probably more than in individuals with poor writing control. Make them extremely off essentially a futile effort. Lower blood sugars, then you know, because I loathe without necessarily improving overall by ischemia. Um, So here's, um, another analysis of the same thing on I'm just showing you that a number of studies on this topic off his men. So here's type of icing universes, pricing variability, looking at, um, main glucose and standard deviation of glucose if both their abnormal, that's when you have a most type of like India. Um, and, um, The other point, though, is there. If you want to stay well, what about other complications? It turns out, look like seaweed variability, it's strongly assert, not just with having place the media, but with a lot of bad things. So there's a literature that we're gonna explore a little bit. Catherine scored a vastly. These forces crises variability, Um, but certainly hypoglycemia tracks with SCV. Whether you look at, uh, individuals with a history of Mac microvascular, everything's. Or if you simply look at the charity internal medial thickness, you could find that there's a strong relationship between these, um, use because monitoring tracks off with your apathy. So what are the factors that are important? Well, here's an analysis of major versus diabetic for property showing that the area under the curve is 0.75 So pretty sturdy as a marker off by city, a mark complexity and variability than the predictor of diabetic neuropathy, uh, or economic Iran much the same findings. So if you look at the standard deviation of budget or made or the coefficient of variation, standard deviation divided by the mean find that there are significant relationships, many of these parameters and autonomic dysfunction, Um, but here they went a step beyond that, and they said, Well, if you look carefully and do multi variant analysis. When you look at, um, how did all these factors work together? Um, in multi variant analysis, short term measures of flexing, variability or not and strongly associate ID as long term measures of placing the variability essentially variability of they wouldn't see is really important. So if a patient comes to you, they, they would see, is 71 month and I've quit three the next month for three months later effort. Those individuals are better or worse and better and worse seem a particularly at risk on. So if we go through these measures like scenic variability, this last one visit visit changes may be something that we essentially, we look at definitions. He look and we see Well, now it's better. But before, it was worse. Alex comes Chris again. Um, but it is going to be very important. So let's look at the data on a one C. Variability. Um, first of all, what does it represent? Um, so here's, um, a very interesting study from humanity care journals, which looked at, um, a one c variability court tiles, or it looks like quintiles actually. Um and then are the likelihood of donit areas. So it appears that those individuals highest gentile off. They would see variability also were 3.5 times more like not good. There's a variety of ways fighting makes perfectly good sense clinically, but this suggests that there may be a really important explanation. So here's another study. Individuals with Type two diabetes looking at they wouldn't see standard deviation. Turner tithe. Highest versus lowest. Are they looking? Age sacks? Rachel Diabetes, Diet insulin therapy that kids? Um, well, a number of factors appear relevant but very interesting. If you look at social presence, which we know tracks mhm, among many other medical grounders ability. Phone graduate. We see that there's really a shift in distribution, so those with lower a onesie standard deviations seem to be relatively evenly distributed across all social classes, whereas those with high frequency variability our have a higher district of higher percentage in the lower social classes, lower percent higher social place. So, um, this may be very important factor on maybe it's not a good so variable or measurement, but perhaps it's one that tells us something of that individual on very important way. So what is it? Would see standard deviation track with. Here's a meta analysis type one diabetes. Risk of diabetic neuropathy. Risk of cardiovascular events off, uh, risk of my brother. The area was not the pretty much everything that goes wrong. Tracks with variability of a one state, uh, same meta analysis. Um, a few years ago are looking up for any studies. Type two, They would see variability tracking with property. Brilliant background in Korea. Okay, Foot ulceration and very communist work out with short term and long term follow up, um, adolescence with type one diabetes, um, relationship between very court trials and al luminaria, right? Not are you including home? So again, those individuals who are unable to leave you study level of control, seeing another fashion to have. Where's that? Here's an analysis that Erica Patrick did. Uh, that was again about done about 10 years ago. I'm the united, uh, with that order J. So they took data from the tradition, and they looked at the woodsy percentile, adjusted for the standard deviation of the A one C and showed that are that's the um yeah, the A one c percent out, adjusted for standard deviation. Didn't seem to explain, read Knox E as well as the standard deviation of a Lynsey adjusted for meaning. Let's see, suggesting that it's kind of underappreciated, very important element in what was diabetes. So another article a one C standard deviation versus a nuanced microalgae. Manchuria Analysis Type one and type two diabetes. So they used the Kilpatrick study and a variety of others. Um, a pretty strong relationship. Um Caracas Prediction. Thes air receiver operating booth. The solid line is the coefficient of variation. A onesie dotted line that anyone's to the area under the curve, a one C coefficient of variation. It's clearly greater than that meeting with C rockets. Um, and here's a Taiwan started looking at diabetic neuropathy. And again, if you look at. But here they looked at the fastest in the first provision variation. Same sort of data. Um, uh huh. This is fascinating. A study that showed that COPD tracks with pricing variability in population or at least respiratory symptoms. Another one on the same topic. So, um, this is really an important clinical marker. Entities interesting in this data that's available to all of us. Great for clinical research, and it's just beginning to be appreciated. Um, so here's in another study of prescribe. That's good disease relationship like sitting variability. Um, eso theme. The A one c standard deviation corrected for everything is at least is important Age. Yeah, duration of diabetes L D l levels. So a nature way of of looking at an individual, staying What is this person's risk But events, uh, here, uh, relationship building versus lower or higher standard deviation, vagrancy, um, mortality, same analysis or or higher standard deviation of a one state tracked with survival. Um, so recent Italian study, same findings again. Same sort of both Jared analysis. But here they looked at, uh, a mean a one C, um, or the standard deviation of a Lynsey again found that standard deviation, they see appeared to be more expensive. Um, so here is survival curves, um, and forget exactly what for lands represent. But essentially, it's the, um, mhm the higher versus or standard deviation off a one C, uh, tournament. If you find the population appropriately sure that waiter places we're survived, Um, another study our company here. It's expressed a little differently. So, um, the hazard ratio off mortality increases as sustainable deviation it would see what's up? Um, another one. Looking at the coefficient of variation of fasting glucose. You don't actually need a c to do this. Um, and so what about individuals? Don't have diabetes. So this is the offset. Which a study? Hypertension on the question that was asked here is the fasting glucose a z a categorical, veritable, uh, versus mortality on. They were able to show that multi variant analysis, uh, a very building. Selsky glucose is not preventing population track with with adverse outcome. And those in the two lowest court piles of variability had about half the mortality rate of those to hire port trials. Um, so this is also in meta analyze. Um, and that's a glucose variability is a similar risk factor. Data See, variability. Um, here's a population of individuals who do not have diarrhea. Can you have no more abilities? And the question was simply asked, among people with hypertension or non hypertensive young females or males, Um, what is the five year likelihood of efforts Erotic events vs the, uh, the 81 ceased Energy aviation. So what does this mean? That there are, if you leaving aside, what are the numbers of boxes represent. It's just that as a one, C variability goes out. There's a higher likelihood of base. Um, this one lets skip over on. So so final question is just quite scenic variability that we should look at. Um, so here's a study from the, um, Korean National Health system. Insurances. Korea has a a rather remarkable way of track. Allow this population in terms of medical act, and they have a lot of very interesting at the geologic studies. So here they together a measure off variability off cholesterol, blood pressure fast post a variety of factors, and they created a variability score. They found that vary abilities or allow these factors tracked with mortality in my practice. So it may well be that this is not exactly a diabetes. That's but a but it's really a test off appearance overall ability of the individual following medical regimen. So that's the story that there's there's a lot to look at and up. We should be very careful in analyzing it would see metals off, look yet use glucose monitoring, but we should also all right, go beyond that and think of why are we what what data we get from this? How you then use it to better. So this is most of the references for this or in a commentary that is impress internal type. I don't know if it's quite a mind yet, but it will be out. Thank you a lot. A couple of questions. What is, uh, e like a towards people? Just maybe, uh, Whatever. Whatever. Uh, because I always thought that that was part we started article in some of the complications. Gravity's work. A college. So has anybody looked to see if you like? I like Peter that Carling diabetic nations there. There is a literature, a one C front front toasty ratio as a possible measure of location. Um, but I think it's pretty soft. Um, but it may be that that's another part of the story. But if you're a 30 year old with a 17 year old, 70 year olds are hired like haters than 40 year olds off. So it's utterly crazy that we think older people that you're a one c on we say to them you're a one c is 5.9. Uh, my that pathetic. Um, I didn't with Howard says Fine E Medicare E Unless you coated in a very special and one other thought that brings us to these people because some of those people who are very variable could that have something todo like a level. So pardon? It's the best explanation of variability seems to be in documents on. So could it be that that I think they can regulatory one play a a oh, has likely be gone for vocal? Uh, you could equally argue that people who are that have a captivating response. We're gonna have greater variability. And certainly we think that type boats have a colony and God track. It's hypoglycemia, unawareness. But some movement statement. Um so the answer is, there's a lot of that. The previous discussion? A A. You are a history. Uh, he's our revolution. How about that? It's well, I sort of agree, but epidemiologic. They want to see it was quite a good way. It's gonna build that the population for college. Let's see, please every or not 11 once. Certainly, grupos ira ones go on build that he's stop with the question search that positive negative predictive values of N. C. Art undesirably Um for this? No, I love one direction. Um, so I certainly like doing a Quincy's, but it is utterly frustrating to see that, but, I mean, convinced renal disease. A So, uh, no I e Somebody just came yesterday. We're, um yeah, about his 40 do about it. Our intention? Absolutely. Yeah. Um, his a one c and A culture is utterly described. So is are very care. Doctor. Put him on for quite right. Our most favorite drugs. Never had a blood sugar recordings. Six left density. Quoted What? You and so, um, it Z, but it's not. Yeah. Okay, uh, the variation seem really interesting, but I wonder if it is also just my partner and so many other aspect of day. So it must be in many of the studies. Are they taking sort of all the patients Historical agency data that's available for the taking a snapshot of time saying five years here. Last one. E think that some of the models control for a number of a one c test they conference because that's sort of a So there's no standard on, and most of them bomb just such population. Yeah. See, test and look at the variability of is more control. You have over it better. Dr. Outside, of course, should be very difficult, right? Okay. It's his every member in a book relationship, E o. Not just very built the high court place bird, right? That would explain a lot. Three supporting cast. It's that true. So that's a those short terms and and in that announces they found that type of election year and birthplace and variability of what's ALS track with, um, so is it just type of life before the type birth? Or for, you know, so all of these are track with one another. That's part of the problem that those individuals or oh, glad stevia e u setting also him for blasting also have great variability. It's time wouldn't calculates variability. It just seems like the pressure increased. Various. I heard I would like to see That's just it. Probably, Yeah, I don't think we can know. Okay, you know, since they're not really acceptable e se. That's certainly possible that it's a globalizing, attractive Events work for America. Last week there was a forest. It was a different blusters or different kinds of time. Let's see and he actually also say that these are genetic problems with Jesus daughter involved. So be possible. Sort of like we all those spider course of diabetes and genetic that they have wrong. Check down a Yeah. Good idea. Another site? Yeah. Whole fucking okay.
