up. Good evening, everyone. My name is Elias Siraj, Professor of Medicine here at EVMS and Chief of Endocrinology. And then I'm also part of the ACE Board of Directors member. And then more importantly, I'm the Editor-in-Chief of SAP. So today is the first session of the 2022 SAP Live. For those of you who may not know the history, last year we had a new SAP, a reformatted SAP 2021. And to accompany the new SAP, we started the SAP Live, which consists of a series of seven or eight evenings throughout the year covering the different sections of endocrinology to complement the full SAP experience. So we did very well last year. So we decided to continue this year. So today is going to be the first of seven, I think, or eight, I think seven. And so I would like to welcome everyone for joining us. I'm very glad to know that it's not just the fellows who are attending. We also have attending physicians and we also have nurse practitioners and PAs. And this is very good to know. So I would like to thank the ACE staff who has been very helpful in coordinating those events and also in developing actually the logistics of it. I would like to thank all the section editors of SAP for the different sections who have been helping with preparing the questions and selection of questions, selection of speakers, selection of moderators. And I wish everyone will have a great experience. And thank you very much. So I will leave the podium to today's presenters. And I think Dr. Viral Shah will be the moderator and Dr. Arshina Sadu will be the presenter. Dr. Shah. Thank you, Dr. Siraj, for kicking off this kicking off this 2022 SAP meeting. And while I'm sharing the slide here, again, good evening, everyone. And when you will become an endocrinologist, even like right now in a fellowship program, I'm sure one out of five patients, or probably even more than that, would be diabetes, right? So we can kick off this with diabetes. Let me share my screen. All right. And again, thank you for sharing your evening with us. And I'm sure you will enjoy this. Okay. Can you see my slides? I think we'll have to swap. Yeah. Looks good. Oh, it looks good now. Okay. All right. Thank you. And again, this, as Dr. Siraj mentioned, this SAP was prepared under his and Dr. Gopalakrishnan's guidance. I am today your moderator. My name is Dr. Viral Shah. I'm an associate professor and a clinical researcher at the Barbara Davies Center for Diabetes located in Colorado. And I have a wonderful speaker, good friend, colleague here who is going to speak and present the cases. Dr. Archana Sadhu. She is a system director for diabetes program, as well as directing the transplant endocrinology, not just the diabetes, at the Houston Methodist in Houston, Texas. Here are our disclosures. I'm going to keep slide for a couple of seconds for you to review. Nothing major, nothing related to this presentation either. So what we're going to do today is Dr. Sadhu will present each case. We have about total seven cases. After the case, you will see a poll questions on your screen. There will be four options. In the case, select the right answer. And then we will discuss the answers of that particular case and why this is the right answer and why other three are wrong answer and more detail about that. If you have any question, meanwhile, about the case or surrounding the case, feel free to put that in a Q&A chat box. We'll take that at the end of that particular case. All right. Then we'll start with our first case and Dr. Sadhu, to you. All right. Well, welcome everyone. Hopefully we'll get through all the seven cases, but I really want to make sure the objective here is for you to understand the concept of the case. So if we have to pause for questions, please enter them and we can discuss them. And Dr. Shah will help us guide to the questions. So let's get started. Case one, this is a 67-year-old woman who is seen in consultation for management of type 2 diabetes. She's on pretty well-established drugs, historically, which are metformin at a maximum dose of one gram twice daily and extended and extended-release glipizide, 10 milligrams a day for many years. She's doing well, really doesn't have much complaints and her home glucose monitoring log shows that her glucose ranges between 74 at the lowest and 165 throughout the day. And she's denying any symptoms of hypoglycemia. She also follows a cardiologist and he adjusts her blood pressure medications, but had a recent admission for heart failure exacerbation and was noted to have an ejection fraction of 35%. Right now she's denying any chest pain or shortness of breath on her visit. So on examination, she has a good blood pressure reading and respiratory rate is normal. Lungs are clear, really nothing of significance on her cardiac exam, but she does have a little bit of trace edema in her ankles. And then you review her labs and you see that her A1c is 6.7% and creatinine is 0.9 with an EGFR of 93. She does not have microalbuminuria with only 20 milligrams per gram of creatinine in her urine. So the question is now, which one of the following would be the best next step for this patient? And choose one answer. The first, continue the metformin and discontinue the glipizide. Second, continue the metformin and change the glipizide to dapagliflozin. The third, continue the metformin and change the glipizide to linagliptin. Or the last, discontinue both metformin and glipizide and start semaglutide. So please enter your answers here. All right, we have really an interesting good case and I'm sure you see that all the time in clinic. An older individual with type 2 diabetes, congestive heart failure with reduced ejection fraction. Let's see, what do you think? What should we do next? It's really great to have so many different classes of drugs now for management of type 2 diabetes. It really gives us an option for the patients, but also makes diabetes a little bit more complicated these days. And this is probably a typical case that a lot of primary care would see. All right, so now we have responses here. And very interestingly, I think every single one say that answer B is the correct. I think we are really an august audience here today. So let's talk very briefly, Dr. Sadhu, what do you think? Why not the option A where you just stop the glipizide and just continue with metformin? So the option for number one, certainly the patient's well controlled on those two agents. Their A1c is a target. And if cost was an issue for patients, and we do have to keep in mind costs in many situations, that continuing that may be a good option for the patient to maintain glycemic control. But I think the key to the entire case came in the very last sentence, which was the patient had just seen their cardiologist, just had an admission for heart failure, which now the guidelines direct us in a different class of drugs when patients are identified as having heart failure. And as all of you recognize that this is the indication for starting SGLT2 inhibitors. Now, this is independent of glycemic control, right? So the ADA guidelines, as well as the ACE guidelines and the new ACE guidelines for type two, which will be out shortly, all lean us towards starting an SGLT2 inhibitor whenever patients have diagnosed heart failure because of the tremendous benefits in the cardiovascular outcome trials. We can see that in the next slide, I believe, has all of these trials listed for you. And it continues to grow. We did the same question last year and added several more trials, right, Dr. Shah? Yeah, I remember the table was small and now the table is pretty large. These slides here, it's already, this table is shown here, so. Exactly. And also in the last year, two of the drugs, Ampliflozin as well as Dapliflozin have indications for heart failure, even when diabetes is not present and indications for use when there is reduced, as well as preserved ejection fraction. So it is a hands down winner for patients with heart failure. So this is what we want to do for all of our patients with that indication. Again, if costs allow. Now, one of the other options was switch them to a DPP4 inhibitor, option C. And again, it wouldn't be a wrong choice to do that. Certainly, the linagliptin would have less hypoglycemia risk than a sulfonylurea, a little bit more costly as well. But if this was an elderly patient or any patient with hypoglycemia as being the issue, you may want to think about that, although Dapliflozin also does not have hypoglycemia risk. So not really the best choice for the patient. And then discontinuing both of those and starting semaglutine, well, then you wouldn't really get that heart failure benefit for this patient. And that is something that we were seeking for the patient, for sure. Semaglutide and all the GLP1s all have other benefits too. They do have significant weight loss benefit, good glycemic control, even chronic kidney disease protection. But it doesn't make sense in this patient to not address the heart failure specifically based on that table of CBOTs that we just showed you. Right. Great. And thank you for discussing all the options, Dr. Sadu. And I think, you know, for fellows, the key here is the type 2 diabetes, heart failure with reduced ejection fraction, and SGLT2 has shown great benefits regardless of A1C. So remember that in mind. So A1C may be a distractor here. And remember in the board exams, slightly different than real life, that all the drugs are assumed to be approved and covered, and there are no financial barriers. So you have to select the best answer. Right. So we will not go into like reading those things. We already discussed about this case and why SGLT2 should be the choice. You can read more into the standards of care by the American Diabetes Association, gets published every year in January. And the upcoming ACE type 2 diabetes guidelines. Thank you. Now let's move on to the next case. Another interesting case. And again, Dr. Sadu, let's go for that. All right. So this is a different scenario here. We have a 35 year old gentleman with a 26 year history of type 1 diabetes, and he's coming in for a routine follow up visit. So he's been on standard basal bolus therapy with Blispro and Blargene insulin. And he reports that he's been compliant with the dosing and frequency. He rotates his injection sites regularly and follows a good low carb diet. And he recently started utilizing CGM, but then noted that he's had several episodes, five to six episodes of asymptomatic hypoglycemia, at least five to six a week. His BMI is normal at 24 and vital signs are otherwise unremarkable. And the rest of his exam is notable for a decreased monofilament sensation, peripheral neuropathy. Labs show an A1C of 7.4. His serum creatinine is 1.1. And then you look at the AGP report and you see that his CGM shows 5% of his readings to be below 54 milligrams per deciliter. So that is quite low. And these are happening on the AGP graph between 2 a.m. to 6 a.m. So he's concerned about both the hypoglycemia, but also his drive to maintain good diabetes control, good A1C to be specific. And so he wants to discuss this in a shared decision-making conversation with you. Just one clarification here that he's on a glargine U100. Okay. Yeah. Thank you. So the question here is which of the following next steps would achieve the patient's treatment goals? One, decrease both the basal and prandial insulin doses because of his concern for hypoglycemia and the CGM report. Two, decrease just the basal insulin glargine dose. Three, substitute his basal insulin with Degladec or four, substitute his prandial insulin with Aspart. All right. Let's see what you guys think about this 35-year-old with type 1 longstanding diabetes. He does very well with A1C of 7.4. For that age group, it actually is, you know, in that young adult age, maybe 35 is a little beyond young adult. They tend to have the worst A1Cs of the entire cohort of age groups when you look at the type 1 diabetes exchange. At the same time, I think he's motivated. He wants to do even better, right? So that's the intention here. What do you think to help him so that he can have probably better A1C without hypoglycemia? There we go. So now you guys are split between A, B, and C. Some things that we need to decrease both the basal and the prandial insulin doses. And what do you think, Dr. Sadhu, why that option is probably not correct? Well, you know, his A1C, while okay for that age group, as we just mentioned, is really still above target A1C in terms of a risk factor reduction for complications, right? The DCCT trial showed us that A1Cs should be less than 7% to avoid all of those microvascular complications. And now with the CGM technology, you know, we're really going towards time and range. We want the optimal time and range to avoid complications, but he is already slightly high. And so decreasing all of his insulin doses while improving hypoglycemia will not achieve that good glycemic control. I 100% agree with you, but then what do you think about reducing his glargine? Just the glargine, don't touch the prandial one. Well, that would seem to be an obvious choice, right? He is having nocturnal hypoglycemia, very clearly shown on the AGP report. And glargine would be the insulin that's the culprit for that. And that would be something that might be reflexive to do. But again, we may increase his A1C by reducing his total insulin dose for the day. So that's an option. So the next option then would be to consider substituting the glargine with degladec. That's an interesting option. And why would that one be better than reducing glargine? Because of something called the switch trial. So the switch trial was done with a randomized double-blinded crossover study for glargine and degladec insulin, and clearly showed that degladec had significant reductions in symptomatic hypoglycemia and even more impressively in nocturnal hypoglycemia. So this might be the option for the patient where you're trying to balance that nocturnal hypoglycemia with maintaining good glycemic control by switching to degladec. And the last option of just switching the prandial from one rapid acting to another, that's not where he's having a problem. He's having a problem nocturnally, so that wouldn't do much at all. And I think we don't need to even explain about B because no one selected that option B. So that's very obvious. Good, at least we don't have to waste time on that. Okay, all right. Again, read about the switch trial that was published in GMI in 2017. All right, now we're going to move to the case three, and here it is. All right, so this is a 39-year-old woman who was referred for evaluation of dizziness. She has a history of type 2 diabetes and had, in fact, a Roux-en-Y gastric bypass surgery three years ago for severe obesity and a BMI of 39. And she got very good effects and great weight loss from that. But recently she's been reporting these episodes of dizziness that usually occur in the afternoon, and along with it comes sweating and some confusion, and they all get better if she eats. She does not have these symptoms in the morning, and if she skips a meal, she's also okay. She has measured her blood sugar during one of these episodes and has gotten a value of 55 milligrams per deciliter. Otherwise, her medical history is not remarkable. She does not take any other medications, although she was on insulin in the past before her Roux-en-Y for her type 2 diabetes. On physical exam, she has a BMI of 26. On normal cardiovascular exam, she has surgical scars that are well healed. Some white striae are noted over the abdomen. Currently, her A1C is 4.8%. So which of the following is the most likely diagnosis for this woman? Number one, insulinoma. Number two, nestidioplastosis. Number three, surreptitious sulfonylurea use. Or number four, insulin autoimmune syndrome. All right, so you have got four choices. Let's see, what do you guys think? Meanwhile, let's discuss this, Dr. Sadu, that any patients who have an hypoglycemia, we need to document so-called Whipple's triad, right? Do you want to talk something about that? Right, so the Whipple's triad is really the very basic, making sure that these very nonspecific symptoms that sometimes patients will have for many other reasons are really related to glucose. You have to have the symptoms, you have to have a documented low glucose when you have the symptoms, and then a correction of the symptoms and the glucose with ingestion of carbohydrates. So those three things must be met for Whipple's triad. So in this case, let's say it met, and then now you need to investigate further that what is causing this hypoglycemia. So now we have got our responses here, and it sounds like an overwhelmingly 86% of you thinks that it's an STD or blastosis, but there are some minor words around insulinoma and the insulin autoimmune syndrome, which is very interesting to me that someone answered that. Let's talk about each of these. Two people, two people were thinking that. Yeah, so a very common referral for endocrinologists, actually, after patients have had bariatric surgery, typically Rheum Y, and really has to do with basically the hyperactive beta cell. So these patients were insulin resistant previously with type two diabetes. Usually a prolonged nature on medical therapy often, and then they lose this tremendous amount of weight and then become much less insulin resistant. However, that threshold for the beta cell to secrete insulin is not reset. That's kind of how I like to explain it to the patients. Your beta cell is still in that hyperdrive mode as it was before the surgery and weight loss, but it's not really just the weight loss that causes this. And we are still yet to clearly define the physiology of this post-bariatric hypoglycemia, but it probably has a lot to do with GLP-1 and increase in hormonal changes as well. But what's happening in these patients is because they were insulin resistant for so long, they have hypertrophy or hyperplasia of the beta cell and overproduction of insulin, that when stimulated with carbs is when they get a postprandial hypoglycemia. So the key to this, the key to the histology is documenting mesidioblastosis with a biopsy, but obviously we don't do that routinely. But if you were to, you would see hyperplasia of the beta cells. But most often we can diagnose this by the Whipple's triad, by documenting a postprandial hypoglycemia, usually an oral glucose tolerance test will do this. And sometimes though you do need to go beyond the two hours to document that postprandial hypoglycemia. And I often order insulin levels along with the glucose tolerance test to actually see what the insulin levels are. And they're not subtle. We're talking about three, 400 millunits per liter sometimes that then causes the hypoglycemia. Not to be confused with hypoglycemia that occurs very early after eating, also in the same patient population, which can be more of a dumping syndrome, but they often have GI symptoms as well with diarrhea when they have that. So a very tricky diagnosis and rare complication, but one that endocrinologists will probably see. Insulinoma, let's talk about that. So with any hypoglycemia, the first thing you wanna do is document the time and inciting factors. Of course, insulinoma hypoglycemia occurs in the fasting state. That's the classic history for that. They wake up with fasting hypoglycemia or if they skip meals, they'll get hypoglycemia. And then the key here in this case was that they already mentioned that the patient skips the meal and feels okay, right? So that excludes the insulinoma. Right, right. And in fact, meals are the problem for these patients. Not the fact that they can't eat, but the composition of the meals. The higher the carb, the more likely and more severe the hypoglycemia for that. And the autoimmune insulin syndrome, super rare. I don't think I've ever, well, I shouldn't say that. There are some antibodies that will disrupt the insulin signal and binding to the insulin receptor that could also cause the syndrome, but usually never in the context of bariatric surgery. So in the city of blastosis becomes pretty obvious for this patient. Right, and just again about the sulfonylurea use, I would just say that again, that think about the drug, it causes the persistent and prolonged stimulation of beta cells, right? So the hypoglycemia will happen both in a fasting state as well as a postprandial. Right. Not just the post, you know, like a postprandial, which is typical in the city of blastosis. So, okay, now I think you got the answer. So we got a question in a chat field that would GLP-1 antagonist be helpful in the cases of nasopharyngeal blastosis? Very interesting question. So I'm just asking you Dr. Zab. Super interesting question. And I don't have your answer, unfortunately. So there is some literature and a lot of case reports using GLP-1 receptor agonist. However, clinically I've not had great success with that. And if you're doing, it theoretically could help with the Inkerton dysregulation, I suppose, but I've not had success with it. There isn't any guidelines to support the use of it for this indication because there aren't really any randomized controlled trials that have shown that benefit. Interestingly though, I've recently read a paper about the Exendin being used in an investigational context, actually, and that might actually help GLP-1 itself to mitigate these postprandial hyperinsulinemic surges. So I think it depends on the patient. Again, I see a lot of these because we have a pretty busy bariatric practice at our center, and I have not had success with that. Typical treatments include, well, the first always is the very low carb meal. And we're talking about 15 to 30 grams of carbs or less per meal. And then other dietary modifications along with that, definitely no simple carbs, make sure they're complex carbs. And eat slowly. There's just a lot of other dietary things that can be done that usually treats a lot of these patients. The second step would be A-carbos, which of course, you know, works at the intestinal fresh border to reduce carbohydrate uptake at the fresh border. So then they're not stimulated. Dioxide is toxic, but has been something that I've tried before as well. Then the last option would be surgical pancreatectomy. Partial pancreatectomy usually works. Although I had a very interesting patient where we did a partial pancreatectomy, she still was hyperinsulinemic, hyperglycemic, ended up getting a total pancreatectomy, although the surgeon went in to take a little bit more, ended up having to take the whole pancreas. And then we actually treated her subsequently with a pancreas transplant, interestingly. So now she is- Complicated case sounds like. She's very complicated, but even more fascinating is that she continued to have hypoglycemia even after the pancreas transplant, having a very healthy, normal pancreas. So there is something else going on with her important physiology that's beyond the eyelets that we haven't figured out yet. I'm sure it's an interesting for researcher and there are a lot of, I think, the trials happening in this area too. Another question in this case is that, this person says that the insulinoma can also present with the postprandial hypoglycemia. And don't you think that we should actually look at the insulin, proinsulin, c-peptide to just necessarily distinguish between insulinoma and acidioblastosis? Well, the pathophysiology of the two are very different. And yeah, sometimes it can be confusing. And that's why I actually do look at, when I do my own glucose tolerance on these patients, I am looking at all of the secretory products of the beta cell insulin, proinsulin, and c-peptide and looking at their ratios as well. But the presentation is very different. Patients with insulinomas, obviously have not had gastric bypass. Patients with insulinomas are actually overweight or obese because they're always eating to keep up with the hypoglycemia, which is a very different presentation. Patients with insulinomas also are hypoglycemia unawareness. Sometimes they don't know that they have it until their glucoses are hitting 20. And sometimes they'll even function perfectly fine in their 20s and 30s and will need to be even lower than that and have seizures in order to come to medical attention. So presentations are very different. For a gastric bypass, you know, horse is a horse. It's pretty obvious that it's gonna be acidioblastosis. It would be very rare for them to have had gastric bypass. I suppose they've had an insulinoma for so long and they overate for so long and they became obese and then got treated with gastric bypass. That just sounds, you know, very unreal. So I think that the history is the key here. Yeah, I think with respect to time, we'll move on. But one more question that I would like to take. What do you think about the use of a somatostatin analogs for treating the necidioblastosis? I have no experience with that actually. So I can't comment. And I don't really read a lot that as a usual therapy for it. It's interesting to think about. We certainly do try it for other chromaffin cell tumors, but I've not seen it for necidioblastosis. Have you, Dr. Shah? Have you tried to do that? Honestly speaking, no. But I'm sure that if you find literature, someone might have tried this because it does make sense that why not to use this, right? But no practical experience of using that. Great question. Yeah, practically speaking, I think the best success for most patients is CGM with modification of diet and or A-carbos that usually will help a lot. Okay, let's go on to the next case. And we discussed this in depth. Here are the references. Again, it's all there in ASAP. You can open up and read that. Now, another interesting case. So, all right. So case four is a 48-year-old black male who was referred for an abnormal test that he got in a health fair. He's otherwise healthy. He has medical history. He has sickle cell trait, but has never required any treatment. He works full-time and his job involves very sedentary activity at a desk. He walks his dog 10 minutes a day. He doesn't smoke. And his father and paternal uncle have diabetes when they were diagnosed in their 60s. His mother has hypertension, no cardiovascular disease in the family. He's five foot seven inches and weighs 189 pounds with a BMI of 29.8. Pulse is okay and regular. Blood pressure was a little bit high, 142 over 90 on otherwise a negative on physical exam. He's concerned about his abnormal blood test and worried that he may have diabetes. Okay, there we go. So here are the tests. His hemoglobin is normal at 13.9. His fasting glucose is 127. And A1C performed using the standard NSGP method. That's important to note actually, because a lot of health fairs use point of care type A1C tests that are not standardized using this methodology, and they don't have the same accuracy. So that's why that was included there. His A1C is 6.6%. Serum creatinine is 0.8. And his GAD antibodies are low at 0.01. So how would we manage this patient next? What would we do next for them? Perform a two-hour oral glucose tolerance test. Repeat a fasting plasma glucose measurement. Use a CGM for them, or start lifestyle intervention and or metformin. Okay, great. Remember African-American guy with the sickle cell trait. I think that might help you to answer one of those four options. Or I may be misguiding you. Let's see, what do you guys think? Okay. Where they're thinking very heavily about this question. I think they're going to get it all right. Let's see. They've got a smart group here. Oh, who's next? All divided, and so. Then I think we need to discuss all four options then, Dr. Sadu. So let's start with the first one. Why not to do a two-hour OGTT? So one, they're very difficult to do for the patient, right? They have to come in fasting. You have to do this stepwise blood draws. However, it is a good option to confirm the test. But if you could go back a couple of slides, let me just review with the labs, Dr. Shah. Yeah, so the first question is, do we really need to confirm this, right? And so I'm going to go back to this slide. This is the slide, or? Yes, that one. So we have two indicators here, only two different indicators that there is something going on with his glucose metabolism. One is the fasting plasma glucose, and the second is the A1C, right? So to diagnose diabetes, you need a fasting plasma glucose of 126 or above, or an A1C of 6.5 or above. So he's kind of clinched the diagnosis here. So putting him through a two-hour OGTT would not add value. The pretest probability is high. So why would we do that? Okay, so the second choice, if you could move forward, I forgot what the second choice was. Yeah, again, you know, for fellows that you do not require a second test when there are already two abnormal tests. And I think the question here probably in your mind is that, do we really need to rely on A1C when there was a diagnosis of the sickle cell trait? Do you want to talk about that, Dr. Sadhu? And then again, I'm going to go back to those options. Yeah, so several things do affect the A1C, right? And hemoglobinopathies are classically the ones that we want to be very cognizant about and know that they can affect the A1C. So there are anemias of chronic disease or anemias of hemolysis. Anything that affects the red blood cell lifespan, either accelerated or prolonged, will affect the A1C. Usually accelerated red blood, immature red blood cells from anemia, blood loss, or any other synthetic problem will cause A1Cs to be falsely low. Falsely high A1Cs can happen with iron deficiency anemia unexpectedly. So that is one type of anemia where we can see an A1C that's higher than needed. And then we can also, A1Cs can also vary based on ethnicity. And African-American race is actually one that can have higher A1Cs despite normal glucose tolerance tests. So for those reasons, I think it wouldn't be totally wrong to confirm your diagnosis with a two-hour oral glucose tolerance test. The question is, does sickle cell trait change this? And in this case, I think that the fasting glucose and his family history, it's very unlikely to be false. And we're not just using that one test. We are using multiple clinical as well as other laboratory tests. Repeating a fasting plasma glucose measurement that's easy to do. You bring them in fasting again, but again, it's an added step. CGM, we don't have any diagnostic criteria for diabetes using CGM at present. So the other thing is, starting your lifestyle intervention and metformin on this patient. And I can't recall how many of our audience members chose that. I think that was about 20% if I'm not wrong. So that's the correct answer. Yeah. So interestingly enough. Yes. So if you want to advance the slide, we can talk a little bit more about why, so the diagnosis of diabetes really should be two different tests or the same test at two different times. So you could do two fasting glucoses if the A1C is not available or not reliable. But given his other risk factors, age, weight, and family history, we all know from the Diabetes Prevention Program that this group of patients do very well with lifestyle modification and first-line therapy of metformin as well. So I think we would just jump over to that. Right. Again, the key here is that, remember that minor hemoglobinopathies that would not affect the rates of lifespan much are not affected by the standard way of estimating A1C, which is like NGSP, that's the main message. That's the key, yeah. You need to use that standardized method. Okay, the question here, somebody put that in the chat field. I have three patients in my practice with the hemoglobin main variant and presented with a falsely-identified A1C level. Good, interesting. Do you have any experience with that hemoglobin variant, Dr. Sadat? Which variant? I'm sorry, I didn't say that. Wayne, W-A-Y-N-E. Oh, I don't. I actually have never seen a patient with that variant. Yeah, I'm sorry, go ahead. Yeah, and I can't answer that question, but in general to say that if you have any suspicion that a hemoglobinopathy is affecting that, we certainly can use an oral glucose tolerance test. And I think that's where the group was kind of divided is using that oral glucose tolerance test. Again, I just want to give you this resource here. So this is the website for NGSB. So if you Google that, it will give you that which kind of methods would affect what kind of a variants of hemoglobin, right? So probably that particular variant that you are mentioning here, and if you do a certain types of tests which are available in the market may not be affected by that variant, right? So it's a lot of different tastes do have a different sensitivity and specificity around those different variants. So that's where that website will be helpful for you. Okay, a couple of questions, Dr. Sadu. How does hyperbilirubinemia would change A1C? Is that question referring to the assay or the ability to glycosylate hemoglobin? I don't know, but I think that's a good question that you opened up, right? And it's more about the methods. Oh, it refers to- The accuracy of the test. There we go. I don't know of a direct relationship between bilirubin and the test assay interference. I don't, what I'll often see is liver disease has chronic anemia or blood loss. You know, there are slow blood loss from their varices or whatever their signs of chronic bleeding. And that will definitely affect the hemoglobin level, which then of course will affect the value of the A1C. But if, I'm really not aware of any direct interference from bilirubin. However, point of care glucose tests are affected by severe hyperbilirubinemia. And that is interferes, depending on the type of reaction for the point of care glucose. So glucose oxidase versus dehydrogenase, I believe is the other one. You can have interference from severe hyperbilirubinemia. I think it has to be really pretty high though. And the A1C, I'm not aware. Are you Dr. Shah? Have you seen that before? You know, I think there are a lot of situations that we may come across in a clinic where we might think like, would that affect the hemoglobin A1C estimation? And what we would do, the practical answer would be checking on the NGSP website and see that the method that you are using in your clinic is really affected by those factors. Number one, number two, maybe repeating some other tests, right? So that's what we all do. Yeah, having an oral glucose tolerance test in that patient would make a lot of sense. Another question says they have a patient with a low A1C by venous draw, but high BG on a venous draw all the time, high with the fructose amine high. So I think you are referring again with that particular case of hyperbilirubinemia. And that to me, it sounds like probably there is a hemolysis going on because you have glucose markers going up, but then A1C is down, which might suggest the hemolysis. And that is reason for hyperbilirubinemia as well as false low A1C. So probably needs some further investigation here. Okay, with the respect again, with the time we'll move on to the next case. And if I missed any of your questions, we might take at the end. Again, here are the references that you can read in details. This is a simple one. Let's see, Dr. Sadhu, back to you. All right, so 55 year old man presents to his primary care provider for management of his diabetes and weight gain. He's on metformin. And in addition to lifestyle modifications, he was advised about adding once weekly GLP-1 receptor agonist to his treatment regimen. Oh, it's not moving. There we go. Okay, so which of the following statements correctly explains one of the mechanisms how GLP-1 receptor agonist can improve this patient's glycemic control? I am sure everyone would. I think, I would hope so. I would hope so. And we do not require a further discussion here. Okay, stimulation of glucose-dependent glucagon secretion, stimulation of glucose-dependent insulin release, stimulation of pro-glucagon gene expression, or stimulation of orexogenic receptors in the hypothalamus. All right, don't think too much. GLP-1 receptors do a lot of things. They're a pretty phenomenal class of drugs with multiple actions that affect- But there is only one right answer here, right? Yes, yes. This is a test question, so only one right answer. But it really tests your knowledge of the mechanism of action of these drugs. All right, okay. 80% are right. Stimulation of glucose-dependent insulin release. There is 5% kind of a split between other A, C, and D options. Right, so number, so that's the answer. And it's glucose-dependent insulin secretion, which is the beauty of these drugs because unless you're hyperglycemic, the drug doesn't cause hyperglycemia below threshold. It actually does the opposite. So question, answer one is incorrect. It does not stimulate glucose-dependent, glucagon secretion. Think about it that way. If the glucagon goes up, the person will have a hyperglycemia, right? These drugs are used to treat hyperglycemia, so that cannot be right. So, and then pro-glucagon gene expression really does not work in that kind of fashion. It really is about release, not changing gene expression. And you can think about that because it works immediately and anything that changes gene expressions will take a lot longer. And then it actually suppresses the hypothalamus hepatite center, right? So it does not cause stimulation of those receptors that suppress the glycogen. That's how it promotes weight loss. So that is not right. Okay, great. Again, you can refer to this reference about understanding more details of how GLP-1 analog works. And let's move on to case six. And this is a very, very interesting one. Hold on, I'm having a little screen issue here. Okay, case six, 40-year-old woman with type 1 for 30 years having a follow-up evaluation and she's having worsening glucose control in the past few months, despite no major changes in her lifestyle or weight. She reports that at times the insulin does not work as it should. And physical findings, you find this picture. So the key to the answer to this question is understanding what that picture is representing, obviously. And what is the pathogenesis of the changes you see in this patient's skin, their dermatological changes? One, they are considered to be a direct anabolic effect of insulin on skin adipose tissue. And two, they are considered to be a direct anabolic effect of insulin on skin adipocytes. Two, use of continuous subcutaneous insulin infusion or insulin pumps will increase the risk of these changes. Microscopic examination is expected to show lobules of large, mature adipocytes. Or they are considered to be immune-mediated inflammatory reactions to insulin. All right. Let's see, what do you guys think? And I can probably go back to the picture again so that if you have a last minute thought, or if you want to change your thoughts, you may. This is not an easy one. I think it's an easy one, but let's see. All right. We are about to get the answer. Okay. The audience is split with all four different answers. So let's talk one by one. First of all, what do you think is this, Dr. Sadhu? Is this a hypertrophy or it's an atrophy? Yeah. Well, that's going to be the key to this answer, right? Exactly. If you can go back to the picture. That's where I am right now. Oh, sorry. I have two screens, so I'm getting a little double screens here. So this patient, so you can have a lipodystrophy related to insulin and they can be either hypertrophy or atrophy. And I think in this patient, you see the divots, where the skin is going inward a little bit, and it's probably where the injections are happening. And she is having lipoatrophy in this case of the subcutaneous fat tissue. And this is actually considered to be an immune mediated inflammatory response. So the last answer is what you would find on the histology if you were to biopsy this patient's skin. And if you were having direct anabolic effects of insulin, it wouldn't be atrophy, obviously. And so I think we have the next slide that shows maybe the histological changes. Yes, it does. And I think I messed up here on the screen. So let me just correct that. Okay. Yep, there we go. Okay, so you can see focal fibrosis changes at the injection sites. And you can have findings of lipoatrophic areas within the adipose tissue layers of the dermal skin with, and the key is immunoglobulin deposition and complements when you do the actual histology of pathology findings. So I think this kind of, this article describes all of the different lipoatrophy lesions. Picture C is the one we used for the question, but they can look very different in different patients. And then the histology below. So I would encourage you to take a look at the article and the reference and learn about what's happening in these patients. And exactly what the patient would describe is what they would, what would be clinically pertinent is that they do not get absorption of the insulin at the same dose like they used to. And then hence poor glycemic control. Right, and again, hypertrophy is more common clinically and atrophy is not that common, but yes, we just wanted to highlight that it can happen. And here in histology, you can see lymphocyte and the eosinophil infiltration, suggestive of an autoimmune reaction leading to this atrophy, so. And then the HNA staining will show you the different kinds of inflammatory cells as well. Right, this is an F, yeah. Okay, all right, so that's this case. And let's go to the last one, inpatient care. Oh, that's important, especially, but our fellows will know this. They see this a lot, right? 63-year-old man is admitted to the ICU with sepsis and septic shock due to cholecystitis complicated by perforation, unfortunately, and peritonitis. He started on insulin support with IV and IV antibiotics. His history is significant for hypertension, type 2 diabetes, and he's being prepped for surgery. And so he started on IV insulin for his glycemic control with a target blood glucose of less than 200. Data and literature point to a difference in outcomes in patients with proposed glycemic target of less than 180 versus those more than 180. So which of the following outcomes would be expected in this patient? A reduction in overall mortality, a decrease in the incidence of myocardial infarctions, a reduction in wound infections, or a decrease in the incidence of atrial fibrillation? Okay, so what do you think is the right answer here when you reduced or improved the glucose control in inpatient setting? And just a little note here that this recording will be available on Monday. So if you want to go back, listen to this conversation, you can. Because we're so engaging and we know we all want to replay and get every word of wisdom, right? So as you expected, Dr. Sadhu, I think most of those 80% got it correct, that reduction in the overall mortality is the right answer. Yes, and I see a few of you chose wound infections and that's not entirely wrong, especially in our cardiothoracic literature. Not only is there an improvement in mortality, but also a reduction in deep sternal wound infections that's been well-documented. So important to have perioperative glycemic control less than 180, and also in critically ill patients, that's the NICE-SUGAR trial. There's several trials. Initially it was Grete Vandenberg, was the first landmark trial. Her ICU that she did intensive glycemic control versus standard of care, the target was much lower, 80 to 110, but she also showed tremendous benefits in those patients. One of the subtleties of her trial that showed that benefit that didn't get replicated in other trials was that first was predominantly surgical unit, predominantly cardiac surgery. But there are, and then that was validated by other cardiac surgery trials. But eventually we had the NICE-SUGAR trial that looked at 80 to 110 versus 140 to 180 and actually showed that the 140 to 180 group had a much better survival. Then the intense control and less hyperglycemia, obviously. So that has become the target guidelines for critically ill patients. However, in some patient populations, it is appropriate to go lower, 110 to 140, but not as low as 80 to 110. And that population is supported by the cardiac surgery literature. In our institution, we're a big transplant institution and we actually use the lower target for our media post-transplant patients. They're very insulin resistant and very unlikely to get hyperglycemia. So we try to go lower with them. Lower the better, but without hyperglycemia is actually the clinical curl there. So we keep it under 180. Right. And I think in the future with the increasing CGM use in inpatient, not in ICU setting, I'm saying, I think we might get a little better data. Let's see. You know, it's funny you should say that because when I was asked to comment on the NICE-SUGAR trial, and that was 2008, my immediate response was, well, when we can use CGM, it'll still be supported to use lower targets because we can do it without hyperglycemia. And that was the problem there. Right. With that, I think we had done all seven cases. We went two minutes over the time, but I hope you won't mind that two minutes. I think we had a really interactive discussion today. Again, we would like to thank every one of you to spend your an hour with us this evening. Hope you enjoyed this. Again, I want to say thank you so much to Dr. Archana Sadhu for really wonderful discussion around all these seven cases. And it's more about the concept rather than that particular case. And I hope we made really the concept clear for you guys so that it can help you in a board exams. I did not see any kind of a last minute chat questions. So I guess we do not have any further questions. So with that, again, I want to say thank you to everyone and big round of applause for Dr. Sadhu. Well, thank you, Dr. Shah for excellent moderation and thank you all for joining us. And I hope that you continue to learn and thrive and all pass your boards. Good luck. Definitely.

type 2 diabetes

heart failure

SGLT2 inhibitor

type 1 diabetes

hypoglycemia

basal insulin

glargine

degladec

sickle cell trait

A1C