Good evening and welcome to the ASAP Live 2022. This is the second session for diabetes review. Welcome. This session has been developed as part of the ACE board review and under the leadership of Dr. Elia Sarraj, who is the editor-in-chief for ASAP, as well as Dr. Geeta Gopalakrishnan, who is the chairperson of the Fellows Education Subcommittee for ACE. Hi, my name is Alela Mazzari and I'm going to be the moderator but also be helping with the questions as well. So I'm an endocrinologist at Loyola University Medical Center. I've been there for a while, morphed through the system, and I've been in attending for a bunch of years now. I've been involved with ACE since I was a fellow, I was one of the presidents of when we had the chapters at ACE, and I've been involved with ACE in multiple different ways, and I'm excited to be here with you today. Thank you, Dr. Mazzari. And I'm Arman Krikorian, I'm your co-moderator, I'm the vice chair and residency program director for interim medicine at Advocate Christ Medical Center in Chicago, Illinois, also. I've been with ACE also since I was a fellow in 2003, so totally dating myself there. I've been involved with the organization since, and I currently sit on the board of directors of ACE. Neither of us have any disclosures that are relevant for today's discussion. Today's session will run as a series of case discussions. You are more than welcome to type your questions in the Q&A box at any time, and then you can upvote questions that were posed by others, and we would be delighted to address those questions and answer them. After each case, you are going to see choices for different answers, and this will open a Zoom poll. When that poll opens, please feel free to go ahead and select your answers, and then we will discuss those answers together. Questions from the audience will be addressed at the end of the case discussion, just to make sure that we maintain a certain flow. So without further ado, we're going to go right into the first case for this evening. So our first case is the case of a 52-year-old man with type 2 diabetes who comes to the emergency department after an elective surgery for his knee. He has nausea, vomiting, diffused abdominal pain, but no chest pain, no fever, no cough, no dyspnea. On admission, you can see the heart rate is about 95 beats per minute, respiratory rate is 18 breath per minute, blood pressure is 120 over 70, and the oxygen saturation is actually pretty good at 99% on room air. Now, this is a quick overview of his initial lab studies, so I'll give you all a moment to just take them in. You can see the sodium, potassium, chloride, bicarb, which seems a little bit low, creatinine looks normal, you can see the pH as well as the glucose, the troponin, lactic acid, and the white blood cell count. So going back to our gentleman, he has been diagnosed with type 2 diabetes five years ago after he sustained a myocardial infarction, he has been managed with metformin and empagliflozin. His most recent A1c was 8.2%, he has no known microvascular complications. So he was admitted to the ICU for treatment with intravenous insulin, and both his metformin and empagliflozin were held while he's in the hospital. Diabetes improved significantly, and now discharge is planned. So which of the following is the appropriate management approach for this patient's diabetes at discharge? And you can see the options, stopping all oral therapy, start basal bolus, stop empagliflozin, start an incretin, stop metformin, start incretin, continue metformin and empagliflozin, which were his home medications. So let's take maybe 60 seconds to answer, you can go ahead and enter your answers in the poll. It looks like we have an even spread of the answers between stopping empagliflozin, starting incretin therapy, or continuing metformin and empagliflozin, his home medications. So Dr. Mazari, I'm going to ask you to walk us through this case, it looks like the audience is split. All right, so we're going to go to the rationale for what they're really trying to flag you on this question. So what they wanted to alert you to was that this patient has euglycemic diabetic ketoacidosis or DKA in the setting of sodium glucose transporter 2 or SGLT2 inhibitors. And this was in the setting of a recent surgery that could have been a trigger for this. If you guys remember, when we were looking at the lab data, his glucose level was less than 200, but his beta-hydroxybutyrate was elevated. So that is one of the things that when you're looking at the labs, look for anything that might be impressive from that standpoint. So the pH was slightly low, the beta-hydroxybutyrate was 4.2, but if you look at his glucose, it was only 192. So not impressive when you look at it, but with the presentation that he came with, you want to kind of have that be on your radar. So after appropriate treatment and correction of the ketoacidosis, the SGLT2 inhibitors should not be continued at discharge. So that means any of the choices that have that is already wrong. So what should we do? So until insulin deficiency and or latent autoimmune diabetes in adults can be ruled out, the patient should be given insulin therapy at discharge. And so what they were trying to have you go for was option A. This patient did not have lactic acidosis. So as a cause of his metabolic acidosis, therefore metformin can still be considered as an insulin sensitizing agent, but this has to be in addition to insulin and other agents in the future. So you don't want the patient not to be on insulin, even if you are going to be using metformin. So let's go into a little bit more in depth discussion about how this kind of occurs if you are seeing it in a setting of an SGLT2 inhibitor. So SGLT2 inhibitors are oral hypoglycemic agents that decrease blood glucose by lowering the renal threshold for glycosuria. In 2015, in response to numerous case reports that suggested an increased risk of DKA when used in patients with type 1 and type 2 diabetes, the Food and Drug Administration issued a warning that SGLT2 inhibitors may increase the risk of ketoacidosis. And an interesting fact is that one of my colleagues at Loyola actually reported one of the cases, which was one of the earliest cases that was reported. So the proposed mechanism of DKA associated with the SGLT2 inhibitor class is not exactly understood or only partially understood. The glucose lowering effects by increasing urinary secretion of glucose is an insulin independent mechanism, and the lower circulating insulin levels may mimic starvation conditions, and therefore it may lead to increased ketone body formation. It is also postulated that SGLT2 inhibitors may promote renal tubular reabsorption of aceta acetate. So these two mechanisms together can contribute to an increased risk of ketoacidosis when used in patients with type 1 and type 2 diabetes. SGLT2 inhibitors also act on pancreatic alpha cells and cause an increase in glucogon levels in patients with type 2 diabetes, which is postulated to increase hepatic ketogenesis. And then you also have increased urinary glucose loss, hence the plasma glucose may be only minimally elevated at presentation, then that patient can look like the quote unquote euglycemic DKA, and the diagnosis may be missed if you're just focusing on the glucose level itself. There have been numerous case theories and case reports that have been identified cases of ketoacidosis in patients with diabetes who are on SGLT2 inhibitors. The phenomenon has been described with medication used in both type 1 and type 2 diabetic patients, and the glucose concentration may be again, less than 200 milligrams per deciliter. And this euglycemic DKA is more common in patients with insulin deficiency who are treated with SGLT2 inhibitors. Most cases identified had some external metabolic stressor, commonly surgery, which was the one that applied to our patient, illness, injury, excess of exercise, or severely reduced carbohydrate diet. Euglycemic DKA, again, looking for a glucose that's usually less than 200 or not impressive when you're seeing somebody in DKA is a rare presentation, so it's important to keep that in mind. A high index of suspicion is required because these patients do not present with a dehydration and the marked hyperglycemia that we usually see in DKA. Although it has been associated with SGLT2 inhibitor use, the overall risks are low, and the benefit of this class of medication outweighs the risks. When a patient develops euglycemic DKA, the best therapeutic option involves stopping the offending agent, which would be the SGLT2 inhibitor in this case. And that's why they were opting for option A. And remember, that was the initiation of insulin therapy. The initiation of incretin therapy without option B, which was the option B, is not sufficient enough for the care of this patient. And the continuation of empaniliflozin, which is option C and D, is not appropriate and may replace the patient at continued risk. And one of the things is I actually saw a patient like this in the ICU, and when I started talking to her, one of the first things that struck me was that she was not particularly overweight. I asked her if her weight was much higher before, and she said no. So I suspected maybe there was something going on, that she could have a lot of diagnosis that we didn't know about. So when she was in the ICU, I asked them to go ahead and send a diabetes autoimmune panel. I saw her as outpatient about a week or two later, and it was positive. And so in that patient, she didn't have type 2, she had LADA, and that really made a big difference about how we proceeded with our management. So Dr. Mazari, that's fascinating that you mentioned that. And I'm sure the talk about acetoacetate and all the components of the ketogenesis brings fond memories to everybody from biochemistry. But a practical question that I face all the time is, if a patient developed euglycemic DKA, granted in the immediate stage, as we just heard from you, incident initiation is probably the safest therapy for them. Would you ever reconsider an SGLT2 inhibitor for those patients, or does that rule them out essentially forever? So it depends. So one of the things that they didn't mention about this patient, we didn't have any data about the BMI. So whenever I see a patient who comes in to see me, and they could be anywhere in their 30s to even 60s, or even older, believe it or not, I've diagnosed LADA in a bunch of patients within the age group of 50s and 60s. That is the first thing that I would do. A low BMI or a normal BMI should alert you that maybe there was a misdiagnosis of LADA. And in those patients, really what ends up happening is you need to know if they're insulin deficient or where are we in that setting. And the other thing that's also important is understanding if patients have a certain diagnosis that the drug is not technically approved for, or in the US, the type 1 diabetics, it's not approved for the use in those patients, you want to be careful because now you're going off-label. It is approved in other countries, but not here. So that's one thing. The second thing is if I really wanted to re-challenge them with it, there's other options that we have that could potentially be better, like the GLP-1 agonist, or at least I would want to ensure that they do still have capability to make insulin, and there is maybe some background insulin on board to lower the risk of this occurring again, versus in somebody who never was on insulin and only on the SGLT2 inhibitor or other orals, but not insulin. Absolutely. Absolutely. Thank you for sharing that. Thank you for sharing that. All right, I think we can move on to our second case. I do not see any questions from the audience so far. All right, so we're going to go to case two. Case two is a 46-year-old man with new-onset type 2 diabetes who presents to established care. He has a history of hypertension and hyperlipidemia, and recently had a myocardial infarction requiring angioplasty. His current medications are metformin, 1,000 milligram two times a day, lisinopril 20 milligram a day, carvedilol 25 milligram two times a day, atorvastatin 80 milligram at night, clopidogrel 75 milligram daily, and aspirin 81 milligram daily. As you can see, these are his laboratory tests, mainly saying that the A1C is above target at 7.1, his renal function is okay, the liver tests are okay, and his lipid profile doesn't look too bad, triglycerides are 154, HDL is 44, and his LDL is less than 55. His vital signs include temperature of 98.6, blood pressure is 120 over 80, heart rate is 65, respiratory rate is 12, his weight is 200 pounds with a height of 5'7", which gives him a BMI of about 31.4. His physical exam findings are unremarkable, and he has made changes to his diet since his hospitalization. He measures his blood glucose twice a day, with levels ranging between 140 and 186 milligram per deciliter. Which of the following will be the next step in therapy? Would you A, add a sulfonylurea, B, add a GLP-1 receptor agonist, C, start basal insulin, and D, start pioglitazone? You should be able to see the question, and we will wait for the responses before we move on. Okay, it looks like we have our responses. Oh, this is beautiful. We have majority, I mean 100% going for adding a GLP-1 receptor agonist. That's very good. Okay, let's see if that's what it was supposed to gear you towards. All right, so at least we don't have a house divided. Let's go through the rationale of this case. As you know, GLP-1 receptor agonists, and there are more than one on the market now, whether they are injectable or oral, they have been demonstrated to decrease major adverse cardiovascular events, or MACE, in patients. This is really one of their biggest strengths. They also decrease cardiovascular mortality and improve renal outcomes. So a lot of positive outcomes in addition to decreasing the hemoglobin A1c. Now, in this particular patient that we discussed, this patient has several cardiovascular risks and a recent cardiac event. So you can see the GLP-1 receptor agonist, as the audience astutely decided, will really benefit from being on one of those medications. Not only to decrease the hemoglobin A1c, but also to decrease their cardiovascular risk. They improve glycemic control. They also have the positive effect of decreasing body weight, reducing blood pressure, and also an additional modest improvement in the lipid profile. Now, the reduction in the three-point MACE, it really appears to occur mostly by decreasing fatal atherosclerotic events because of improved coronary flow. So then GLP-1 receptor agonists, they have been shown repeatedly, and this looks like to be a class effect, to be cardioprotective. They're usually well-tolerated. As we all know, GI side effects are the most common side effects that are reported. Cost remains a limitation in their use. The third-party payers still have coverage that is not uniform for this drug. So patients may be facing some cost limitations. Now, we have always to remember that those medications should not be prescribed if a patient has a history of pancreatitis or they have a personal history or a family history of medullary thyroid cancer. Now, going on the other options that we had there, sulfonylureas can decrease the hemoglobin A1c. So they're significant, actually, by about 1 to 1.5%, but they usually lead to weight gain, and they're not associated with any cardiovascular benefit, unfortunately. Insulin also decreases hemoglobin A1c, but it carries a risk of weight gain, as we know, hence why option C was not a favorable one. And this patient really needs a class of drug that offers the additional cardiovascular benefit. Now, pioglitazone, as you all remember, is a PPAR agonist, and it can improve glycemic control, and it has been shown to be beneficial in non-alcoholic steatohepatitis. However, it can increase weight, partly through fluid retention, but also it can increase weight overall, and this is why it won't be beneficial for this particular patient. And we have on the screen the references that go with this case, especially the leader publication committee for the leader trial that was one of the major trials showing the cardiovascular benefit for this patient. Dr. Krikorian, is there anything else in the patient's history that may want you not to prescribe it to them? We have some patients with neuropathy and other things that can manifest in other ways. Is there another potential contraindication or questioner that you would ask your questions if you're thinking of a GLP-1 agonist? Absolutely. Thanks for that question, Dr. Mazzotti. So gastroparesis is obviously a concern. A lot of our patients with diabetes do suffer from gastroparesis, and one of the mechanisms of action of GLP-1 agonists is to slow the GI tract emptying. So you can see that if somebody has pre-existing gastroparesis, giving them a drug that adds to that by slowing the GI tract even more can compound that problem and add insult to injury. So I would not consider it as a contraindication. I would be very cautious in its use. Do you consider that Dr. Mazzotti as an absolute contraindication? I have not been prescribing it because I'm worried that it's just gonna make it worse for them from that standpoint. And there've been cases where we thought they might have gastroparesis, but this was after the fact they had been on it. So one of the things is you're gonna screen them for them. And I've seen GI sometimes wanna screen them. You wanna make sure they're off their GLP-1 agonist because otherwise you're gonna have a... It's gonna confound what you're looking for. So I've been pretty cautious in not really using it in that class, just because I'm worried. Fair, very fair point. And I'm curious about your thoughts about the newest kid on the block, the Zepatide. And I'm sure everyone on the call is aware that that's probably one of the latest GLP-1 receptor agonists, and it's been quite popular because of its effect on weight loss. So Dr. Mazzotti, what has been your experience with it? So I have been prescribing it. I'm excited about it because the data is very promising, especially we've been using a lot of the weekly GLP-1 agonist and with this, the data comparing it to ozempic, there's, I believe there's surpassed two study that showed that it does lead to more reduction or higher reduction in A1C as well as weight loss. And as you guys can imagine, what we're really seeing when our patients coming with diabetes management, we're trying to have a global approach, right? We're not just trying to bring down their sugars. We want to help them with their weight loss. And if there is renal protection, cardiovascular protection, all of those is really, we're in an exciting time. We can offer our patients that. And then if it's a once a week medicine, then that improves compliance as well. And the funny part is because there is an issue with ozempic being on back order, this was one of the medications that we were using in that setting. And so far it's been going well, but again, it's a newer kid on the block and we don't have any hard end points or data regarding cardiovascular reduction or MACE, but hopefully that will come down the line. Thank you for that. And yeah, definitely we've come a long way from when we had very limited options, essentially metformin, sulfonylureas and pH and regular. And now we can offer not only a variety of medications, but also, as you mentioned, impact their outcomes be on top of the immunoglobulin. It ignites hope in a lot of patients because they can have weight loss and you won't believe how many people are just excited because of that factor. Absolutely. Thank you for sharing that. So I think we can move to our next case. And our next case is a 32 year old gentleman with type one diabetes who was diagnosed at the age of 12 and is coming from a routine follow-up visit. He reports that he has gained about eight pounds and now weighs 200 pounds with a height of six feet. So his BMI is 25. He has so far no diagnosed comorbidities from diabetes. He works as a computer programmer, does not smoke, consumes alcohol only socially. And interestingly, his diabetes is managed with an insulin pump using Lispro in the pump and a continuous glucose monitoring device, the CGM, with the following pump settings. So as you can see, he essentially has two basals, one between midnight and 9 a.m. at 0.6 units per hour, one from 9 a.m. to midnight as 0.8 units per hour. And then he has, you can see his bolus ratios are essentially one, one unit for 12 grams of carbs. And he has three different insulin sensitivity factors with a target of 110 to 120. And as we download his readings, we can see his active insulin time has been set at four hours. His lab testing shows a hemoglobin A1C of 7.3%. And then you can see his ambulatory glucose profile in figure one. And we're gonna come back to this figure later, but I'll let the audience just take a minute to look at the different values that are there, whether it is the end target range, as well as the extremes between the low and the high, the coefficient of variation and the percent of time that the CGM was active. And you can see the overall graph as well as the daily graph on the bottom. And then if we zoom in on a particular timeframe, we can see the individual pattern during the day on three separate days, on a Tuesday, on a Monday, and on a Sunday with him. So the question that we have to face is, which of the following statements best describe the findings on this patient's CGM report? A, his time in range shows low rates of hypoglycemia. So no changes are needed to the basal. B, he has hypoglycemia overnight and hyperglycemia before bedtime. Therefore, the midnight basal rate can be decreased and the 9 a.m. basal rate should be increased. C, his coefficient of variation is high. So the insulin sensitivity factor can be changed to one for 30 milligrams to provide more corrective insulin. Or last, D, he has postprandial hyperglycemia with high variability. So the insulin to CARB ratio can be changed to one unit for 10 grams and he should be educated on accurate CARB counting. So let's maybe take a minute as we think about our answers and enter them in the poll and then we'll go through our discussion. Looks like we have unanimity again. So our audience is pretty unanimous for hypoglycemia overnight, hyperglycemia before bedtime. So decreasing the midnight basal rate and increasing the 9 a.m. basal rate. So Dr. Mazzotti, what do you think? This is gonna be the controversial question. That's what I think. All right. Okay. So let's walk through it because sometimes when we look at the answers, part of the answer is more correct and maybe not the other part. So it's a question of what would be the best answer choice. So in 2019, the nomenclature and targets for all CGM reports were identified to allow easier interpretation of the data as well as to provide targets for time and range. And you're gonna hear that parameter a lot more, abbreviated TIR. So this is presented as the AGP and then you're looking at the different components. We kind of looked at it at the previous page which is it's looking at the dates that the data was downloaded, percentage of time that the CGM is active. This is super important to look at. Average glucose, glucose management indicator which comes up as GMI and kind of gives you an A1C equivalent based on the data that's available. But that only comes up if the patient has been using their sensor at least 70% or more. There's a coefficient of variation or glucose variability and that we wanna aim for less than 36%. And the reason why we want that is because when it is above that, there's a higher risk of hyperglycemia associated with it. And then time and range which you wanna aim for at least over 70%. And then there is the AGP graph profile over the 24 hour period with median and interquartile ranges. So it gives you a more schematic picture of what it is that the general trend for that patient is. So you can take a quick look at it and understand in most patients what's going on. Now, it is also very important to look at type 1 and type 2 diabetics and aim for certain targets. Again, this still needs to be individualized. You're trying to minimize hyperglycemia over 250 and over 180. So aiming for less than 5 or 25% respectively for those ranges and then aiming at least for a time and range of over 70 and minimizing hypoglycemia. So aiming for less than 4% for less than 70 and less than 1% for less than 54. But keep in mind while these are guidelines you still have to decide what fits the patient best. So if they have hypoglycemia or an unawareness or their older patients are more frail you might wanna relax their targets a little bit more to really avoid hypoglycemia. But then if you have a pregnant woman and you really wanna tighten their control and the hyperglycemia becomes a bigger issue. So the patient in the vignette, the AGP identifies several opportunities for improvement. So we're gonna kind of walk through it and it's important for you guys to go through it systematically and see what is the best way for you to flow when you're looking at this. One of the first things I look is percentage use because if they're not using it enough like 12%, 25% it's really hard to extrapolate data from that. And you won't even get a GMI based on very low usage because you can't really look at that. That'll give you your average glucose and then you wanna know where their breakdown is. So this patient is only 46.5% in time and range and we need that much higher. Majority of their time they're spending high but they are still having low sugars which is above the target of hypoglycemia you wanna have for this patient. And then when you look at the schematic you can see the lows are happening more in the early morning and then the highs are happening more in the afternoon and where we're seeing it in the like maybe 3 p.m. on where you have the highest glucose readings. So what I usually do then I start going with the patient as I have the printout of everything with me and I go to the, let me see, sorry about that. Did you want me to go back one slide Dr. Mazzarri? No, I lost where I was because of my computer did something funny but that's okay I can figure it out. So what I usually go to is I go to the most recent data and when I look at the most recent data the patient can tell me what is going on with their activity, their diet and their date and then flip backwards and find out what's going on from that standpoint. So let's see. I apologize, I lost my screen because something just popped up. So I will try and get back on. No problem. If you tell me what screen we're on then I can remember from memory. I got it. Oh, okay. Oh, go ahead. No, I was gonna say I have the screen that we're on now shows the different days. So it shows the cross-section of three days essentially and the individual patterns on those days. And then what you can see at that point is that the patient is having hypoglycemia in early mornings. The timing of it is a little bit different and then you can see the highs happening later in the day. The one thing to keep in mind that we do not have in this question is we do not have the patient's pump data. So we don't know when they bolused, when they corrected and all of that. That's really important because you're superimposing the CGM on what's happening with their pump data. And looking at this, they didn't tell us this patient was on auto mode. So we're assuming that they're on manual mode because otherwise we would have more data about that as well. So that's kind of how you wanna look at it and see is the patient looking like they're counting accurately. If you see the sugar go up and then you see a bolus, they're obviously the timing of that is wrong. So you wanna really extrapolate as much as you can for that. All right. So are we on the next one, which is the, he has a higher than target range. All right. So very good. So he has a higher than target range of hypoglycemia with 5.3%. Remember we want it to be at least less than 4% from that standpoint. And then the AGP graph demonstrates what we already saw. So lower sugars in the morning, and then it's gonna be higher later. So the largely overnight in the fasting state, you see the low sugars. So this can be addressed by lowering the basal insulin during those hours. He also has the hyperglycemia at night, beginning at 3 p.m. and continuing through midnight. And so for this, the insulin to carb ratio can be changed to provide a larger mealtime bolus. This patient was on a one to 12. So potentially lowering it to one to 10 would be helpful, which is option D. All right. So we are on, although the insulin sensitivity factor can also be changed to provide a larger bolus dose, it is more crucial to address what's happening with the carbohydrate bolus first. He has a high coefficient of variation of 40.4%. Remember, our goal is to get it less than 36%. However, we look at the AGP graph, there's no day-to-day or even meal-to-meal consistency. And it's really hard when you're trying to find a pattern going through these reads to see what the patient went. And the patient would benefit from further education about carbohydrate counting when they're bolusing and trying to get their low sugar than 4% and then going from there. All right. So therefore his basal rates would need to be decreased overnight despite the A1c value, which would be option A. So now I'm on the next slide, which is his pattern of hyperglycemia are more likely not from his basal rates because they coincide with his after lunch and after dinner meals. So increasing the basal rates would not correct this. That's why option B was wrong. And then although his coefficient of variation is high above the desired range of 36, adjusting that would not address where we're seeing some of those problems going on. So, thank you, Dr. Mazzotti for, I mean, this is a comprehensive overview you provided for this case. And I know it can be tricky and you astutely mentioned that usually also we would like to overlap the pump data on that. So in real life, how do you do it? So you have your patient and then you look at, you take your time and you look at the patient you look at, you take your time and you look at everything comprehensively and you try to understand step-by-step how they went through their days and what did they do? Yes, I literally have the printout of the pump data and I have the printout of the sensor and I flipped through it with the patient and I have a pen in my hand where I start writing down what's going on. And then if I see like a sharp increase of glucose and I look and there's no bolus, I'm like, hey, did you eat anything? And did you not bolus for this? Or I see this one up and then like about an hour later you bolus, did you forget to bolus? So really we sit there and decipher all of that. In the new age where we do have the automation there's a lot of buffering that goes on with it because the automation helps patients. So we do our best to do that when we can offer it to patients and they're willing to go on that. But when they're on manual mode, I literally sit down and side by side and go through what's been going on. Got it. Okay, so in this particular case, I think the trick was, should we change? And I know you and I have had a little bit of discussion about that. Should we decrease one basal and increase one the other at the same time or should we just do one change at a time? What do you usually do in your practice? Do you change a bunch of things on the pump or you just do one incremental change at a time? It depends. If I am worried if I make two changes that potentially can lead to hypoglycemia that I'm not sure what it was secondary to, I won't. But if I feel like I can decipher the two different things then I will make more than two changes. I try not to make three or four changes because in that case it can be a little bit tricky. So if you're increasing a basal at an increment of the day while you're changing the insulin to carb ratio to give a higher bolus, now the patient's hypoglycemic and you don't know what did it. So it really depends. And I think like in certain scenarios, kind of like what we saw here, I think adjusting the insulin to carb ratio to help with the hyperglycemia is helpful but I still think it's reasonable to go down on the overnight basal because there was hypoglycemia going there too. I fully agree with you. And I think this is sometimes how, answering a board question is a little bit tricky and you have to choose the best one which may not be your ideal one but this is the best option that we have. Now you mentioned something about automation and auto-mode. Does that give a particular challenge when you're dealing with those patients? It actually gives a solution a lot of times because in those cases, when patients are not bolusing or potentially the over bolus, the automation helps buffer the highs being very high and potentially preventing low sugars. But as you know, the same way as using a CGM, they really have to stay in automation for it to give them optimal therapy benefits from that standpoint. And there are three different automations. They work differently. You have to understand the nuances between them and which would be the best fit for that patient. So we've had one for a while, then the second automation came about and then most recently, the third automation algorithm is now available. So we sit there and figure out what is the preferred one for each patient and talk them through it. Got it, okay. Thank you for that. Thank you for a very robust discussion. I think we're ready to move on to our next case. All right, Armand, I'm gonna do mine through mine. So I'm not seeing it a little bit. Is it a little bit different than yours, but I'm fine with clicking through mine. I just wanna make sure we're on the same page. Okay, so case number one. All right, a 20 year old woman who was diagnosed with type 1 diabetes about a year ago is being evaluated. At the time of diagnosis, she was experiencing increased frequency of urination, nocturia and diminished hunger. With a decrease in eating as well as about a 15 pound weight loss. She was a college freshmen studying pre-nursing and attributed it to the life change with starting school. Her mother has a history of type 1 diabetes as well. Going to the next slide, her hemoglobin A1C was 14.4% and a random blood glucose concentration was over 400 milligram per deciliter without ketoacidosis at the time of our presentation. If we look at the labs, we can see that the C-peptide was detectable and in the normal range and her GATT antibody, islet cell antibody and insulin antibodies were all negative. Next slide. She was started with basal bolus insulin therapy with her A1C improving to 6.9% after six months. Her stimulated C-peptide was 1.4. Her concurrent blood glucose at that time was 175 and her urinalysis conducted at the current visit showed positive for glucose. Genetic testing was subsequently performed and the patient was told that she could transition to sulfonylureas. Next slide. Now we're gonna go over the question choices. What is the genetic defect most likely to be identified in this patient? A, glucokinase gene, B, hepatocyte nuclear factor 1A, C, hepatocyte nuclear factor 1B, or D, hepatocyte nuclear factor 4A. Next slide. So here we have a split as well, so about 25% chose glucokinase gene, 25% have had a nucleofactor A, 50% have had a nucleofactor B, and have had a nucleofactor 4A but did not get any votes. All right, can you walk us through which percentage won? Sure, and you know, so my little confession slash secret is this is one of those that I always have to go back and look it up, whether it is in clinic or, you know, if I'm sitting for the boards is the one that I focus on memorizing and making sure I memorize at the very, very last minute and refresh my memory. So as we all know, maturity onset diabetes of the young or MODY is the most common type of monogenic diabetes, and it's characterized by beta cell dysfunction, early onset, and it is transmitted in an autosomal dominant fashion. So the first and the second phase of insulin secretion is impaired in individuals with HNF1A mutations or hepatocyte nucleofactor 1A mutation, resulting more often in overt diabetes and accounting for about 70% of the cases, so it's actually the most common one. These patients are very sensitive to sulfonylureas and this treatment is usually effective for several decades, which is great for them. However, insulin therapy may be needed when the insulin production is severely decreased and usually this is at a later stage. Now diabetes caused by mutations of the HNF4A gene is much less common. It's about 5 to 10% of the cases, but it should be considered when clinical characteristics of HNF1A are present, but the gene analysis does not detect the mutation in this gene. So it's kind of a diagnosis by exclusion. Some factors that can help distinguish the 4A from the 1A are later age of diagnosis and the lack of pronounced glycosuria associated with the former, which in our case, we had the glycosuria in the case of this was kind of a tip off. This patient has the glycosuria, so most likely she has a defect in 1A and not 4A. Now the glucokinase modi is characterized by kind of a mild non-progressive hyperglycemia and is best described as the disturbed beta cell glucose sensing. Actually pharmacological treatment is usually not recommended because the hyperglycemia in this case is resistant to oral medication due to the set point alteration, the glucose homeostasis. So this is why that option was not the most likely option in this particular case. And the diabetes in 1B modi develops usually during adolescence or early adulthood. Patients exhibit some degree of hepatic insulin resistance and about half of them do not respond to sulfonylureas and require very early insulin therapy. That's why this patient most likely does not have a defect in the 1B gene. And I put the references on the screen for everybody, but really the take home message for me at least for this case is that we have to just be able to recognize that this is not your usual type 2 or type 1 diabetes and recognize those warning signs that we should be looking for something else. And then if we don't have them memorized, it's okay to just go ahead and search them up and find out which one it is, but at least avoid the trap of thinking, you know, this is just type 1 diabetes or type 2 diabetes and treating it that way, which would be doing the patient a disfavor. Any other thoughts on that, Dr. Mazzotti? Yeah, so I have two. So when you're suspecting this, how detailed of a family pedigree or diagram do you usually try and come up with? And the second thing is with all genetic testing costs and whether insurance covers it, are there any thoughts you have regarding those two points? That's a great question, two questions. Thank you for those. I just scrolled back to our options there just to remind everybody. So yes, I try to construct a detailed family tree as much as I can because the autosomal dominant transmission for the 1A mutation obviously is a tell, and if we see it skipping generations, then that might be throwing the diagnosis into question. As far as cost, yeah, it is definitely a challenge obtaining authorization for those costs and making the case. Sometimes I've had to go for direct conversations with the third party payer. The lure, I guess, that I sometimes use is, hey, if they have the mutation and I can keep them on a sulfonylurea, that's usually a cost saving for the third party payer rather than using insulin for life. So there is a payoff there, but I'm curious about your experiences also. Yeah, so we tend to have these messages that go through our old endocrine group and it has shifted over time. How can we cover this? And there are some times that are certain experts in this area that can be of assistance. I believe one is at U of C and other places. So we kind of endocrine crowdsource about what are some of the ways that people have been able to be successful at getting it covered and consider those options as well. Absolutely. Absolutely. Thank you for that. And I think we are ready to move on to our fifth case. All right. So this is a 50-year-old woman with diabetes type 2 for about 10 years who's brought by her daughter to the emergency room. The patient had not been feeling well and was doing well actually until about a week ago when she began complaining of urinary burning, which she was treating with cranberry juice. The daughter noted that the mother had increased urinary frequency and thirst. And this morning, prior to coming to the ER, she was confused, which led her to bring her in. She had run out of her metformin a few months ago, but had not followed up with her physician and does not check her sugars. So going to the next slide, on exam, her blood pressure was 101 over 58. Her heart rate was elevated at 114, had a mild fever of 100.4. Her height's 55, her weight is 190 with a BMI of 33. The patient is drowsy but arousable and only oriented to person. Her oral mucosa was very dry, her skin turgor is diminished, otherwise her examination findings were normal except for the tachycardia. Her glucose was elevated at 980 milligrams per deciliter, and in the emergency room she received two liters of normal saline over two hours. Going to the next slide, these are her labs. So looking at what we see, obviously the glaring thing is the glucose of 878. You can see her sodium is elevated at 150, her potassium is slightly elevated at 5.3, her bicarb is 30, her BUN and creatinine are 56 and 1.9, and her osmolality is 369, which is elevated. Her pH is 7.42, and the urinalysis shows about 50 to 100 white blood cells. There's one plus ketone and her serum ketones are negative. Going to the next slide, now we're going to come up with what we should do. So in addition to insulin, which of the following IV fluid regimens would be the most appropriate for continued fluid management in this patient? A, IV half normal saline at 250 to 500 ml per hour and then changing it to half normal saline when the D5 half normal saline, when the glucose is less than 300, B, half normal saline at 150 to 200 ml per hour and changing it to D5 half normal saline when the glucose is less than 150, C, normal saline at 250 to 500 ml per hour and changing to D5 half normal saline when the glucose is less than 300, and finally D, IV lactated ringer solution at 250 to 500 ml per hour, and then changing to D5 ringer when the glucose is less than 150. So we will wait for the answers to come in. Usually when I get such a question in the boards, it takes me a while to untangle all of them because they start looking the same. Do you get glossy eyed? I totally do. I try to break it up in parts. All right, so the answers are in. So we had zero for option A, 25% for option B, 75% for option C, and zero for option D. So it is a split, but leaning towards C it looks like, starting with normal saline. Got it. Thank you for that. And really, as everybody figured that out, we're trying to go through the optimal management for fluids and electrolytes for a patient who's experiencing hyperosmolar hyperglycemia. I'm going to try to run through this case so that I give enough time for the last case we have for you, and we have about six minutes left, so I'll be mindful of everybody's time. So our patient obviously had a UTI, which could precipitate a hyperglycemic state, noncompliance with the medication. In addition, clambering juice is high in carbohydrates, and there is scant evidence that is actually helpful for urinary tract infections. So our patient met all the diagnostic criteria for HHS, and it's important to remember that the water deficit in HHS is quite high. It's about 100 to 200 milliliters per kilogram. So fluid management, and our colleagues in the emergency room are very attuned to that. Fluid management is very, very important in those patients. Giving fluids by itself, as you know, improves hyperglycemia. It also decreases the counter-regulatory hormone production. Correcting the hyperglycemia also helps with the insulin resistance, so it's making the insulin infusion more effective as we initiate insulin in those patients. And optimally, the goal is to decrease the glucose by about 50 to 75 milligrams per deciliter per hour. You have on your screen the formula for the water deficit and how to calculate it. So when you apply it to our patient, really the estimated fluid deficit is about seven liters. So that's very, very significant as a fluid deficit. Now, the consensus statement from the ADA is to give normal saline at 500 to 1,000 milliliters per hour during the first two to four hours. Then you slow down, you keep the normal saline, you just slow down to 250 to 500 milliliters per hour if the sodium is low, or you switch to half normal saline, 0.45% saline, if the sodium is normal or high. And then when the glucose decreases to 300, the IV fluid should be changed to contain 5% dextrose, keep the insulin going until the patient is mentally alert and the osmolality is less than 310. So consequently, because this patient had already received two liters of normal saline and the sodium continues to be high, changing her fluid to half normal saline at 250 to 500 is the appropriate at this point. And then adding 5% dextrose when the glucose is less than 300 is the most appropriate step for her, which would be option A. I'll run through the rest of the options. Option B, as you recall, gave us half normal saline, but at a lower rate, which is really too low to replace the fluid deficit appropriately. The regular normal saline at 250 to 500 and then changing to half normal saline when less than 300 is not appropriate because based on the guidelines we just reviewed, the continued diffusion of normal saline with a high serum sodium does actually increase chloride levels and can cause hyperchloramic acidosis. So we definitely want to avoid that. And then when there was a study that compared using lactated Ringer to normal saline and half normal saline, it actually found that the time to correcting hyperglycemia using lactated Ringer was longer. This is why using any form of lactated Ringer is not advocated in the guidelines for either DKA or HHS. And these are the references for you. And I'll just go immediately into case six. In case six is a 43-year-old woman with type 1 diabetes since age of 13 who's coming to you for evaluation. She has required four paramedic interventions over the last six months for hypoglycemia. She maintains a higher glucose to avoid this hypoglycemia. And this has unfortunately caused diabetic ketoacidosis on several occasions for her. Her A1C has been above 8 for years now. She works as a legal assistant in a busy practice case for her three children at home. She has been taking continuous subcutaneous insulin infusion as well as a CGM that was added recently. She has had wide fluctuations and her Clark score was calculated to be 5 for hypoglycemia unawareness. The physical exam, her BMI is 26 and essentially otherwise normal. The only notable findings is that she had the insulin pump insertion, mild lipodystrophy, decreased sensation to monofilament, A1C of 8.5, microalbuminuria, and a GFR of 82. And the last question for this evening, she is exhausted and she read about transplantation to quote unquote cure diabetes and she would like to know if this is an option for her. So what would you advise her? And I'll let you quickly go through the options and answer them and we'll probably have a minute. So we won't give this case, I think it's true justice, but I'll ask Dr. Mazari to comment on it. And we got our answers mostly split between choices A and B. Dr. Mazari, what do you think? Yeah. So one of the things that you want to kind of make sure there's an objective reason for this is they mentioned her Clark score and her Clark score, as you remember, was above five. So one of the things that will happen is when patients have true hypoglycemia, an awareness, that is one of the indications for it. And then the Clark score is one of the ways that you can look at this. And then there is also the bold score, which basically asks, do you know when your hypos are commencing? And it goes based on a seven point Likert scale and either of those, if it's above four would qualify. So it is something we definitely need to keep in mind. And one of the take home points of this is that there is a much better longevity with pancreatic transplant these days than it was before. And also islet cell transplant is something that has come up as well. We like to have dual organ transplants, kidney and pancreas in appropriate patients. So in this patient, she wouldn't qualify because her renal function was okay. So it would be either pancreatic cell or islet cell transplant. The reason why dual transplant is helpful, it seems that the pancreatic lifespan of that transplant tends to be longer in that setting. So if somebody who has renal failure and type one diabetes, it is great to consider them. But again, this would not be this patient. As far as the islet cell transplant is concerned with that, what ends up happening is that you can have it at certain centers, but it is not maybe readily available for all patients. And this patient would potentially benefit from islet cell transplantation alone. And in that, I'm going to go to the, to kind of review that information, because what you have, the longevity of that is a lot better than it was before. And in this patient, it can be very helpful. So according to the international pancreas transplant registry, the survival rate for patients who had a pancreatic transplant alone was greater than 95% at one year and greater than 90% at five years. Graft survival of up to 94% at one year and up to 84% at three years. So this helps reduce diabetes burden, decay and hypoglycemic events, which this patient was suffering between both of those and further diabetic complications, which she already had a bunch of them as well. So again, islet cell transplantation is currently only performed under investigative protocols and a few U.S. centers. People do very well with that as well. So the transplant function at one and five years after transplant is found to be 93 and 81% respectively. A1C concentration was less than 7% with no symptomatic hypoglycemic events occurring in about 82 and 54% respectively. And then you can also have insulin independence in about 67 to 40% of patients at one and five years after islet cell transplantation. So it is a very good option to consider in the appropriate patient. And in those with type one diabetes and hypoglycemia unawareness, but preserved renal function, islet cell transplant resulted in insulin independence with A1C concentrations of less than 6.5% in 39 and 25% at five and 10 years respectively. So that is the main takeaway point. And the American Diabetes Association published a position statement in 2006, outlining the indications for considering pancreas and islet cell transplant in patients with type one diabetes. And this is for patients who do not have kidney failure. So if they have a history of frequent acute and severe metabolic complications, which can include hypoglycemia, marked hyperglycemia or ketoacidosis, that's one, clinical and emotional problems with exogenous insulin therapy that are so severe that it can be incapacitating to the patient. And then the third one was consistent failure of insulin-based management to prevent acute complications. So those are the main takeaway points for this question. Thank you, Dr. Mazari, and thank you for this comprehensive discussion. I put the references for our audience for this last case, and I know we went over a little bit. So any last thoughts, Dr. Mazari? Well, I'm very glad that we were able to do this, and hopefully the people who joined us found this to be informative. I am glad that they didn't get 100% of it right all the time, which means the questions were difficult enough or challenging enough that we were able to have good discussion points and allow you to look for certain specific things in the questions to flag you about what are they trying to ask you or what do they want you to recognize? Thank you for that. And I believe I learned a lot from this discussion, too. So thank you for all the teaching points. Thank you. Same to you. Thank you. Have a wonderful evening, everyone. Thank you so much for joining us. Take care. Stay safe. You, too. Thanks.

diabetes management

euglycemic diabetic ketoacidosis

SGLT2 inhibitor

insulin therapy

GLP-1 receptor agonist

blood glucose levels

hypoglycemic episodes

pancreatic transplantation

hyperosmolar hyperglycemic state

fluid management