In this Grand Rounds presentation, David W. Lam, MD, discusses euglycemic diabetic ketoacidosis in patients with type 1 diabetes. He discusses the current state of type 1 diabetes care, and the risk factors and mechanisms associated with the development of euglycemic diabetic ketoacidosis. He describes the tendency of patients to use off-label, adjunctive treatments for type 1 diabetes, and how they increase the risk for euglycemic diabetic ketoacidosis. Dr. Lam also provides an in-depth overview of the principles of management for this condition.
I'm honored today to introduce Dr David Lam for his grand rounds on you glycemic diabetic ketoacidosis in the modern era. Dr. Lam received his medical degree from the University of Maryland and completed his internal medicine residency at Thomas Jefferson before moving on to complete his endocrinology fellowship here at Mount Sinai. As medical director of the Mount Sinai Clinical Diabetes Institute, he champions diabetes related initiatives and care pathways across the Mount Sinai health system, ensuring and promoting quality health and care for those living with diabetes. As director of the hospital based diabetes clinic, Dr Lam has led multiple initiatives specifically for the in patient management of diabetes. Dr. Lambs Research interests include diabetes technology for both Type one and Type two diabetes, as well as outcomes for hospitalized diabetes patients. Please join me in giving a warm welcome for Dr David Land. Okay, thank you for such a nice introduction and thank you all for for spending your Tuesday morning with May on for the warm invitation to give you guys grand rounds. In terms of disclosures, I do have or have had investigators support from the following companies, some of which whose medications that will be discussed during this presentation. There will also be a discussion of unlabeled or unapproved investigational Excuse me medications those which are listed here. Um, in the sense in the context of this is a discussion of off label use in type one diabetes, as it's been reported in the medical literature. This is specifically not necessarily a recommendation for their use, though. So to start with a case, this is a 29 year old female with the history of type one diabetes and asthma who presents to the emergency department with nausea and vomiting, which started the morning of presentation, she reports. Elevated blood glucose is over the last 24 hours, despite administering correction doses of insulin through her insulin pump. Suspecting that her insulin pump was not functioning properly, she administered a correction dose of subcutaneous insulin via syringe, which based on her blood sugar, which did improve her glucose control. However, the next morning she still continued to feel poorly and actually started to experience nausea and vomiting, which prompted her to present to the emergency department. She denies any sick contacts. Fevers followed IPSA or Polly area. Her diabetes history is significant for being diagnosed at age six. She has no known microvascular complications. Past medical history is consists of Type one diabetes, asthma, anxiety, her social history. She does not smoke. She's a social alcohol drinker with one glass of wine the evening prior to admission. No recreational illicit drugs. And she's actually a graduate student visiting New York City, and her endocrinologist is out of state medications. She takes insulin Weisbrot via continuous subcutaneous insulin infusion pump, otherwise known as an insulin pump. Canada flows in 100 mg once daily and all prize lamb on exam. Her heart rate is elevated at 120. Blood pressure is 1 14/54 her BM minus 24 her exam is notable, really just for dry mucous membranes, lung and abdominal exam are unremarkable. Lab data on a mission to the ER is significant for bicarbonate of 12.2 ah, glucose of 1 91 and a calculated and I'm gap of 25. Her Venus blood gas has a pH of 7.21 in her urine demonstrates ketones greater than 160. The impatient diabetes services consulted do the presence of Quetta Nouria, but in the absence of hyperglycemia and ultimately she is diagnosed with you glycemic diabetic ketoacidosis in the setting of a likely insulin pump malfunction combined with concurrent use oven SGL t two inhibitor Can it flows in? So this case really inspired me on demand Has raised a lot of discussion amongst our colleagues within our division, uh, to raise the awareness of this entity called you glycemic Diabetic ketoacidosis, for which I'll refer to just simply, is you glycemic DK The objectives for this talk are to first identify risk factors that are associated with the development of you glycemic DK in patients with type one diabetes and then to discuss and the diagnosis and understand the general management principles of you. Glycemic DK So the traditional definition of regular plain old diabetic ketoacidosis is important to first understand. So it's one of our few diabetes emergencies, and most medical students probably can tell you the exact diagnostic criteria for DK. But this consists of a blood glucose greater than 2 50 a metabolic acidosis when an anti in gap and ketosis. However, in you glycemic DK the press, there's still the presence of metabolic acidosis in ketosis. But with normal blood glucose is now. This presents a very a diagnostic dilemma. You ask any patient with type one diabetes or really any clinician what is the hallmark of diabetic ketoacidosis and they'll tell you it's hyperglycemia. Our patients with Type one diabetes know that if their blood glucose is air elevated, that's when they have to think about DK you glycemic. DK, therefore, presents a significant dilemma now. This is not necessarily a new diagnosis or a new phenomena. In 1973 it was first reported by Monroe and colleagues. Excuse me in a case, Siri's off about 211 cases describing the metabolic arrangements in diabetes, 37 of which had what they considered to be you glycemic DK they and I quote this paper considers the other extreme of the broad spectrum of diabetic metabolic decompensation, namely severe ketoacidosis with a plasma bicarbonate of 10 or less without pronounced hyperglycemia the blood glucose being less than 300. We have called the syndrome you glycemic diabetic ketoacidosis for lack of a better term. So how did it? How do we think this happens? There were two proposed mechanisms based on the majority of patients that were presenting in this case, Siri's with Type one diabetes. Many of the patients were reported to have been starving or significantly restricting their carbohydrate intake. So what starts with starvation leads to a reduction in caloric intake, specifically carbohydrates and a concurrent reduction in insulin dozing. This results in a relative insulin deficient state and then shift the metabolism to become dependent more on like policies and an increase in free fatty acids, leading to ultimately and increasing keto acids. Concurrent is an increase in counter regulatory hormones with an increase in urinary glucose loss, and this, combined with glycogen depletion in the setting of starvation, leads to UGC Mia. The combination of UGC Mia and metabolic ketoacidosis leads Thio. You glycemic DK another significant cohort in this in these 37 patients where pregnant patients who actually had poor control of their diabetes and we're in in response were reducing their carbohydrate intake. So in pregnancy, due to increases in placental oxygen and cortisol, this contributes to insulin resistance. With the reduction in the starvation that happens when women are trying thio control, their blood glucose is a bit better. There's a relative insulin deficiency and then the same pathways of increased like policies and increase in free fatty acids and increase in keto acids. In addition, in pregnancy, there's an altered renal glucose threshold such that there's an increased clearance of glucose from the from the kidneys leading to glucose area. Again, the combination of glucose e area and an increase in ketosis leads to you glycemic DK Now this was not a very commonly reported diagnosis. Ah, quick pub med search. Um, looking at the number of times you guys systemic decay was mentioned in published literature reveals that it was a relatively unreported diagnosis up until about 2015. In order to understand both, why are patient had you glycemic decay and why, until 2015, this was an under reported diagnosis. I think I'd like to first take a step back and talk about just the general state of Type one diabetes care, its limitations and it's challenges. And then talk about why patients with Type one diabetes may be seeking off label treatments such as our patient in the treat in pursuit of a better class seem in control. Finally, I'm going to circle back to you guys stomach DK and talk about mechanisms of more modern post 2015 DK and then also close with the principles of management and you guys to make DK. So what is the state of diabetes care? There are two classes of medications that approved for Type one diabetes, insulin and Kremlin tied. This pales in comparison to the 12 classes that are approved for Type two diabetes. There are a host of FDA approved devices and and, uh, for insulin delivery and glucose monitoring. This includes the bear standard of insulin pens, vials and syringes glucose meters. But more recent advances have included continuous glucose monitors, which consists of a subcutaneous sensor which detects interstitial glucose and translates this to predict near real time. Blood glucose is insulin. Pumps, such as what our patient was using are basically devices seen here in this picture that deliver rapid acting insulin. They contain pre programmed rates which specify the our hourly rate of insulin infusion, and they also provide the patient guidance with how much insulin to take based on carbohydrate intake and also their blood glucose levels. More advanced therapies include the combination of using insulin pumps with glucose sensors, including the threshold suspend systems which basically will halt insulin delivery if a glow glucose is detected on the sensor predictive low glucose suspend, which actively predict if a patient is about to be experienced. Low hyperbole sr Excuse me and therefore, in response to that reduce insulin delivery. And lastly, what's considered to probably be the most advanced therapy currently is a hybrid closed loop automated insulin delivery, otherwise known as the artificial pancreas, which could both increase and decrease insulin delivery based on sensor blue blood glucose is so with all of this technology and a whole whopping two classes of medications available for treatment, why would any patient with Type one diabetes use an off label, non FDA approved medication? Well, the D, C, C T and edict trials really demonstrated the benefits of intensive glucose control. And this kind of these were landmark trials in which patients with Type one diabetes were studied over 6.5 years and looked at the intensive, intensive control versus conventional therapy and what they showed in the 6.5 years with the D. C. C T. In the 17 year followed with the edict trial was that there was a significant reduction in microvascular complications as well as a reduction in cardiovascular risk. But achieving blood glucose control to the level of which the D. C. C. T has really set the bar is difficult. The majority of patients with Type one diabetes are not meeting this goal. So this graph here is data from the T one D exchange, which is a conglomeration of diabetes clinics, one of which might sign is a part of and consists of about 26,000 patients living with Type one diabetes. And in this graphic, it shows the mean hemoglobin, a one C reported across the spectrum of ages. And you'll note here that no matter what age, most people are reporting an A one c greater than 7%. So the vast majority of people really aren't meeting their goal. And this is for a number of reasons. First of all, insulin therapy causes hypoglycemia in this same 26,000 patient cohort. Nearly a quarter of the patients reported severe hypoglycemia. So this is hypoglycemia, the results in seizure or coma since their diagnosis. Not only is there a limitation in, uh, in hypoglycemia with insulin therapy, there's also weight gain associated with insulin therapy in the D. C C T trial, the intensive armed patients gain nearly 5 kg in the three year period, and in another cohort, the Pittsburgh GDC cohort with Type one diabetes. They also reported increasing prevalence of overweight and obese in type one diabetes over the over between 1986 2007. This here shows in the gray in the black. The prevalence for em is greater than 25 greater than 30. So suffice it to say, Type one diabetes care isn't exactly where we want it to be, and it's also fraught with challenges, namely, weight gain and hypoglycemia. Yeah, and therefore patients with Type one diabetes are seeking off label therapies to avoid the negative effects of approved treatments, all in the pursuit of achieving better glycemic control. So what's out there? What are the medications that people are using? I'm going to start with talking about three major classes that have been reported in the literature for off label use in Type one diabetes. The first classes met Foreman. It's a big win. I'd which reduces hepatic Lucchini in Genesis and promotes peripheral glucose uptake again this is a medication that's approved for use and type two diabetes, not Type one diabetes. The potential benefits are quite long, so there's long term safety and efficacy data for Type two diabetes in Type two diabetes used as monotherapy, there's no hypoglycemic risk. There's weight loss associated with metformin, their potential toe lower insulin doses. It's cheap, and it's a normal medication compared to the multiple injections that patients with Type one diabetes have to use. In addition, there's a low side effect profile, the most common of which are nausea and diarrhea. So does it work limping and colleagues looked looked at Met Foreman being added to insulin therapy for overweight adolescent outright. Excuse me, an obese adolescents with Type one diabetes in a double blind, placebo controlled randomized trial. They looked at adolescence with the mean duration of diabetes of seven years, and they tie traded metformin to 1000 mg twice daily compared to placebo with insulin adjusted. As for clinical judgment, their outcomes demonstrated no significant difference in hemoglobin, a one C at the end of three months. But however they did note a reduction in total total insulin dose as well as B M I. Nearly a quarter of the patients in the metformin arm were able to reduce their insulin dose by 25% and a quarter of the patients were able to reduce their bm my standard deviation by Excuse me z z score by by, uh by 10%. And in addition, there was no severe hypoglycemia in the metformin group. Yeah, What's that? Excuse me. There was more severe hypoglycemia. The metformin group in the removal trial. This was a trial looking at adults with type one diabetes, not necessarily overweight. With at least three of 10 specified cardiovascular risk factors, patients were randomized to either received that foreman 1000 mg twice daily or placebo. Now the investigators here specifically, we're looking at the potential for metformin to reduce after sclerosis and cardiovascular risk in, uh, in the setting of that this this has been observed in type two diabetes as a surrogate for atherosclerosis. They looked at the mean far wall, corroded into the media thickness and is the primary outcome. In addition, they looked at as a secondary outcome hemoglobin a one c changes in the primary outcome. There was no significant difference, however, in the secondary outcome. They observed a drop in hemoglobin a one C three months. However, this was not sustained over the 36 month study period. They did note a decrease in insulin dose ing over the study period that was sustained as seen in the right graphic here. But in their conclusion, investigators said that there was no evidence to support the use of Met Foreman and Type one diabetes to improve glycemic control. So not a very exciting Siris of two cases looking at metformin. The next class we'll talk about our GLP one receptor agonists. Um, specifically, I'm going to be discussing Laura. Glad tidings sanitized however there are. There are other agents again. This is a medication that these air medications that are FDA approved for Type two diabetes and arugula tide has a separate indication for the treatment of obesity. GOP receptor agonists work by decreasing postprandial glucose gone, and they also are responsible for decreasing postprandial hyperglycemia. They delayed gastric emptying, provide early society and are associated with weight loss. The potential benefits for Type one diabetes being uses an off label medication include potential weight loss ah, lowering of insulin doses and a relatively low adverse risk side effect profile, including nausea and vomiting. However, there is a rare, serious Advest adverse effect of pancreatitis. Looking at the data for using GLP one receptor agonist and Type one diabetes, I highlighted three of the major trials that have been looked at a larger population of patients. You'll see here in the first trial over 26 weeks, Laura Gla Tide was used in 90 patients without a significant difference in a onesie drop. However, a significant decrease in weight in the lower aglow tied arm Adjunct one and two or two Phase 38 trials industry sponsored, which looked at laurel tied and Type one diabetes. I jumped. One looked at it for 52 weeks, did not demonstrate a significant difference in a one. C. Lower and capacity, however, did show a significant decrease in weight and adjunct to actually did show a difference in a one C and the difference between adjunct to an adjunct one. Where that there were insulin. Uh, there were insulin. Doses were kept in the Thai tray shin in the outpatient setting, and there was also again decreases in weight. So overall, with GLP one receptor agonists the data is not the most convincing for decreasing hemoglobin A one C. However, it does suggest there is associated weight loss. The third class and I think that the one that's the most relevant to our discussion here are s guilty to inhibitors, namely Canada flows in which our patient was taking em, pickle flows in and capital flows in. These are all FDA approved for Type two diabetes, the sodium glucose co transporter, as the name would suggest, co transport sodium and glucose in the proximal tubules. They lead to glucose re absorption in the blood inhibitors, promote renal excretion of glucose and reduce the blood glucose and insulin independent manner and for this reason, are particularly attractive for Type one diabetes in that it does it in insulin. Independent manner and potential has the potential to work. I'm gonna talk a little bit about the Type two diabetes trials because this is a relatively new class of medications. Canada flows in, was compared to cities Lipton in a 52 week trial and demonstrated a lowering of a one C reduction Lord. Excuse me, a lowering of a one C more weight loss. However, a higher rate of genital fungal infections and pickle flows and used in combination with insulin and metformin compared to placebo, was studied over 52 weeks and demonstrated a greater than a greater a onesie reduction, total daily insulin dose reduction and also weight loss. It's important to note that both Canada flows in and M pickle flows and also have cardiovascular outcome trials which have demonstrated or suggest cardiovascular benefit. Typical flows in was compared to glimpse side. While it showed similar a onesie. Lowering, it did shows a superior weight loss and fewer severe hypoglycemia compared to the self on your class when used in conjunction with insulin and to aural medications. That pickle closing compared to placebo over 26 weeks showed a decrease in a one C of 10.8% again, total daily dose of insulin decreased and weight loss. You'll see that there's a common theme amongst amongst these three classes, highlighting insulin dose reduction and also weight loss, two of which have been the major obstacles in achieving glycemic control in Type one diabetes. However, there was a higher rate of hypoglycemia with the typical flows in group, and so for these reasons, it's been become quite attractive for people with type one diabetes to potentially use in an off label. Fashion s guilty to inhibitors. The potential benefits or weight loss, lower insulin doses and a potential cardiovascular benefit. In addition, it's an aural medication, which makes it much more convenient than taking multiple subcutaneous insulin doses. So what does it work in Type one diabetes? So I've highlighted two trials. There are many more, which includes smaller cohorts of patients. Um, excuse me, uh, the first of which is typical. Frozen studied in eight weeks and 40 patients, and it showed a reduction in a one C from 87.6%. But a pretty significant decrease in insulin dose ing and wait Canada flows in tested in two different doses compared to placebo also demonstrated a reduction in a one C and weight loss as well. So well, the data supporting the the use of off label medications and improving glycemic control is doesn't is not overwhelmingly positive. There are potential benefits, and therefore they are being used. So let's go back to you guys, um DK and specifically our patient in the modern era. This was first reported in 2015 as a select as a collection of case Siri's by collaborators. They described 13 cases of reported You glycemic DK associated with SLT two inhibitor use, namely, Canada flows in in nine individuals, seven with type one diabetes and two with type two diabetes. What they noted, though, as evidence and has demonstrated in the C. G M plot, which shows the blood glucose is on the day of hospital admission, where a relative stable blood glucose profile and I've highlighted here where 200 mg per deciliter and 300 mg per deciliter fall and you'll note that the vast majority of blood glucose is fall below 200. And in this sort of diagnostic dilemma which we've kind of talked about in the first case, um, they postulated hypothesized potential theories and it came with it a a word of warning. And this led ultimately to subsequent popular subsequent published publications highlighting the risk of you glycemic DK and eventually in 2015 led to an FDA drug safety communication where they revised the label of s guilty to inhibitors for diabetes to include warnings about too much acid in the blood. Are you glycemic DK and serious urinary tract infections. So what's the prevalence? How common is this? What's a bit hard to determine? In the controlled trials, the rates of DK are relatively low. Canada flows in a 0.1% in empathy about 0.9%. However, in the FDA adverse reporting system of 7800 s, guilty to advance their 192 DK episodes, 71% of which were you glycemic DK and 39% of which were into patients with type one diabetes. So how does this happen? S guilty to inhibition results in first increased renal glucose. Excuse me? An increase in renal clearance of glucose and therefore fasting glucose or had leukemia. Genesis can actually be maintained with lower insulin doses in when you're when SLT two channels are inhibited. In addition, lower insulin doses can ultimately to ketosis similar to the mechanisms that I discussed earlier. There's an increase in blue gone which, which can further, uh, predispose someone to you guys to make DK, especially if they're not taking adequate insulin doses. Lastly do. Due to the diuretic and natural effect of U of S g l T two inhibitors, there's a negative influence bound negative fluid balance Increasing counter regulatory hormones in Quetta Genesis ultimately guilty to inhibitors can uncouple ketosis from the expected finding of hyperglycemia and decay shown against this mechanism that I have demonstrated in earlier slides, you'll see that s guilty to inhibitors. One can reduce the patient's insulin dose here and in the setting of starvation with reduced carbohydrate intake further increase ketone formation S o. T. To intimidation also increases urinary glucose losses the combination of which results in the metabolic acidosis in UGC mia resulting in you glycemic DK. And as I've mentioned here, it presents a bit of a diagnostic dilemma. You hyperglycemia is really one of the hallmark features of DK. I'm gonna show here in this slide a chart comparing some of the common lab abnormalities in D. K versus you glycemic DK with SLT two inhibitors. Glucose levels are typically elevated but in you glycemic DK their normal to slightly elevated the pH and DK is low. However, it could be significantly lower and you guys Simic DK bicarbonate levels also are significantly lower and potassium is a bit of a mixed bag. You can either have low normal or increase potassium levels with SLT two inhibition one because of urinary losses, but it can be normal to increase because of it relative insulin deficiency. So when you can't simply rely on the labs to make the diagnosis, you ultimately need to do the most simple thing. You need to talk to the patient. So why, 45 years later, has you guys seen DK become more common? Well, I hope, I hope I have demonstrated that there's an increasing use of off label medication, not not of which was occurring 45 years ago when Monroe and colleagues first demonstrated their case. Siri's Not only is there increasing use of loft label medication, there's been the advent of s guilty to inhibitors, which promote the renal glucose loss. So as clinicians, we simply can't assume that our patients are only taking approved medications. We have to rely on our history taking skills. Justus Muchas the lab results in making the diagnosis. Luckily, the principles and management are actually quite straightforward and very similar to the principles of management of regular old diabetic ketoacidosis. Even in 1973 Monroe colleague stated that the principles of treatment are to correct fluid and electrolyte loss and to re establish carbohydrate metabolism. These were the same core principles. Is the treatment of diabetic ketoacidosis, namely toe To address the volume depletion? We have i v fluids to address carbohydrate metabolism. We have ivy insulin, and we have electrolyte depletion to correct electrolyte loss. Here, again is the potential mechanism for s guilty too inhibited inhibitor induced you glycemic DK insulin addresses, the reduction and insulin therapy and I v fluids with dextrose addressed the urinary glucose losses as well as the volume depletion. So while the treatments are pretty much the same, the actual treatment nuances can be very slightly insulin and DK is often dosed in a weight based fashion. However, typically in ugc decay because of the UGC MIA lower insulin doses air required dexterous with I V fluids is commonly used towards the tail end of therapy in D. K. However, in you glycemic DK is often needed that at the start of treatment in order to promote and allow the continued use of I V. Insulin and potassium commonly needed in D. K is often needed in much larger quantities and you glycemic decay because of Reno losses so back to our patients. This is this 29 year old female who presented with you glycemic decay in the setting of s guilty to inhibitors was started on ivy insulin on presentation. Once the diagnosis was made dexterous containing i V fluids were added to maintain glucose levels and maintain normal glitzy MIA. However, due to a persistent metabolic and I'm gap acidosis, um, this necessitated an increase in her insulin infusion rate and a complement an increase in i v fluids. The gap approximately closed after 18 hours and she was eventually transitioned back to a a subcutaneous insulin regimen. She was discharged home with discontinuation of Canada flows in Pictured Here is a graph of her labs in the light blue. You see her glucose levels in the purple or her bicarbonate levels and in the pink you see her insulin infusion rates at time zero ivy Insulin was started with the expected drop in blood glucose levels. However, this resulted in a need to decrease the insulin infusion, however, and the initiation of dextrous fluids At these two time points, the patient was noted to have a persistent and I get acidosis seen by this sort of stable bicarbonate level and therefore the insulin infusion rate was increased. And again the dextrous and containing fluids were also increased to maintain normal blood. Glucose is eventually in 18 hours for serum bicarbonate had risen and and I gap it closed and she was transitioned at that point to subcutaneous insulin. So the take homes for you guys seem DK treatment is that I ve insulin is absolutely required, even though the patient is you glycemic in order to suppress ketone formation. Dexterous with I V fluids is often necessary at the initiation of therapy and really often in increasing amounts to permit the continued treatment with ivy, insulin and now a close with the word of caution. So take a frozen is a new investigational drug which is a combined SLT one and two inhibitor. Not only does it work on the renal pathway for s guilty to work also works in the gut where SLT one is found. This is being investigated actively as a treatment for Type one diabetes Garden colleagues in the New England Journal in 2017 demonstrated benefits of combined SLT one and two inhibition, showing a lowering of a one C A decrease in weight lowering of blood pressure and also a lowering in the total daily dose of insulin. However, they did report higher rates of DK 3% compared 2.6%. This medication is currently under FDA review for the use in addition to insulin therapy for Type one diabetes. And so this is in the horizon. And one of the major reasons that I really wanted to speak about this topic is that not only are off label medications being increasingly used in the treatment of Type one diabetes soon patients will be using FDA approved potentially use FDA approved medications, which may increase their risk for you. Glycemic DK I think as clinicians, we both have toe have an increased awareness of this potential consequence. And as providers that treat patients living with Type one diabetes, we also have to educate our patients about the potential risk. So, in conclusion, off label use of Type two diabetes medications is common in type one diabetes, and it's essential to take a detailed medication history, uh, to make the diagnosis of you glycemic DK yeah, you glycemic DK must be suspected in any patient who's presenting with signs and symptoms of DK, metabolic acidosis or Keto Yuria. Even in the absence of hyperglycemia and the treatment of you, glycemic DK consists of the same core principles as diabetic ketoacidosis. However, it may be slightly more complex. Insulin is absolutely required for this treatment. With that, I'll close thank you questions. What thanks very much is it correct that this syndrome is unusually common in one of two year olds compared to other age groups? And if that's correct, where do we go with research? That s so the question was, Is this common in one and two year olds? Is that was that? Actually, it is not as common in one and two year olds. Typically, one and two year olds will be on monotherapy with just insulin on. They wouldn't have been. You would not have used SLT one and two inhibitors because oftentimes this isn't being used in off label fashion in the pediatric endocrine world. However, if the question is historically, if this was more common in young Children, um, also not as commonly reported until more school age when, uh, when patients come potentially significantly reduced their carbohydrate intake and have, uh, sort of the starvation induced used likes. Um DK eso not not so common and very young, which is we're thankful for. Excellent. David. Um, so one of the things you showed a lot of your trials airplane it's got before. What evidence is there? You said insulin doses type, even in type two has Advantage Thio. The major benefit, I think, is more in terms of weight loss unless hypoglycemia which are not necessarily. I think those are subsequent benefits that has providers that we often see but not necessarily absolutely documented in the literature to show that with less weight with less insulin used, there's an improvement in long term outcomes. Um, however, the risks of hypoglycemia on also waking are pretty well established. I don't know that just being also great talking two questions. What is? I thought I heard you say that Google God goes up against you. I didn't know that if they misunderstood, I've been on that. Then we live in a world where ultra low carb diets are very much in vogue for for type one diabetes and so you could see the same for a scenario. The and I guess the third thing is, it reminds me of diabetes treatment. Three in 1921 before the resistance. And I mean, this was a sort of baseline treatment. You're trying to get people to this. Yeah. So the first with blue Coogan increases in SLT two inhibition. I don't believe that the exact mechanism is completely understood about why they observed this. Um, but it is a phenomenon that's been seen in postulated as a potential theory for why patients who may be on SLT two inhibitors have an increased risk. Um, the second question about the sort of fad of keto diets and ultra low carbohydrate diets? Uh, certainly. And I think that this is common both in the type one diabetes world as well as the Type two diabetes world, as a way to really significantly simplify treatment as well as a way to improve glucose control control weight on DSO. I think that, um it speaks to the importance that as clinicians, we have to talk. We have to understand what's our patients pattern in terms of how they eat on what dietary patterns that they're having, because if we know that they are following this sort of very low carbohydrate diet and reducing insulin doses. We have to warn them of the potential for this adverse effect. But I agree. I think it's gonna become on. It probably is, um, in increasing phenomenon where it's the sort of the triad of you guys. Stomach DK was the result of SGL two inhibitors, reduction of insulin and these sort of low carb diets. Third, But is this part of Is this happening now? People with the ultra low carb diets right with you? Yeah, So there there are There is key tones present in patients who are following these low carb diets. I don't think that it's well reported in large trials or large cohorts of patients, because it's kind of hard to get a group of a lot of people following the Keto diets. I don't know, off hand the incidents of you specifically you guys seeming DK I know anecdotally, I've had a couple of patients who do do this, um, who have had decay and the therapy effectively as an outpatient. We tell them to eat more carbs and take more insulin, and it resolves, uh, they basically call you up saying, Hey, I feel funny I have nausea and vomiting Or maybe not vomiting, but my blood sugars air fine. So I don't know what's going on. Um s So I think that it is happening. I don't know of a large report that specifically focuses just on you guys Sena DK with these Keto diets, though I think there was a third part of the question. Oh, yes. This is how diabetes was treated. Any call on the edge of Decay Day, everybody? Yeah, you know, I think that that on, Do you know I would share that there? I think that there are some providers that still advocate for that specific approach to treatment for these very low carbohydrate diets. And you're right. They probably are teetering on the edge of borderline ketone formation. The question is whether, you know, oftentimes these s guilty to inhibitors are used more when someone's not reaching target on, uh, maybe a patient has other motivations. Thio use them namely weight, weight loss or, um, reduction in some therapy. But those people who are already following this very low carb diets may not be that bothered by their low dose of insulin requirements. And maybe they're already achieving good glazing control so that the off label use maybe less crystal clear. Uh, really appreciated that. Have there been any genetic variants associated with predisposition that might be used to stratify patients with their? Um, that's a great question. Not that I'm aware of. I think that the challenge up until now has been the relative. I mean, while it's, you know, I think in the in the If you just listen to this talk, you would think that every person coming into the ER with nausea and vomiting that has type one diabetes might have this. But I think in reality across the nation Onda cross centers you know, it took the collaboration of I think about six or seven centers to come up with those 13 cases, um, in 2015. So I don't think that there's been the ability to gather such a large cohort of patients that that might be that have had this diagnosis and then can identify genetic variants which put them at risk. Eso. But I don't know of any. Let's thank take some time
