This session is going to be about SGLT-2s, and we have three outstanding speakers. The first one is going to be Roma Yanchandani. I know Roma for the last, who knows, 20 plus years, and we have this inpatient love. She was a professor at Michigan and recently moved to here, to California. She's a professor of medicine and director of diabetes quality and vice chair of medicine for quality and innovation at Cedars-Sinai Health System. Her lecture today is going to be the use of SGLT-2 in the inpatient setting. She's going to review the literature on the use of SGLT-2 in the hospital, identify safety issues of the SGLT-2 in the hospital. The second speaker is my good friend, Neera Rasooli. She's a professor of medicine at the University of Colorado. She's a director of diabetes and endocrinology clinical trial programs. She's going to speak today on the efficacy and risk of using SGLT-2 for the treatment of patients with diabetes. And the third speaker is going to be Christine Kulasa. She's an associate professor at the University of California in this beautiful city of San Diego. She's a director of inpatient glycemic control. Her lecture is on collaboration with non-endocrinologists using SGLT-2 inhibitors for a patient without diabetes, such a hot topic right now. And she's going to describe indication of SGLT-2 inhibitors in non-diabetic patients and review how we can successfully deal with non-endocrinologists. So the first speaker is Roma. And before I get Roma here, each speaker is going to have 20 minutes. And then we're going to have like 20 minutes for Q&A or your comments. If they use less than 20 minutes, they can take some questions before the end. How do you, you just, do you know? I think so. Yes. Oh. Use this. I'll use this. Thank you, Gurma, for the introduction. And thank you to Ace for this invitation. And you heard a lot about SGLT-2s during your few days here. And I think there's not that much about inpatients. So I'm happy to share some of the data with you. I have no disclosures. I want to base everything on a case. It always helps to hone things in. So Mr. T is a 60-year-old patient of mine who had a three-month diagnosis of non-ischemic heart failure with reduced ejection fraction. First hospital admission for shortness of breath and fatigue. Type 2 for five years, well-controlled with lifestyle and metformin. He has no known microvascular complications. Metformin was held during the admission, and then they were titrating all his other medications. Cardiology called to say, I want to start an SGLT-2 inhibitor. Blood glucoses off the metformin were 180 to 200. He was on a scale. So this is a patient we are going to see very often, and a question which cardiologists probably won't even ask us anymore because they're so comfortable with, getting so comfortable with these medications, but I just want to put the data in there. So patients with heart failure, if you look in the general population, about 25% have diabetes. And if you look in the inpatient setting and in trials, it's 40 to 45%. And this, so diabetes is pervasive, heart failure is pervasive, and together the complications and progression of heart failure is worse with diabetes. And there are many reasons for diabetes to cause heart failure, ischemic cardiomyopathy, some of the RAS activation, fibrosis, advanced glycosylation end products, and a lot of autonomic dysfunction issues. So some of the things that are important for hospitalization. What is the rate of hospitalization for diabetes in patients with heart failure? So this is an older survey. And if you look between 98 and 14, this looked at all CVD conditions for which people were hospitalized. So if you look here, here is men, women, and then these ethnic groups. If you look at men, the rate is going down, but this is heart failure, and these are all the other issues including cardiovascular, acute MI, ischemic stroke, et cetera. Heart failure still had the highest hospitalizations for men and women. So the news is good, but there's still a big discrepancy. And if you look at the non-Hispanic black population, you see a very high rate of hospitalization for heart failure. So looking at both of these facts that you have a high prevalence and a high hospitalization risk, these are patients who we will see in the hospital a lot. In 2015, 16, all of the story of SGLT2s started out, and these are the drugs. I say these are drugs that keep giving, and we hope they keep giving. So the class effect of SGLT2s is well known. The SGLT2 inhibition in the proximal tubule is standard for all these medications. That's how they work. They have some effect on MACE, and Dr. Rasooli will talk more about these outpatient trials. And they have good effect on heart failure in all of the drug studies, and now diabetic kidney disease. So this has made them in the first or the top medications for heart failure. And if you attended this morning's lecture, there were some cases that exemplified that. So in the outpatient, we are sure this is the drug we are going to put patients with heart failure if there are no contraindications. What are the considerations for inpatient use? So this is the DAPA heart failure study, and this looks at the incidence of death or worsening heart failure, looking at when you were last hospitalized. So if you were never hospitalized, you had a cumulative incidence for death or heart failure admission of 20%, 25% if you were hospitalized more than 12 months ago. And this gradient went up to close to 35% if it were less than 12 months ago, telling you that either these patients are sicker, or there is worsening of their heart failure, and they'll get hospitalized in the near future. And the second thought is, what is the time to benefit after STLT2 inhibition? So again, the DAPA heart failure trial. So it looked at the outcomes of timing to heart failure like I talked about. And if you see this slide down here, so this is DAPA, and this is placebo. And you can see that the separation occurs really early in the course of the therapy. Now if you were hospitalized less than 12 months ago, your absolute risk reduction was nearly 10% with using DAPA. If you were hospitalized more than 12 months ago, the risk reduction was 4%. And if you were never hospitalized, the risk reduction was 2%, which tells you that there is impact on when you were recently hospitalized. And this benefit was sustained over 24 months of this study. And if you look at the MPAR-REG study, again, improvements in New York heart failure functional class with MPAR. And if you look, it's rapidly apparent in 28 days, and then sustained over 52. So recent hospitalization and quick action of these drugs make a case for starting them in the hospital. There are three inpatient trials now. What I'm presenting is a meta-analysis. It was so good to have a meta-analysis, even though there's only three trials. The drugs that were in this meta-analysis, MPAR, SOTA, and DAPA. So MPAR-Gliflozin trial is MPAR-RESPONSE-HF. It's a small trial of about 80 patients. MPULSE is the larger trial right here, just published. And it has about 500 patients. SOTA-Gliflozin is an SGLT1 and SGLT2 inhibitor. The SOLOIST worsening heart failure trial had a larger population of over 1,000 patients. Unfortunately, it had to be stopped early because of the pandemic and funding. The DAPA trials are not yet out, except the DARE-19. The DARE-19 I'll talk about briefly is a trial in COVID patients hospitalized. And the DICTATE trial, which is going, the inpatient DAPA trial will be completed next year. Now, if you look at all these three trials, in the MPAR heart failure, there's both diabetes and non-diabetes patients. In the SOTA, it's only diabetes. And in MPULSE, there is both diabetes and non-diabetes patient. The follow-up is different. In MPAR-RESPONSE, it's 60 days, nine months in SOLOIST, and 90 days in MPULSE. And the randomization after admission was also different, 24 hours after hospitalization in MPAR-RESPONSE. In SOTA, they had a 50-50 split in just before and just after discharge. So it was in the tail end of a patient's admission. And in MPULSE, it was within three days of admission. And this is the forest plot looking at the meta-analysis. They looked at three outcomes, all-cause mortality, rehospitalization for heart failure, and change in cancer study cardiomyopathy questionnaire. That is the New York Heart Classification Questionnaire about symptoms. So if you look at all-cause mortality, that improved and favors SGLT2. If you look at rehospitalization, there's a significant improvement, a 48% reduction in odds ratio, a 48% reduction. And the change in KCCQ is over 4, which is supposedly very much in favor of the SGLT2 inhibitors. They looked at three adverse outcomes, hypoglycemia, hypotension, and acute renal failure. And there was no difference. These were the only ones that they really studied. So let's look at these trials separately. MPAR-RESPONSE acute heart failure, as I said, small trial, starting early. Patients' primary endpoints did not improve that much, which is with change in dyspnea, diuretic response, which was weight upon base of diuretic, length of stay, or BNP changes. But the urinary output went up a lot in the four days. And so the fluid benefit, fluid balance improved. But the secondary endpoint, which was a reduction in heart failure, death, or readmission at 60 days was dramatically different. So here, and there were no major side effects. So here is the first study that looked at this. So Soloist, I call a peri-discharge, so it's 50% before and 50% after discharge. Decreased hospitalizations and urgent visits for heart failure and cardiovascular death was the outcome. As you see again, early separation. And there was much improvement of about 33% reduction in all of these events. And it did not matter whether you have, so Soloist had some patients with preserved ejection fraction. It did not matter what your EGF was, what part of the world you were on. If it was started before or after discharge, and the after discharge was two days, sex of the patient, age, or EGFR, Soda was much better. So the SGLT1 inhibitor is that blocks glucose absorption of the intestine. And there was a lot of diarrhea in this trial, in addition to all the other side effects. The last trial inpatient that has been published is MPulse. In this trial, patients with acute heart failure were randomized within three days of hospitalization. So the group they had new was patients with new heart failure, not chronic. So this was their first admission, and they were diagnosed in the hospital. They had also 30% of patients with preserved ejection fraction. So a little different group. And the analysis was also different. They looked at VIN ratios. This is a new way of looking at things and quite complex. And all the benefits, which were the similar benefits like the other trials, were all in favor of MPulse-Lifosin. In addition to clinical benefit, time to death, heart failure exacerbation frequency, time to heart failure exacerbation, and the KCCQ questionnaire. And again, it didn't matter if you were new or an old chronic heart failure patient. It did not matter whether you had diabetes or not, what age you were, your sex, what your BNP was, EGFR, and whether you have Hep-Bep or Hep-Ref. So three good trials, giving us some encouragement to start these medications in the hospital. The last trial I want to talk about is DARE-19. DARE-19 looked at SGLT2 inhibitors in the hospital for COVID patients. They had a large number of patients, and these patients all had some risk factor for heart disease. They excluded critically ill patients, and that reduced the power of the study. The primary outcomes did not differ differently. The adverse events were pretty similar. They had some volume depletion, some worsening renal failure, and euglycemic DKA. But if you look here, all of these were similar between placebo and DAPA, but there was more euglycemic DKA with DAPA-glyphosin. So when I went back to the hospital pharmacy and said, hey, you know, I see all this data. What is our hospital use of SGLT2 inhibitors? And if you look at the trend, this is from CDERS, 2019, 2020, 2021, we're one of the largest MI populations in LA. And then this year, right now, we're actually halfway up 2021. This slide was submitted a little bit earlier. And this use is only going to grow. So if the use is only going to grow, what are some of the considerations? Why would you start SGLT2 in the hospital? They provide synergy to your other heart failure medications. They cause diuresis. They cause natriuresis. The SGLT2 is a co-transporter of sodium and glucose. You can maximize your time to benefit. You can allow adjustments of other diuretics with the SGLT2s. You can adjust diabetic medications if the patient has diabetes. You can counsel for side effects. They also cause, they also help treat hyperkalemia a little bit. So when you have a patient with heart failure, you have ACE inhibitors and MRAs, or minor corticoid receptor antagonists, which cause hyperkalemia. So the SGLT2s reduce that risk. And if there's any renal issues, you can watch that. You can reiterate and educate for euglycemic decay, and we'll talk a little bit more about it. And you can increase compliance. We know that if you start something in the hospital, the compliance is much better. So this is a study looking at compliance in heart failure patients, and it looks at if you delay heart failure drugs. It doesn't include SGLT2s yet. This is ACE, beta blockers, and loop diuretics, which are the mainstay of treatment. So in this study, if you see, the big pies are patients who kept the same medications they were on after they were discharged in three months, and a very small group started new medications within three months of when they left the hospital. In this study, a few drugs were started, and they had adverse consequences in heart failure. The time to benefit, if you start much later, is obviously reduced. Your recommendation may be lost in translation, so you're telling the primary care to start it. Primary care is not comfortable. Primary care says maybe cardiologists can start it. So there's all this handoff, which nobody knows to manage. It's harder to monitor adverse events outpatient, and these drugs still require prior authorization for lots of patients. And if you can set up a process in the hospital that works, and many hospitals have done that. Other cautions for inpatient use, euglycemic DKA, it's not a high number, but it's seen more in SGLT2 versus those without. When you have a procedure, you need to stop the drug for three days prior to the procedure, for all three except for erythroglyphosin, where you stop it for four days. I apologize for the spelling. And the caution, so you don't want to start this in a patient with labile clinical condition. You want the patient to be stabilized. Increased euglycemic DKA risk is when patients have poor intake, multiple procedures, and if they have a UTI or a Foley in place, then the risk of infection goes up, so you have to be a little bit careful. Active infections, anything with an active infection where you're sick or septic, your catecholamines, et cetera, are high, and then you have a risk for euglycemic DKA. And hypokalemia is less of an issue, but if a patient is severely hypokalemic, you want to watch it. New studies, very recent publications show it doesn't cause major hypokalemia. But if someone's low, you want to watch that. I just want to say a couple of words about euglycemic DKA. We get this question all the time. The incidence is low, but it's variable due to uncertain case detection. In the outpatient trials, the incidence is extremely low because the trials are so well controlled, there is no real world experience of surgery and infections or lack of education there. In Australian case series, which is real world series, it's 1.2 to 1.8 cases for 1,000 patients. And the factors that are associated. So what is DKA, as you all know? It's the imbalance between glucagon and insulin. So when you have patients who have type 1, whose insulin doses are going down with the SGLT2s, you have a high risk of going into euglycemic DKA. That's why it's not FDA approved for that. Long-standing type 2, which are really insulin requiring, but it can happen in type 2s otherwise. And NPO status is a big deal. So when you're NPO, you have a lot of ketosis happening on top of insulin deficiency that can cause DKA. I see it a lot in patients who are on ketogenic diets. So when I start a patient with an SGLT2, I always say, no low carb diets. You can have to have some carbohydrate with every meal, or your anion gap is going to go up. Anorexia and alcohol itself causes a euglycemic decay with hypoglycemia. So if somebody has a very high alcohol use, you want to warn them for it. And then any stress of surgery will precipitate decay, as you know. So there is also some emerging data that SGLT2 stimulate production of glucagon and raise the levels of glucagon in the body. And you'll hear more about it in the next few years, I'm sure. So when do these patients present? They can present within weeks, or months, or years after starting the SGLT2. And because their sugars are not that high, the symptoms are always missed. Patients and providers both miss it because their blood glucose is between 180 and 300. How severe is the decay? That is how your labs will present with the hyperglycemia. And there are a few treatment nuances. Of course, you stop the drug. Fluids are a big deal. These are very severely dehydrated patients. So whether you use lactated ringers or normal saline, and that's a whole big lecture. Which one you use for this? DKA. You want to use that starting right away. You have to give insulin therapy, even if your patient is within low 100s and 200s of blood glucose. Unless you give insulin, you're not going to break that cycle. Most case reports use IV insulin, 0.05 to 0.1 unit per kilogram per hour. There are many anecdotal cases of treating patients between our colleagues of using subcutaneous insulin. Kaiser just published a protocol a few weeks ago about their subcutaneous insulin. And they included euglycemic DKA in that. Since the blood glucose is pretty tight for insulin therapy, you have to start dextrose right away. So it's basically insulin and dextrose. You don't have to wait for long till the sugar comes down. This allows insulin use without causing hypoglycemia. Dextrose, 5% to 10%. Or if you need to go up to 10% sometimes, because the anion gap doesn't close with 5%, if the patient's going to be NPO, you want to continue the IV carbohydrate treatment till everything clears up. So yes, you can use them in the hospital. You have to have some safety guidelines. And Dr. Kulasa will talk about these. This is what we built in Michigan with the cardiologist, the heart failure, with the nephrologist, the CKD guidelines. One of our colleagues in Duke, Tracy Setje, has her pharmacist build this in the orders where it warns you of the EGFR cutoffs, type 1, genitourinary infections. And they have a BPA that fires if you have euglycemic decay risk. This paper is going to be presented at the ADA, so I have no data for you for that. So this new proposed algorithm for guideline-directed medical therapy for heart failure, your patient is admitted to the hospital. Inodilators or IV diuretics to bring the patient into some clinical stabilization. When they go to PO diuretics, you start an ARNI beta blocker, which are sort of the stalwarts of treatment. And SGLT2 is moved into the inpatient guideline. And here you can start, and there's many people saying that this has to be started even before a beta blocker. On discharge, you add your MRA, and then you titrate all of this inpatient. And this is a cardiology and primary care paper. What are the uses in the future post-MI? We don't have that much data. There's one study called MBODY study where Empire started two weeks post-MI. Effect on cardiac and sympathetic parasympathetic activity was the only thing they evaluated. There's a post-CABG paper looking at minimally invasive ECC and there's reduced inflammatory burden and five-year outcomes are improved. But if you look at this graph on the right, there's a lot of MI, STEMI, large MI papers. And of course, cardiologists are using it even without this evidence. So this is all going to increase the use even more. So in summary, MRT can be started on SGLT inpatient. It has proven benefits, and you'll hear about that from Dr. Rasooli in length. Data is available to initiate in the hospital. Starting in the hospital has several benefits. Side effects can be significant in hospital population. You know, in the hospital, these patients have NPO and all of the other things we talked about. You want to build guardrails and warn your faculty and trainees about it. And studies for post-MI and CABG initiation are in progress and you will hear a lot about them in the near future. Thank you. And I'll pass it on to Dr. Rasooli. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. I just want to thank also ACE for inviting me to come and present here. But it's a little bit tough to be in the last day of the session with a title that has been spoken about several times. So maybe I will start with a trivia. Anybody knows what a French lilac flower and apple tree have in common? Okay. Think about it a little bit. Metformin was a compound. I mean, one of the diabetes medication we use came actually out of a flower, French lilac. And then SGLT2 inhibitor also coming from apple tree bark. I mean, like a couple of centuries ago, French chemists found that a compound named fluorescein was in apple bark, apple tree bark that caused glucosuria. It took a while to find out where this compound is working. SGLT receptor were found. And then about 10 years ago, a decade ago, finally we had a medication, a drug that used for treatment of diabetes and was approved in the US. Canaglyflosin was the first time. So how this sodium glucose inhibitor work? We heard about that. I just briefly touch base here that in people, non-diabetic individual, we usually filter about 180 gram of glucose. But all of this glucose get reabsorbed through mainly through SGLT2, which is a sodium glucose co-transporter. And only 10% goes down to the distal tubule and get reabsorbed by SGLT1. So what happens if you block the action of SGLT2? All of this glucose got filtered is gonna kind of get excreted. SGLT1 get upregulated, tries to reabsorb glucose, but it cannot do the job of the big brother, SGLT2. So this medication were approved originally for diabetes treatment. So I was told to talk about efficacy and risk side effect of this medication. Efficacy, I mean, originally was glucose-lowering medication. So when everybody think about SGLT2, the original indication was diabetes medication. But nowadays, because of all of the trial that we have, we think about glucose-lowering effect and non-glucose-lowering effect. So two different category. And if you think it that way, it's easier to decide when to prescribe or who will benefit most. And obviously, like other medication, there are some risk. So my job is to review all of this trial in less than 20 minutes. So talking about glucose-lowering effect, they're a modest anti-diabetes medication, to be honest. Most of the trial, about 0.6, 0.7 in the A1C lowering effect. This study that I find, it was a meta-analysis of a lot of trial, putting them together and comparing the max dose of each SGLT2 inhibitor, canagliflozin, dapogliflozin, and empogliflozin in different color to see what happen when it's added to oral agent or as a monotherapy. This is a total of 17,000 patient. And you will see that canagliflozin slightly at the maximum dose was better than other two, but in average, they lower A1C something around 0.7, 0.8. But you remember that FDA guideline that recommended all of the new diabetes medication, they need to prove that they are safe in regard to cardiovascular outcome trial. And because of that guideline, a lot of cardiovascular outcome trial were designed. SGLT2 were no exception, so they had cardiovascular outcome trial. And if you remember, it was 2016, actually. I remember I was in Stockholm, Sweden when Emporreg was announced. And we were all surprised. Anti-diabetes medication prevented cardiovascular event or major cardiovascular event. And we didn't expect that. It came as a primary endpoint, followed by that. Canagliflozin showed the same thing that can prevent MACE. But the other two, SGLT2 inhibitor, dapagliflozin and ERTO, they just showed non-inferiority. So that was the primary endpoint. But this study, they all had secondary endpoint that prompted us to design more studies. So again, I'm showing this meta-analysis that put the cardiovascular outcome trial together. And they chose different population because they were all at high risk, but some trial, like Emporreg, chose only patient who had established cardiovascular disease but the other two chose patient who were at high risk and for primary prevention. And here in meta-analysis, here it shows the class of SGLT2 decreased the risk of MACE in people who had established cardiovascular event by about 14% in the top part. But in the lower section, it just looked at a subgroup that didn't have any history of any established cardiovascular disease. And in high risk, the MACE reduction was not significant. So talking about secondary endpoint, one of the secondary endpoint of this cardiovascular outcome trial was mortality. So the primary endpoint typically was non-fatal MI, non-fatal stroke and cardiovascular mortality. And as a secondary, they had individual event as looking at the individually as an outcome. And just to bring to your attention, empoglyphosin is the only one that reduced mortality as a secondary endpoint. But to put it in context, compared to all of this medication that are well known to prevent or decrease mortality, for example, a statin, in 1990s, 4S showed us a simvastatin can reduce cardiovascular mortality. In a patient that it was pre-statin area, they were not on a statin. And you needed to treat 30 people to prevent one mortality in a statin. Then we had hope study that showed in a population that one third of them were on a statin, you had to treat 56 people for five years to prevent one mortality, one CB death. And then at the era of empoglyphosin in 2015, 16, it was very exciting that we heard that treatment of 39 people with empoglyphosin for three years, it can prevent one cardiovascular death. And these are the people who were protected by ACE and statin that which previously were shown to reduce mortality. So that was secondary endpoint. But other secondary endpoint of this trial showed reduction in heart failure hospitalization. And when you have a secondary endpoint from a trial, you always think, was it really power to show that? Should we rely on that? What kind of population they looked at it? In all of those CB outcome trial, they didn't intentionally look for patient with heart failure. They just looked patient who were at high risk for cardiovascular event. So to prove that really this medication are useful in treatment of a heart failure patient, you need to change your cohort. And also you need to power for this outcome as a primary endpoint. And that's where we have all of this heart failure trial. So let's go through them very quickly. We have DAPA heart failure that enrolled people who had heart failure class two to four. And their BMP should have been elevated. They had EGFR less than 40. Half of them had diabetes. The other half didn't have diabetes. And they looked at the composite endpoint of hospitalization for heart failure and CV mortality. And the relative risk reduction was about 26%. And you need to treat only 20, 21 patient with heart failure to prevent one hospitalization or cardiovascular mortality. And I'm gonna skip this part of the difference between diabetes and non-diabetes because in your next lecture, you're gonna hear more about that. So let's talk about other HGLT2 inhibitor. We have Emperor program, which you can guess from the name is from empoglyphosine. So for most of the heart failure medication that we have, they can work on low ejection fraction people. So Emperor Reduce was the one again, recruited people with heart failure, with ejection fraction less than 40, with BMP and heart failure class two to four. But Emperor Preserve was very novel and because they decided to recruit people who had preserved or mildly reduced ejection fraction, because definition of preserve is usually ejection fraction more than 50, but they decided to recruit people with ejection fraction more than 40. So there were one third of the people in Emperor Preserve that they had mildly reduced ejection fraction. So let's see what happened to these two trial. Do they show any reduction in composite endpoint of heart failure, hospitalization and mortality? And the answer is yes. In Emperor Reduce, as you can tell from name, were HEF-REF people, and it showed about 25% relative risk reduction with a number needed to treat of almost again, 20. I always like to bring this number needed to treat because it kind of gives me a context. How many people I need to treat in my clinic for a period of this one, only one and a half year to prevent one composite endpoint. Emperor Preserved was very similar. It showed relative risk reduction of 20%, but these patients are not as sick as HEF-REF patient. So you need to treat more people to prevent one primary endpoint. A number needed to treat happened to be 30. I was curious to look at the subgroup analysis, what happened between mildly reduced subgroup versus truly preserved. And as you expect, the effect was more robust on mildly reduced versus preserved, but it was not actually statistically significant. Deliver is a study on dapogliflozin on people with preserved or mildly reduced ejection fraction with dapogliflozin. I submitted my slide on May 2nd and the newsletter came on May 5th, I think, that it was positive. So I haven't seen the detailed result, but look like DAPO works similar to endpoint preserved population. So that's why we have now SGLT2 as a part of treatment, as a foundation treatment for heart failure as outpatient. So we have RNA, beta blocker, mineral receptor antagonist, SGLT2 inhibitor. That's why our colleagues in cardiology, they need to know SGLT2 inhibitor really well and collaboration is important. So kind of the summary of what we talked, but let's talk about another secondary endpoint of this cardiovascular outcome trial that prompted us to design a series of the trial on CKD. All of this cardiovascular trial showed that SGLT2 can prevent progression of kidney disease, either if you measure it based on EGFR or albumin creatine ratio, they showed that it can decrease the progression or worsening of kidney function. But what were the kind of critique on those? They were secondary endpoint. They were not designed on patient who had more advanced kidney disease. So they were relatively, I mean, people who were recruited in cardio outcome trial, they had minor or they were at higher risk of kidney disease. Probably you have all seen this heat map of KDGO. So it talks about in the y-axis, your EGFR, different level of EGFR. In the x-axis is your urine albumin creatinine. And if you were on previous session, like Dr. Ampere talked about how important it is to check for urine albumin creatinine because they are predictor of cardiac disease. In average, our patient in cardiovascular outcome trials, a small percentage, they had positive albumin creatinine ratio. But most of them, this shows where the patient in average stood in declared canvas and MPAREC. So they were low risk for kidney disease. So we had to test this in a higher risk population. That's why Credence, I'm sorry, Credence, DAPOV, CKD, and MPO-KD specifically recruited people who at baseline were at high risk for CKD. So they had in average, UACR more than 300 and roughly around 30 to 40 of EGFR. So let's see what happened to these trials. Again, this compares the baseline characteristic of Credence versus DAPL. Primary endpoint, it was composite primary endpoint. One was end-stage renal disease. The other one, worsening of kidney function. One of them chose doubling of creatinine. The other chose EGFR more than 50% decline and then cardiovascular or renal death. One thing that came out of 2008 FDA guideline, I liked it a lot, is all of the cardiovascular outcome trial, they have similar primary outcome. So they have three point MACE and they were all the same. So you could compare them together. But this kidney trial, each of them, they chose a different marker for worsening of kidney function, like this one, EGFR more than 50% decline. Next one that I'm gonna tell you, EMPA chose EGFR more than 40% decline or Credence chose doubling of creatinine. It makes it a little bit difficult to compare them together. But both Credence and DAPL-CKD showed that you can, with SGLT2 in patient who are at high risk for CKD on that red area of the heat map, you can decrease the relative risk reduction of this composite endpoint that I talked about by about 40% and number needed to treat is 20 people. Really good when you have to treat only 20 people for less than two years. To prevent one event, this is really a good choice. EMPA kidney, very similar design. And they stopped it prematurely because DSMB, when they reviewed the result and they are unblinded, they said, it's too good to continue the trial. So you should stop it because the benefit outweighs and there is clear positive efficacy. So we don't have the complete data, but it was in March, the newsletter came out that it was stopped. Okay, we talked about all of this good thing about SGLT2. So what we need to be worried? I mean, look like SGLT2 are great for diabetes, are good for CHF patient, are good for CKD patient, but there are some potential side effect that we need to think about it. Some of them are more common, some of them are rare, but it's serious and life-threatening. Roma talked about ketoacidosis, I briefly talk about it again. Amputation, every time I give a talk, people ask me, okay, are you worried about amputation? Who are the patient may need to be worried? We'll talk some about that and let's go one by one. But ketoacidosis in outpatient setting, I found two trial that I wanna kind of share with you. One of them was a meta-analysis of the seven randomized trial and the other one was more real-world data. On the randomized trial, the rate of decay in outpatient setting was about max couple of patient per 1,000 patient year and relative risk was two and a half more than a standard of care or comparator. So what does it mean? Just put it in context. Means if you treat in an outpatient setting about 1,000 patient per year, you might get couple of patient with DKA and in real world, the range was a little bit wider but 0.6 to 5, 4,000 patient year. So this risk is still there. You need to watch for it. And who are the patient that you need to watch for it because it's important. You cannot kind of scare everybody you're gonna get DKA but these are the patient that Roma talked about, ketogenic diet when they go to prolong starvation. They are heavy alcohol user because they don't eat food and there's a ketosis usually goes up. I had a patient with gastroparesis and we published that case report that we started SGLT2 and went to DKA because of multiple or frequent nausea or vomiting and then these are the patient, hospitalized patient who go through surgery and I'm gonna skip that. So you do keto monitoring and it's based on serum typically because SGLT2 are known to decrease the excretion of ketone body. Amputation, we are worried about, or the data that we have are in two of the SGLT2, canagliflozin and erythrogliflozin in their CV outcome trial, they showed the risk of amputation was very low but it was higher than comparator. And who are the patient that I worried about starting SGLT2 for the risk of amputation? Typically people who have severe PAD, they have foot ulcer and you do a physical exam, you don't feel any pulses, those are the patient I'm worried. Is this really a drug effect rather than class effect? I'm not sure but at least since I have canagliflozin and erythrogliflozin showing in CV outcome trial they are at higher risk, maybe I will stay away from these two if I have a higher risk patient. Fornia gangrene or necrotizing fasciitis or perineum is another infection, it's really life threatening. We didn't see that in the clinical trial, it was more post-marketing reports that they noticed that hey, there are more people are reporting fornia gangrene on SGLT2 compared to other diabetes medication. Obviously there is a bias, selection bias here but we need to watch. If a patient tell you that I have some sort of infection, redness in my private area, do the physical exam, that's very important. There are certain factors that put patient at higher risk. A genital mycotic infection or GMI, that's a common thing, you need to talk to all of the patient about that. It happens depending on what trial you look at up to 14% of patient, one out of five or one out of six they get it and their risk compared to comparator is five, six times higher. So who are the high risk population? Post-menopausal women, uncircumcised men, older population who have incontinence, they're at higher risk, or previously yeast infection. UTI is not technically more common in SGLT2 compared to non-SGLT2 but there has been post-marketing report of severe pyelonephritis and urosepsis with SGLT2 against selection bias and when they did meta-analysis, the risk of UTI was not really higher with SGLT2. I was talking to my fellows and saying, really it's not UTI, it's yeast infection, you need to be worried. So just summarizing that SGLT2, they have actually evolving indication. They were first kind of recommended for treatment of diabetes, then CV outcome trial came, they said, oh, they can maybe decrease their mace and then they were really robust, they had robust effect on heart failure and patient reduced hospitalization and mortality and later on the CKD came, that they are protective, they are foundation of treatment for our nephrologists and we're gonna hear about that. And newer trial that work on the heart failure, maybe SGLT2 decrease risk of, did I say heart failure, I meant AFib, sorry, this is blinking that I'm over time, so patient who have heart failure, they're at risk of AFib, so there are trial on the effect of SGLT2 on arrhythmia and that's it, kind of summarize the effect of SGLT2 on different category of glucose and non-glucose and hopefully it was useful and what is important is choose the right patient independent of their glycemic effect, they have other benefit and our colleagues should know about that and collaborate with us and that's what I, it's a segue for our next talk about collaboration with other colleagues. Thank you. Thank you. Nice talk. Thank you. All right, thank you. So thank you Dr. Umpiarez for the kind introduction and thank you Ace for the invitation. As was mentioned, I'm gonna be talking about collaboration with non-endocrinologists on the use of SGLT2 inhibitors for non-diabetes indications. No relevant disclosures, these are our learning objectives. So this is a quick summary to start on our benefit of this class of medications outside of diabetes. So as we just heard about, they're effective for CKD and across the entire spectrum of heart failure regardless of type two diabetes status. So just quickly to review, our DAPA heart failure here and zooming in because we just heard about all the beautiful benefits of SGLT2 inhibitors on patients with diabetes. Zooming in for our patients without diabetes, you can see their effect is the same. They get the same benefit whether the patient has diabetes or not. With EMPA heart failure, you'll see something very similar. For EMPA reduced and EMPA preserved, if we zoom in on our sub-analysis here, you can see the efficacy and the benefit in both patients with diabetes and without. And same thing with impulse. So these are hospitalized patients and those with de novo heart failure. Again, zooming in, you can see similar effects in both diabetes and non-diabetes. Same thing with CKD. So looking at our DAPA CKD, so these are patients with albuminuria and plus minus type two diabetes. This is the primary outcome was the composite of sustained decline in estimated GFR of at least 50% or end stage kidney disease or death from renal or cardiovascular cause. Again, significant benefit. And zooming in for our patients with diabetes or non-diabetes, you get similar effect. Looking at EMPA reduced and EMPA preserved, you can see the renal outcomes are beneficial. And this was done in both patients with and without diabetes. So now that we have this amazing class of medication that really transcends its initial indication, right, from diabetes to becoming more of a cardiovascular or a nephrology medication, it really is a call to action to figure out what we need to be doing with these medications. How do we collaborate amongst primary care doctors and subspecialists? And do our algorithms need to change? Does our training need to change? Our method of treating patients and how we organize the clinic, does that need to change? So these are some nice guidelines that were just published a couple months ago. And this was a group, a multi-specialty group. So primary care providers, cardiologists, nephrologists, and endocrinologists really looking at all this data and kind of designing these algorithms based on the comorbidity. So this was our prevention and management of heart failure patients. You can see here when we're talking about established heart failure, our SGLT2 inhibitors are first line for the entire spectrum of heart failure. So absolutely, cardiologists do use them and should be. First line without having to see an endocrinologist. Similar with CKD diagnosis and treatment. Here we are, if we look over here under our medications for treatment of CKD, we find our SGLT2 inhibitors and we're using these down to a GFR of almost 20. So again, we have to be aware of these indications that our colleagues are gonna be using these medications for. And then of course, we're all familiar with diabetes. The SGLT2 inhibitors are really first line for patients with CKD or heart failure. So some of the key components to a successful collaboration with non-endocrinologists regarding the use of these meds is really understanding that data and each patient's particular indications for SGLT2 use. Maybe if it was started for diabetes, but they also have CKD, we wanna understand what all we're treating with this class of medication. And be mindful of the impact on multiple disease states as you're titrating your medication up or down. So this came into play just the other day. I had a patient that I saw in the hospital that was on an SGLT2 inhibitor for non-diabetes for over a year and he was just recently diagnosed with diabetes. He came into the hospital for a completely separate, some urinary obstruction and UTI with some pylo. So we had to hold the SGLT2 inhibitor. But the most important thing is I have to explain to the patient because he knows why he was started on it. He wasn't for diabetes when he had started on it and really wanted that communication with his nephrologist and primary care doctor. So it just goes to show that it's very important that we acknowledge that for our patients as well. And collaboration, collaboration on patient care, collaboration on protocols, collaboration on formularies, it's extremely important. Co-management of these patients and communication, communication, communication. So if you're seeing a patient in clinic and you're making adjustments, maybe through the EHR be able to communicate. If you're in the hospital and you're on rounds and you can stop and discuss some of this with these other services, it's very important. So this is the guideline Roma was referring to from University of Michigan. This is a little bit older, but you can see this is a multidisciplinary collaboration on establishment of this protocol for use and initiation of SGLT2 inhibitors in heart failure. So they all got in the same room. They all looked at the up-to-date data at the time and they went through it step by step, establishing the patient population, who this is going to apply to, any exclusion criteria, the agents that have the data there, precautions, and then again, how to adjust and use them in patients with diabetes as well as patients with non-diabetes. And this is something I find I run into quite a bit now with all this heart failure data and all these cardiologists using it. Sometimes we have to remind them it almost has a side effect now of glucose lowering and that we need to make sure we adjust to their diabetes medications, especially if they're on insulin. Similar algorithm for renal disease. Again, initiation of SGLT2 inhibitors in CKD. Similar setup with establishing the patient population, exclusion criteria, agent, dose, and selection. So again, bringing all the latest data together in one algorithm. And then how to use these agents in patients with diabetes versus non-diabetes. And really calling out what needs to be held, what needs to be checked, what needs to be monitored. So with this new use of this class of medications, really does it call for new models of cardiometabolic care? Do we need a new specialty? Any new training programs? Should we be adjusting the way we train our clinicians? So this is a nice little paper that brought up a couple different ideas. Do we need a certificate maybe for cardiometabolic care, a non-accredited fellowship, or maybe even eventually an accredited fellowship? So lots of different options to give providers a little bit more specific training. And comfort using them and adjusting them for treatment of all multiple issues. What about the way we set up our clinic? So we have here classically our referral system. So you've got your patient, their primary care, and maybe we need to refer them to the subspecialists based on their indications. Or do we have a multi-specialty clinic? Maybe we have all the providers here in one room, or we have all the providers with coordinated care in the same center. So those are different approaches. And then this is another one published that I thought was quite interesting, is the idea of a cardiometabolic clinic. And this really comes with the thought of a cardiometabolic specialist. And look at all these amazing resources that these patients have access to that deals with not only their diabetes, but their hypertension, their heart disease, their heart failure, their lipids, et cetera. So some great ideas, and this is kind of where the future is going, is trying to make care accessible and efficient and cost-effective. And the last thought is here about cardiometabolic population health model. So here we've got our patient. We've got our EHR, where we're really looking at their details and their comorbidities. And these programs are often developed with physicians, data scientists, pharmacists, and patient navigators, with each person playing a different role. But really, you're looking at your population. You segment your attributed patient population based on whatever health condition you're looking for. You stratify those patients using a risk management approach. And then based on their level of risk is really gonna dictate what that level of intervention might be. Do you have care coordination or intervention by a case manager for those particularly high-risk patients? Maybe for the medium risk, we have disease management or a disease manager for a chronic condition or multiple chronic conditions, or maybe those patients at low risk, they can just be in their normal primary care and preventative services, and again, addressing all these things at one time. So just to summarize, our SGLT2 inhibitors are an integral part of management of heart failure, type 2 diabetes, and CKD. Key components to that successful collaboration with non-endocrinologists regarding the use of this class is really understanding those indications and effects on multiple disease states, collaboration, and communication, and then thinking about innovative options for improved comprehensive cardiomelodic care for the future. So with that, I will conclude, and thank you, and we can move into questions. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. At what point do you think we'll have a standardized risk list so that like all of the lists would include each one of the risk factors? I was just picking hypovolemia out and it's, you know, I'm in the inpatient side and so we are scanning patients who've been started on SGLT2s by another discipline and trying to figure out if they are fitting into a high risk category that we need to withdraw the medication. And so I was just looking for uniformity. Nida. Okay. What hypovolemia is for sure a potential side effect but because it's asthmatic diuresis, you're blocking your co-transporter, you're releasing a lot of sodium. I agree with you. It's just that it wasn't mentioned by all three speakers and so I was just wondering. I think it depends on how comprehensive we get into the list. But it absolutely is there. It's in package insert and you need to replace it and fluid and. We could do a very long list for, you know, the most common and the least common, but 100% it's in there. But how often do you have seen a patient that you have to stop SGLT2 because of hypovolemia? I think similar to other diuretics, you pause it and you figure out and adjust their regimen. Just adjusting the regimen is always helpful. And you may have to lower the diuretic, that's about it. Or have patient drink more. Hello, hi, my name is Henry Salada from the University of Alabama at Birmingham. I have a question. Do you feel comfortable with the cardiologists when they start SGLT2 inhibitors in patients with uncontrolled diabetes in the hospital? We're talking about patients that are admitted with hyperglycemia A1C more than 11. I've had patients that they, you know, ended with euglycemic DKA. And personally in my clinic, I try to avoid SGLT2 inhibitors when the A1C is more than nine. I know that we don't have any cutoff, but I think that we as endocrinologists, we should look for it. I would like your opinion on that. And second, my second question is, if you can comment about the effect of the SGLT2s producing hypokalemia, is it because of they enhanced uresis or what's the mechanism? So Roma, can you answer the hospital? The first thing, I completely agree with you. Anyone with coming in with A1C high and high blood sugar in the three to 400, there's no place for using an SGLT2 in the hospital. Insulin usually, and insulin alone. And then as they stabilize. So when you're in the hospital, you need to have the patient stable before you start. And that was my point, not in any patient who is decompensated in any way. So that's- So if you start an SGLT2 inhibitor in the hospital, what glucose reduction would you expect? You know, it's hard to tell because these patients may be glucose uric, sorry, hyperglycemic from different causes. So it's hard to tell, but often you, I've seen all spectrums. Sometimes you see a small reduction and in patients who are very hyperglycemic who've not been on any treatment before, you start insulin, you start SGLT2, everything, the reduction is very dramatic. So it's not easy to predict. So I'm not sure we completely answered the question from the doctor from UAB. So if you, let's say you have a patient with low glucose, 240, hemoglobin A1CO9, heart failure, you start SGLT2, but that's not going to touch much the glucose. So what would you use? You add insulin and SGLT2 or do you just start the SGLT2 and see what happens? You know, with 290, I think if you do a correction scale and SGLT2, often patients when they come in heart failure exacerbation, their sugar is much higher. And as you improve the exacerbation, the sugars get better too. I always tell my patients, if your sugars are going up, it's always sometime predicting your heart failure is getting worse. So both of them go together and sometimes the sugars come down with the SGLT2 and a correction scale. So every patient is very different. So I want to make a comment also. I started my efficacy talk on glucose lowering versus non-glucose lowering effect. I will think and set back why I'm starting SGLT2. Am I starting for glucose management? I will say it's useless at that point. So I will go with the insulin and treat because for non-glucose lowering effect, which is heart failure, CKD protection, you know, if you started like a month later, because it's long-term effect and you're gonna take people in long-term, you can wait when the patient is more stable and glycemic control and then think about, okay, now I need to start it because of heart failure. I will start it. But at that point, when patient is decompensated with a high glucose, you can start it, but it's not gonna do anything for glucose that much. So answering your question, probably I would say the effect is gonna be minimum on glucose lowering. Hi, I'm Donald Cross here from University of North Carolina. I was wondering about starting these medications in the outpatient setting. What's your practice of monitoring their BMPs either for hypovolemia or electrolyte abnormalities? So in all of the, can I answer? Yes, please. In all of the trial, when you look at the BMP or EGFR, there is always a dip that there is EGFR comes down and then bounce back. In practice, do we look a month later to see what happened to EGFR? Personally, myself, I don't do, I'm not worried about potassium that much, but about drop in EGFR, depends on patient. If a patient comes to me with an EGFR of 60 plus or 45 plus, even if a little bit deep, I'm not worried. But if I'm a starting patient on an EGFR of, let's say, 23, maybe I will monitor. Not necessarily I will stop it, but I will monitor. So answering your question, I don't do in a routine setting a BMP check in four weeks. I do it next season. Those are the ones I'm always wondering about too because we know those are the patients that are gonna benefit the most from a renal perspective. So it's always a hard thing to judge. Thank you. Sure. Yes. My name is Jerry from New York. First of all, thank you to all three speakers for a nice review. A comment and a question. The comment is, for those of us who are practicing primarily outpatient medicine, the elephant in the room when it comes to treatment are the PBMs. And I'm sure many of us have had experience where I prescribe an SGLT2 for a non-glycemic effect. I get back a PA saying, step therapy, patient has to be on metformin. And statistics show in the United States that once that request comes in, two thirds of prescriptions are no longer filled. So it's organizations like ACE or Guillermo, the ADA, really has to educate the PBMs about the use of SGLT2s. That's my comment. Okay, thank you. No comments? No, completely agree with you. Yeah. The question I have, and that's for our second speaker, and I apologize, I'm bad at remembering names, as professor of pharmacology, I'm curious to know where that recommendation about stopping SGLT2s for three days before procedure, not two, not four, where did that number come from? And how does that fit in with what we know about the pharmacodynamics of the SGLT2s? How long do they stay in the system? I will start, but I will defer to Roma to complete my answer. I know the half-life of SGLT2 is something around 10, 12 hours. So probably after two, three days, SGLT2 should be totally gone. I think that's why they came up with three days, because of the half-life and how many of them you have to have to have a complete washout. But in my case report that I said about euglycemic decay in gastroparesis patient, and this is not only my case, there have been more cases that, for unknown reason, we have this prolonged glucosuria in some patient with SGLT2 inhibitor. Like even if you stop it, you will see glucosuria for two weeks, three weeks after. So I think choosing three days is very probably... Estimate. Yeah, an estimate, and we don't have any data, but I will let you. There's no hard science behind it. It's just that impact, and the fact, as Neda said, is the glucosuria is very prolonged and continues, even though you're not adding the drug, the receptor is blocked for a long period of time. So I know that Ace wrote a paper on SGLT2s and ketoacidosis, and that's where they came up, these three days. So I think Alan Garber got this, the three days looks like, and I don't think there's good data. That's what I was afraid of. And the other question is, for a short procedure, do you do that, or for a long procedure, that's still not answered. So some people do it for all procedures. We don't do it in our hospital for patients who are just coming for a cardiac cath in the morning or something like that. So it's very variable. Can I ask the participants here, how many of you in your hospital are using SGLT2s? Inpatients. Inpatient, in the hospital. There you go, at least half. Yes. We have it for non-diabetic patients, otherwise it's not approved. Yes. Just a comment, I think you rightly said, communications. Can you tell us your name and where you come from? I work in a rural area in Arkansas, Northeast. So I agree, communication is very key, among other specialists who start the SGLT2 inhibitors, because I have to have a separate insulin drip protocol for eugless and DKA, because of this. We've had some severe adverse events where a CABG had to be postponed because of initiation of an SGLT2 in the hospital, and the patient ultimately died. We have two or three cases like that. But having said that, and I have similar protocols where the contraindications to initiate an SGLT2 in the hospital, but I also put in that optimized glucose first, and then start an SGLT2 inhibitor, because I had a group of patients that who have heart failure, being discharged from the hospital, come to see me for uncontrolled diabetes, because they've used different permutation and combination medicines, and I tried to put them on either an EMPA or DAPA, and they said that they're allergic to it. But when I explored, really, what was happening, they were very shy to disclose that they had a genital mycotic infection. So that's just a comment. Thank you. Yeah. Thank you so much. Julio Romero from Boston. So I had a comment and a question. The comment is more about importance of communication for management of those who have type one diabetes, and so I'm just wondering whether there are sort of initiatives to actually create, really, some sort of alerts to start SGLT2 inhibitors in those who have type one without having echo communication, as we discussed. I think that's important. And the other is more of a question about some level of consistency with diuretic regimen management when you start an SGLT2 in the hospital as to whether some of the trials that you actually have presented and some of the differences may be due in the protocol that they have used for diuretic adjustment. Yeah, they don't talk much about the diuretic protocols much. They say they adjust the diuretics based on its clinical efficacy. So there is no consistency across the spectrum? Yeah, there's not yet, but they'll probably, it'll get, I think these are just early trials, and I think the soloist was not really just looking at inpatient. It's just helped us to look at inpatient. It was not geared towards inpatient completely, but I think those trials will be coming up. So I have several questions that I don't know the answer, so that's what I'm asking, but I want short answers. So the first is, Roma, you put a slide that the heart failures in African Americans surpassed double what is in Caucasians. So why explain the high rate of heart failure in African Americans? And if the response to SCLT2 for heart failure is the same in whites and blacks? Yes, in all the studies it looks very similar, whatever the ethnic meant. In one of the studies it looked like they were not very, didn't work out very well for Asians, but I'm, in Asia, the trials of the sites in Asia, but I'm not sure where that came from. That was only one of the inpatient studies. But I think whether you're African American or not, I don't think there's any difference in efficacy in all the studies. Good, so Christy, insulin adjustment. If somebody's taking insulin and you're going to start SCLT2s and the hemoglobin A1C is arrived, what do you do with the insulin dose? Reduce it, depending on the patient and their comorbidities, anywhere from 20, maybe more aggressively, 50%, depending on their total dose and any risk of adverse outcomes. The older the patient, I would tend to be more aggressive. Nita, there are several medications approved for heart failure. That's right, there are diuretics, beta blockers, A's, ARBs, Entresto, MRI, and now SCLT2. So if you get a patient in the hospital with heart failure, I mean, how do you juggle all of these medicines? Do you start SCLT2 before the others or do you just wait with traditional heart failure treatment before you start the SCLT2? That's a good question. I think, really, we don't have any guideline, but there is some expert opinion that it kind of put MRI and SCLT2 after RAS inhibition and beta blockers. So the order that I had a slide that I skipped it quickly. So RAS inhibition, or based on expert opinion, again, we don't have any trial comparing, RAS inhibition first, beta blocker, and then MRI and SCLT2 kind of at the same time. But do we have any data? I don't think so. And it might be similar to the metformin game with the ADA guidelines, right? And how it was always after metformin and then over the years they slowly crept up. Yeah, because. And now it's this. Right. So it might be the same for heart failure over time. Exactly, because the trial that is showing like DAPA heart failure or some other trial, this medication, SCLT2, because there are newer kids on the block, they were added on top of RAS inhibition. Therefore, when you're recommending, you're saying, okay, older one first and then you add the newer one. But if you go the opposite way, are you going to see less efficacy? I don't know. In some articles, opinion articles, some of the cardiologists are saying they should even be given with the beta blocker, which is sort of one of the first drugs which is added. So I think it's going to move up very much in the next few years. And final question that I wrote down listening to your lectures is that the cardiovascular protection and the relationship with GFR. So if you have a GFR greater than 60, did you get better protection that you have less than 40, less than 45? What is that response? I mean, is that something that, I know that the glycemic effects diminish significantly with decreased GFR. What about the cardiovascular benefit? So are you talking about specifically MACE or hospitalization for heart failure? Both. Not that I have answer for them. I don't know. I think when you, I mean, you need to look at the result of this cardiovascular outcome because I'm pretty sure they had post-hoc analysis, subgroup analysis. My recollection in MACE, there was no significant differences. And in heart failure, I cannot tell for sure if there was a subgroup differences. Do you remember? I don't, I didn't think so, but we know that the lower EGFR, the anti-glucose lowering effect is gonna go lowest because kidney cannot get rid of extra sugar. Whether you're gonna have more protection in regards to heart failure hospitalization or less, I'm not sure on heart failure, but I'm pretty sure it wasn't different. Good. Well, I truly enjoyed these three lectures and thank you so much for a great presentation. Thank you. Thank you. Thank you. And thanks for coming.

SGLT-2 inhibitors

efficacy

risks

heart failure

euglycemic DKA

diabetes treatment

glucose-lowering effects

cardiovascular benefits

collaboration

safety issues

monitoring patients