And I'm so, so glad that, like me, many of you wake up thinking about SGLT2 inhibitors. So my name is Uttu Vadiganathan from the Brigham and Women's Hospital. It's a real pleasure and honor to be able to chair this session of improving outcomes with SGLT2 inhibitors in patients with heart failure from evidence to clinical practice. I'm joined by my esteemed faculty and friends and colleagues, including Dr. Stephen Green, Dr. Mikhail Korsbord, and Dr. Alana Morris. I'd like to thank the accredited sponsor, the HFSA, as well as the commercial sponsor, AstraZeneca, for providing the education grant for this symposium, and Vox Media for providing programmatic management services. Successful completion of this CME includes participation of post-course evaluation. So to claim C-credit, learners must complete specific evaluation, and the website's accessible through the HFSA ASM mobile application, as well as through the C-credit kiosk right outside the registration desk. So to complete and claim the C-credit, just log into the site using your last name, registration ID, locate this satellite symposium, the title name, and then complete the evaluation. Please note that the disclosure information is available in the handout. Question cards are located on your seats, so we'll have a chance at the end of the program for a question and answer session. So please, we'll be collecting questions live, and as a note, please turn off any electronic devices to avoid any interruptions. So without further ado, I'll get things started. We'll start this journey with heart failure with reduced ejection fraction. We'll move to heart failure with preserved ejection fraction, and embedded in this discussion will be practical implementation of SGLT2 inhibitors. The journey has come quite far. We now have six FDA-approved SGLT2 inhibitors dating back now to about a decade ago, and here you can see the six FDA labels. Notably, each of the six therapies were, many of them were initially labeled for glycemic control in type 2 diabetes, but then subsequently had additional cardiovascular risk reduction levels that were added in type 2 diabetes. That's for CANA, DAPA, and EMPA, and then most recently, there's been an extraordinary development of the development of these therapies for chronic kidney disease and heart failure. You can see that four of these therapies have specific labels for either heart failure and or chronic kidney disease. We'll review the heart failure-specific data in this session. So this slide is not meant to review the history of SGLT2 inhibitors, but more so to remind you that SGLT2 inhibitors have been long in development and have been long in therapeutic use, and so the safety profile of these therapies have been well, well understood by clinicians, and these drugs were actually initially isolated back in the 1800s, took about a century to isolate as pharmacological drugs, and then were initially developed as therapies for type 2 diabetes, more recently, heart failure and chronic kidney disease. So in heart failure with reduced ejection fraction, we have two pivotal trials that laid the foundation of our evidence-based DAPA-HF with daplophosin, I apologize. And emperor use with empaglifosin, both for large-scale trials of 3,000 to 4,000 patients, and included, importantly, patients with and without diabetes. And so we're well-positioned to test the hypothesis, do these drugs actually affect heart failure status even in patients without diabetes? The primary endpoints were very comparable of cardiovascular death or a heart failure, either hospitalization and or an urgent heart failure visit. Patients were well-treated on background medical therapies, inclusive of the angiotensin receptor neprolysis, and patients faced a high event rate in follow-up, placebo event rates annualized of 15 to 20 percent, so sizable risk in this population. Here you see very concordant results between these two trials of important reductions in all-cause mortality, as well as cardiovascular death. Furthermore, reduction in the primary endpoints of these trials, cardiovascular death and heart failure events. And then impressively, and perhaps for the first time seen with any drug class in heart failure, saw a reduction in kidney composite endpoints, meaning a delay in meaningful kidney outcomes like dialysis and need kidney transplantation in a population of heart failure, which may have high competing risk of heart failure events. And this is perhaps the most important finding from these trials, that these drugs truly modified outcomes in both people with and without diabetes with almost identical effect sizes. So this was now firmly established for the first time in DAP-HF, subsequently validated in EMBR-REDUCED, that these drugs are truly heart failure drugs and should be embraced by cardiologists and heart failure clinicians. There was a third trial that examined patients with heart failure across the ejection fraction spectrum, although the majority of patients in this trial were enrolled with reduced ejection fraction. Solace worsening heart failure evaluated the SGP1-2 inhibitor, sodagliflozin, in people early after an episode of worsening heart failure. The patients were enrolled after stabilization for an acute heart failure hospitalization and were randomized either just before or just after hospital discharge. You can see here, randomization to sodagliflozin led to rapid separation of these event curves with a large magnitude, not only relative effect size, but also because this is such an enriched high-risk population, a large magnitude absolute risk reduction with a number needed to treat to avoid an event in this near-term period of just four patients. This is the second, I think, most remarkable slide in which these drugs are highly, highly safe and easy to use. Unlike any prior drug therapy that we've seen, there was actually numerically fewer serious adverse events and adverse events in the drug therapy arm compared with even placebo. When can you, at the bedside or in the clinic, approach a patient and say, this drug is actually maybe even safer than a placebo therapy? It's largely driven because these drugs really help protect not only cardiovascular steps, but help add resiliency to the system, and so to prevent episodes like acute kidney injury and episodes of other systemic abnormalities. Importantly, many of the issues that were initial concerns with the SLD2 inhibitors really did not bear out in this very high-risk population of heart failure with reduced rejection fraction. There was no excess in serious volume or depletion events. Issues like diabetic ketoacidosis, issues like serious hypoglycemia, and even amputation risk, which was seen in a very early trial of type 2 diabetes, but was never validated in any subsequent trial. The effects of these therapies was largely and incredibly consistent across a full range of glycemia. So, irrespective of where the patient is on the glycemic spectrum, whether they start with a hemoglobin 1c of 5.5, 6.5, or even 9.0, these therapies really do benefit their heart failure status, and this was seen consistently in the left-hand screen in DAPESHF, and again in AMPER, reduced. When patients are initially approached about starting an SGLT2 inhibitor, especially those without diabetes, they often ask, well, you're prescribing a glucose-lowering therapy to me. Should I be concerned about hypoglycemia? Should I be monitoring my blood glucose levels? This slide shows that on the right hand, in people without diabetes, this drug does not lower blood glucose, and in fact, has no excess in serious hypoglycemia. Patients don't need to regularly monitor their glucose levels, and so add comfort in our prescription or management of patients across a broad range of glycemia. The SGLT2 inhibitors have unique protective effects on the kidney. You can see here in red is the placebo EGFR trajectory in patients in the DAPESHF trial. So unfortunately, patients with heart failure, as well as many older patients, have a long-term decline in their kidney function over time. On average, with aging, we expect about a 1 mL permit decline in EGFR on an annual basis. In people with heart failure, that's about doubled to about 2 to 3 mL per minute, and you can see that longitudinal decline in the placebo arm. In contrast, when treated with an SGLT2 inhibitor, there is an early decline that's related to an early reduction in glomerular pressures, and then subsequent stabilization, and you can see the bending of the trajectory in which that curve flattens. And in the chronic phase, in the long-term phase, with SGLT2 inhibitors, you can see that EGFR slope, or the long-term trajectory, is again about 1 mL per minute. And so just back of the envelope, in many ways, SGLT2 inhibitors normalize our GFR trajectory and kidney function decline over time. These drugs have potent effects not only in the heart, but in the system at large, and importantly, we mentioned that these drugs reduce cardiovascular death and reduce the key components of cardiovascular death, that's death related to worsening heart failure, but also death due to sudden death, including ventricular arrhythmias. These are data from the DAPA-HF trial, in which randomization to dapagliflozin led to a sizable 21% reduction in ventricular arrhythmias, recessive cardiac arrest, and sudden death. And so like many other drug therapies in the GDMT armamentaria today, these drugs can lower risk for sudden death, and may actually have important implications in how we decide on ICDs and other devices down the line. These drugs also protect against hyperkalemia, which is perhaps unique to the heart failure clinician. We're often very wary about potassium. We often protect the potassium levels because it allows us to use other important therapies like the renin-angiotensin system inhibitors, and like the mineralocorticoid receptor antagonist. But these drugs, including in both heart failure and non-heart failure populations, protect against serious hyperkalemia. These are, again, data from DAPA-HF, in which the occurrence of hyperkalemia, as defined as either a potassium above 5.5 or even 6.0, was reduced in the dapagliflozin arm compared to placebo. And that's inclusive of those high-risk people treated with a mineralocorticoid receptor antagonist, who we're very concerned and where we watch carefully about potassium levels. So at least in theory, these drugs may actually facilitate our use of other life-changing guideline-directed medical therapies. So in that patient who has borderline potassium levels, potassium of 5.0, where we're perhaps a little bit reluctant to use an MRA, the combination use with an SGLT2 inhibitor may actually attenuate that treatment-tendent adverse effect. These drugs act very rapidly. And so often, in heart failure, we talk about a chronic journey with undulating course and a lifetime of therapy. But it's often helpful at the bedside to communicate rapid benefits. And here, in the next few slides, I'd like to share with you that these drugs act within just weeks to months in not only stabilizing clinical status, but you can see providing clinically important improvements in health status across multiple domains. This is including symptom status, including functional status, and overall health. Practically, when starting these drugs, we're often asked, well, what do we do about background medical therapies? And thankfully, just like the safety profile of these drugs, which really facilitates its use, these drugs are remarkably well-tolerated. In general, in most patients with heart failure, few changes to medical therapy are required. Here's the case of diuretics. This is a curious drug in that it affects the proximal tubules of the kidneys handling of salt and water. And so one may wonder whether the acute inhibition of that transporter may lead to an excess in diuresis. But in fact, this is a short-lived period of diuresis. And in most people, you can see here, this is the longitudinal trajectory of diuretic dose. As most people with heart failure are treated with some loop diuretic, you could see in most people, the loop diuretic dose is about comparable with that faced by placebo-treated patients in this trial. This is the DAPA-HF trial. And so in general, as a general guidance, for most patients, we don't need to make upfront anticipatory changes in our diuretic dosing when starting these therapies. Of course, your own clinical impression is paramount. And so if a patient is hypovolemic on presentation, then dose-reducing or discontinuing the loop diuretic at presentation makes clinical sense. Most importantly is following patient over time. These drugs stabilize clinical status in many patients. And so do allow, you can see over time, over months to years, allows for down titration of loop diuretics because patients feel better, have better control of their congestion. And so paramount is continuing to follow the patient, reassessing congestion and follow-up. I said that these patients were very well treated with background medical therapies. And of course, today, we live in so-called kind of golden era of heart failure with many medical therapies available to us, including the Enchancement Receptor Nephrolysis Inhibitor Sucutrevalsartan. And you can see here, these drugs work very consistently, even in people with or without treatment of the ARNI Sucutrevalsartan. You can see the effect sizes are nearly identical in people receiving ARNI at ACE line or not receiving ARNI. And that ARNI treatment is about 10% to 20%. We've seen, again, consistent results. We'll hear about preserved EF in just a moment. Again, GD&T today is complex. Patients present to you in your own clinics on various treatment regimens. This slide provides reassurance that starting an SGLT2 inhibitor can be done at any phase in the treatment regimen, whether the patient is on minimal medical therapy or on maximal medical therapy. In terms of background use, you can see here the treatment effects of addition of the SGLT2 inhibitors are almost identical. We often find people in our own clinics who have very long durations of heart failure. These people have lived with heart failure for years to even decades. And we wonder, they've been stable for so long, they're presenting to our clinics today. Should we optimize them today? And in fact, here you can see that not only are the people who have heart failure for the longest duration face the highest risks, in fact, of near-term clinical progression, but they similarly benefit from the addition of SGLT2 inhibitors. So it's never too late to optimize someone. On the other side, you see these drugs work within days of initiation to stabilize clinical status. So it's rare to find a therapy where you can truly share that within just a month of initiation, these drugs can actually reduce clinically relevant outcomes like heart failure hospitalization and cardiovascular death. And this is seen consistently across the clinical trial programs. So how do we actually put this together in overall heart failure with reduced EF management? Of course, we have many drug therapies, and each have important effects on clinical status. Furthermore, these drugs are not recommended just for a short-term period, they're often recommended for a lifetime of use. So this cross-trial analysis attempted to estimate the aggregate benefits of these combination drug therapies. You can see here, there was a large magnitude reduction in clinical events estimated with combination medical therapy. When forecasted over a lifetime of use, combination drug therapy versus more conventional regimens like an ACE inhibitor and a beta blocker alone may afford over six years of additional survival to a young patient with heart failure with reduced EF. So thankfully now, these data have really cemented the role of SGLT2 inhibitors as a core component of guideline-directed method therapy and are recommended as class one recommendation in people with heart failure with reduced EF, and we'll see the data for preserved EF in just a moment. So I thank you so much. We're going to now talk about the practical implementation in the context of heart failure with reduced EF. I'm just waiting for the slides to load. All right, so my pleasure to be here today, and we're gonna be discussing a case presentation, hopefully put all the great data from Dr. Vaduganathan in context. So our case today is an 81-year-old woman who was referred to My Heart Failure Clinic after a recent heart failure hospitalization. So her heart failure story actually started in January of 2022 when she was hospitalized for new onset heart failure. She was diagnosed with heart failure with reduced ejection fraction. She was also diagnosed with an ischemic cardiomyopathy. She has a history of CABG, and she actually underwent an ischemic evaluation during that hospitalization, but there were no further targets for revast. She was diuresed. She was discharged. She was initiated on a low-dose beta-blocker and ACE inhibitor at the time of discharge. She did relatively okay for about a year in the sense that she avoided current hospitalization, but that all changed in January of 2023. She was hospitalized for, again, worsening of her chronic heart failure, but now in the context of new onset atrial fibrillation. She underwent TE cardioversion. She was initiated on amiodarone, and she was diuresed and discharged. I think the clinical team at the time was confident that if we kept her in normal rhythm, she would stay out of the hospital and have her heart failure controlled, but that was not the case. Just a few months later, despite being in normal science rhythm, she was hospitalized again for worsening chronic heart failure. She was diuresed, discharged, and then referred to my heart failure clinic. In terms of her past medical and social history, we discussed her low ejection fraction. It was at 25%. Her ischemic cardiomyopathy, atrial fibrillation, but her course was also complicated because she had stage four chronic kidney disease. She also had what I would term at least moderate frailty. In a sense, she used to walk her whenever she left her home. In the home, she'd have to walk slowly with support from family members at times, but her family was her big driver for her quality of life. She lived with her daughter, son-in-law, and had two grandchildren as well she lived with. In terms of her vital signs in labs, when she saw me in the office, it was a 102 over 65 was her blood pressure. Heart rate was 75, BMI 22. I would term her NYHA class three. As mentioned, she had severe kidney disease. Her EGFR was less than 30 at an EGFR of 27. She had borderline high potassium, and she had very elevated natripeptides. In terms of her cardiac medication, she was on a twice-daily regimen of torcemide for lupus piresis. Her beta-blocker dose was rather low, topral succinate fatigue once daily. She was on an ultra-low dose of lisinopril, a statin, a pixaban, anticoagulation, and amiodarone. And I had a lot to discuss with this patient. For the first time, her family was with her. I'm trying to establish rapport. But with shared decision-making, a key thing we decided to do was to initiate dopagoflodin 10 milligrams once daily. And this patient, face value, had multiple characteristics that are often perceived as barriers to GDMT. We all know this, but for example, she had severe kidney dysfunction. EGFR was less than 30. Borderline high potassium. She had borderline low blood pressure. Her systolic blood pressure was 102. She, of course, was older age. She was in her 80s. And she also had, again, significant frailty. But the key in situations like this, it always starts with shared decision-making. When you have these conversations with patients, and the clinicians are top of mind as well, the first thing that comes up oftentimes is when you're talking about starting a new medicine is, well, doc, what are the side effects? And of course, we need to discuss side effects and potential for adverse events. What we don't oftentimes give enough emphasis are what are the risks of omission? What are the risks of not trying this medicine? And this oftentimes comes up, especially in our patients that are older, frail, have multiple comorbidities. So when people ask about side effects, of course, we have to talk about that. But I also talk about, well, what are the side effects of not trying this new medicine that you're eligible for? The side effects of not trying a medicine you're eligible when we're talking about DDMT for HFREF include higher risk of passing away, higher risk of going to the hospital, and higher risk of worsening quality of life and symptomatic deterioration. So for patients to be truly well-informed on whether to rock the boat, so to speak, with a new medicine, they need to understand not just the risks of side effects, but also the risk of not trying this new medicine. And with SGLT2 inhibitors, we're fortunate to have a lot of unique data that often give further context to these risk-benefit discussions. So we'll go through that in essentially a rapid-fire fashion here. So one key thing to emphasize with SGLT2 inhibitors is they have consistent efficacy across the spectrum of age, including among our older patients. So these are data from DAPHF, which show across the entire spectrum of age, you see consistent relative risk reduction of the primary endpoint of CB death or worsening heart failure. Including among those 75 years and older. Likewise, we also see consistent benefit across the spectrum of frailty. What many may not realize is that about half of the patients in DAPHF had at least moderate or severe frailty. And again, consistent relative risk reduction across the entire spectrum of frailty when we're talking about the primary endpoint. What we understand as well is that because the baseline risk is so much higher among frail patients, that same relative risk equates to greater absolute risk reduction among very frail patients. So lower number needed to treat if you're treating your very frail patients. And again, just something to emphasize that think about risks of omission. Withholding an SGLT2 inhibitor from a very frail patient, that patient in a sense has more to lose by being hesitant to treat that patient. But in our older demographic, it's not just about survival and clinical events. For many patients, the most prioritized outcome is just feeling better. But fortunately, we have great data with the SGLT2 inhibitor class for making patients' quality of life better, including in our heart failure with reduced ejection fraction patients. So these are data from the DAPHF and EMPEROR-REDUCE. They're two major HREF trials. And again, shows that SGLT2 inhibitors make patients feel better. They improve symptoms, and this is consistent across the spectrum of age, even in our very old adults. But likewise, similar story in terms of consistency when we're talking about now kidney dysfunction. You know, our patient had an EGFR less than 30, but we have strong data with the SGLT2 inhibitors that have consistent relative risk reduction across the entire spectrum of EGFR, presence or absence of CKD. Again, greater absolute risk reduction among the patients with both conditions. So as an example here, we have data from the DAPF CKD trial. And these are data for the end point, all end points, so to speak, all-cause mortality. And if you look at the panel on the left, you have the patients with both conditions, CKD and heart failure. You have a 44% relative risk reduction for all-cause death and that leads to an enormous 7% absolute risk reduction in all-cause death among the patients with heart failure and comorbid CKD. But it's not just about efficacy when we're talking about heart failure and CKD. For many of us, and you know, seeing patients in the clinic, usually top of mind is, well, what about safety? And we oftentimes worry about safety and tolerability when our patients have significant kidney dysfunction. But fortunately, the SGLT2 inhibitors have strong safety and tolerability profile. Again, irrespective of CKD status and including our patients with very severe CKD. You know, for example, here we have our, these are the subsets of patients in DAPF, HFN, and PERDUS with comorbid CKD. So the patients you're especially worried about potential intolerance. Well, we see whether you're talking about serious adverse events or renal events, there's numerically fewer adverse events with SGLT2 inhibitor compared to placebo. And if you consider that the SGLT2 inhibitor trials enrolled patients with EGFR as low as 20, these data are even more impressive. But it would be a gross understatement to just say the SGLT2 inhibitors are just purely safe from a kidney perspective. We also know they have great kidney benefit. And in our HFREF patients, we have now multiple clinical trials that show they actually make slow progression of kidney disease. And this is just one example here. In the EMPEROREDUCE trial, looking at the kidney composite endpoint of sustained reduction EGFR initiation of dialysis, we have empaglifosin compared to placebo resulted in a 50% relative risk reduction for its renal composite endpoint. And again, when you consider that the trial enrolled patients with EGFR as low as 20, you now have a huge scope of kidney benefit now available to our patients with HFREF. One last point that I'll highlight is that let's talk about blood pressure, something also top of mind for clinicians when we're talking about initiating titrating GDMT. Well, conveniently, the SGLT2 inhibitors in HFREF have minimal to no overall effect on systolic blood pressure and they actually exert in clinical trial data what I call an auto titration phenomenon where they're there when you need it, they're not there when you don't. So for example, if you have a higher blood pressure at baseline, you tend to get some of the pressure lowering. But if you start with a low blood pressure, they conveniently leave the blood pressure alone. This was seen in both trials DAPHF and EMPEROREDUCE. And I'll even draw your attention to the right-hand side from EMPEROREDUCE where you see the gray line, people that start with a blood pressure less than 110 systolic. If anything, compared to placebo, the SGLT2 inhibitor appeared to increase blood pressure, not statistically significant, but still really reassures us that it doesn't seem to lower blood pressure in our patients that start with low blood pressure, again, a very convenient feature of the SGLT2 inhibitor class. So despite discussing all these features that theoretically should favor really rapid, robust implementation in real-world clinical practice, unfortunately, we've seen that the uptake of SGLT2 inhibitors has been slow and it's been highly variable. And these are data from the recently published analysis from the Get Well Guidelines Heart Failure Registry. These are patients hospitalized for HFREF in the United States and eligible for an SGLT2 inhibitor. This is the period of 2021 and 2022, so very contemporary data. We saw that only one in five eligible patients were prescribed an SGLT2 inhibitor at time of discharge. And even when you look at the people that had three indications for the therapy, they had heart failure, they had CKD, they had type 2 diabetes, less than one in four patients were going home on an SGLT2 inhibitor. Then I also highlighted in the red boxes here, going back to our patient case, she had, by these data, she was particularly long odds of being offered an SGLT2 inhibitor in contemporary U.S. clinic practice. She was a woman, she was greater than 75 years of age, she was non-Hispanic race, she did have comorbid CKD, and she did not have type 2 diabetes. So again, these data would suggest she's at particularly long odds of getting an SGLT2 inhibitor despite being eligible for the therapy and despite having overwhelming clinical trial evidence, as we showed, that she was, despite her frailty, despite her age, despite comorbidities, that she would likely benefit from therapy. In closing, we discussed that SGLT2 inhibitors, in my mind, have many characteristics of an ideal FREF therapy. I mean, for patients that are particularly difficult to treat, like the patient that we saw in clinic today in this case presentation, where there's often perceived barriers or maybe relative or absolute contraindications to therapy, SGLT2 inhibitors can often break through and be a safe and effective therapy to treat this difficult-to-treat patient population. When you look at the ideal characteristics here, it really starts with simplicity. This is the only GDMT that is one pill, once per day, one dose, no titration. We already heard about the rapid benefits, both in terms of clinical outcomes and patient-reported quality of life, the safety and tolerability profile. So again, especially when you're thinking about these difficult-to-treat patients, SGLT2 inhibitors really often are a safe and effective therapy. So thank you very much for the attention. All right. Good morning, everybody. So, we're going to shift gears a little bit and talk about, now, the role of ChLT2 inhibitors in heart failure with mildly reduced and preserved ejection fraction. Now, you know, we kind of take things for granted nowadays, and I'm going to try to summarize what took about six years of work to do in about 15 minutes, but we've got to keep in mind that just a few short years ago, it was not clear at all whether we'll ever have therapy or a range of therapies that are actually effective across a range of ejection fraction. And, of course, dealing with two very different conditions, heart failure with reduced ejection fraction, which Su and Steve just talked about, is a condition where the myocardium is really the primary source of the problem. That's where the problem starts. Heart failure with mildly reduced and certainly preserved ejection fraction is a condition where, frequently, the heart is just an innocent bystander. It's really quintessential cardiometabolic disease. It's a systemic condition that's affecting cardiovascular system just like it affects many other organ systems. And so, you know, the range of situations and conditions is completely different in HFMF and PEF, so it was very important to try to understand if you take this quintessential cardiometabolic intervention, will you actually see a benefit as well? Here are my disclosures. What I will start with is just by centering us back on what's really important. What is the goal of care when we treat anybody with heart failure? And certainly, that includes people with heart failure and mildly reduced and preserved EF. So these patients, just like patients with heart failure and reduced EF, are at high risk of death, are at high risk of hospitalizations, and they have especially poor health status, meaning burden of symptoms, physical limitations, and quality of life. And so we frequently talk about this triple goal of care, which is what we try to demonstrate in clinical trials, reducing the risk of death, keeping our patients living longer, keeping them out of the hospital, and emergency department. And equally important is improving the symptoms, function, quality of life, trying to make our patients feel better and be able to do more. And if you have an intervention that can accomplish this triple goal of care, that's ultimately what I would call a high value intervention in patients with any chronic disease, certainly including heart failure. Now, in HFREF, you've already seen this. You know, we have very clear evidence, based on all the trials you heard about from Sue, that SGLT2 inhibitors achieve that triple goal of care. They reduce mortality, reduce hospitalizations, and improve quality of life. And it's therefore not surprising that they have a class one level of evidence, a recommendation, meaning that if you're not prescribing SGLT2 inhibitors in patients with HFREF, unless you don't tolerate it or it's contraindicated, you're not practicing good medical care. And the guidelines clearly acknowledge that. I wrote this editorial in circulation, I guess this was 21, shortly after we had the data in HFREF, but before we had any of the data in HFREF that I call Diamonds in a Ruff. And the reason I call Diamonds in a Ruff, actually, if you Google the Diamonds in a Ruff story, what you come up with is the story of this farmer in India that goes in search of diamonds around the world, spends several days looking for diamonds, ultimately not being successful, comes back home really depressed and bankrupt. And as he's trying to contemplate life and kind of what he's going to do next, one of his farm mates shows him this huge rock that they found on his property that was glinting in the sun. He immediately recognizes it's a huge diamond in a ruff. It turns out all these years he was looking for diamonds everywhere else. And this very farmer was sitting on one of the biggest diamond mines in the world, apparently a true story. And the moral of the story is that sometimes the biggest gifts that you get are the ones that don't recognize that they're sitting right under your nose. And of course, that's what we, the stories that we had with the LT2 inhibitors, they were kind of masquerading as glucose-loading agents that we discovered, thankfully, have enormous benefits when it comes to heart failure and kidney disease. And what I talked about in the tutorial is that we need to obviously try to realize the full potential of these medications. They have real promise, not just in heart failure with reduced DF, but also in heart failure with a preserved ejection fraction as well, because they have a completely different mechanism of action. Again, they're quintessential cardiomorbolic agents, and they're not neurohormonal medications like the ones that we've tested and have proven to work and have tested in half-bath and consistently failed. So, this was a real shot at goal that we needed to take. And of course, what we ultimately learned from the trials that haven't done is that, in fact, they do work, and they work incredibly well in patients not just with heart failure and reduced DF, but also heart failure with mildly reduced and preserved ejection fractions. The first data came from Emra Preserved and showed, actually, on a primary outcome of cardiovascular decimal hospitalizations for heart failure, data that looked remarkably consistent in terms of the overall point estimate of the primary endpoint, as well as the rapid separation of curves that we saw in people with heart failure and reduced DF, and 21 percent trial risk reduction, high statistical significance, small number needed to treat, and again, kind of a signature for this class, very rapid separation of curves and early onset of benefit. And by the way, I know we showed you the data for in terms of how rapid the benefit occurs and how rough. Keep in mind that the whole thing, say, well, you know, it takes weeks or three weeks or four weeks to see a statistically significant benefit. That's purely an operation of statistics, right, because you need to acquire a certain number of events for them to become statistically significant. But if you actually look at the hazard ratio, it's immediately favorable to actually to inhibit the benefits there on day one. So, this medication is actually working, you know, not just incredibly well, but also very fast. Now, much was made of this signal in emperor-preserved, if you call it a signal. The p-value was actually not significant, but because it was an ejection action, everybody was jumping up and down and saying, see, we must see the same thing with SGLT2 inhibitors, as we saw with all the other agents, like spironolactone and succubital valsartan. They may work well in people with mildly reduced DF, but they really don't work very well in people with completely normal ejection fractions. So, this visual trend, even though it was not a statistically significant trend toward maybe attenuation of benefit and high DF, didn't make a lot of sense to many of us, because again, the mechanism was completely different from neurohormonal drugs, like spironolactone and succubital valsartan. But of course, this needed to be tested, and it was proven to be the case, or dispelled, and we ultimately got there with the DELIVER trial, which is the largest SGLT2 inhibitor trial in patients with heart failure, and one of the largest that were done in a population of patients with HFPAF. Now, this was not only the largest, but I would say the most diverse trial of any agent on HFPAF. And why do I say that? So, it was very well represented in terms of ejection fractions, so roughly about a third of the patients had DF between 40 and 50, about a third had DF between 50 and 60, and about a third had completely normal ejection fraction, if you define it that way, at 60 percent and above. It was also very well represented in terms of patients being randomized in a hospital, recently discharged, or not recently hospitalized at all, in a chronic ambulatory setting, and it was the first trial ever, in terms of large outcome trials, to include patients that have what we call heart failure with improved ejection fraction. These are the patients that previously had EF below 40, but with GDMT, actually, the EF got better, so it's not over 40, but they continue to be symptomatic in the setting of heart failure. So, it's never been a trial that prospectively randomized patients to initiation of new therapy. Every HFPAF trial that was done with any other agent before systematically excluded this patient population, so we have very little evidence of how to trim. So what did the trial actually show? So, first of all, in the primary endpoint, it was a very, very similar, nearly carbon copy of what we saw in Emperor Preserve. Slightly different primary endpoints, so now including not just C-death and hospitalizations, but also urgent visits requiring intravenous therapy, but the end result was nearly identical. The 20 percent reduction in the primary endpoint had significant small number needed to treat and rapid separation, of course. But really, the true value of Deliver, I think, really came from subgroup analysis, as well as combining the data with what we know from reduced EF trials. So first, on the ejection fraction controversy, you know, very, very clear message here is that it really makes no difference what your ejection fraction is. So whether it's 40 to 50, 50 to 60, or 60 and above, if anything, numerically, things move in even more positive direction as the ejection fraction goes up, indicating that this whole notion that FGT2 inhibitors have attenuation benefit with higher EF is clearly wrong. They're similarly efficacious regardless of ejection fraction. It also didn't matter if the patients were randomized in the hospital, recently discharged or chronically in a chronic ambulatory setting. And for those that had this heart failure with improved or recovered ejection fraction, there was also no difference if patients were in that category where they always had EF above 40 percent. And this is, again, the first prospective RCT evidence of a clinical benefit in the population of patients with improved EF. In fact, in subsequent publications that Oral Vardini led and was published in Nature Medicine, we also demonstrated that in the group of patients that had heart failure with improved ejection fraction, there was a survival benefit, even though that was a relatively limited subgroup in terms of numbers, even in that small subgroup, relatively small subgroup, there was a survival benefit with dapagliflozin versus placebo. Now, we talked about safety in HF-RAF trials, what did the safety look like in the delivered trial. Again, very, very similar to what we saw everywhere else. There were actually numerically fewer serious adverse events with dapagliflozin versus placebo. There was a balance in terms of events leading to discontinuation, and really, if you go down the list, there is really nothing there that was of any significant concern. Of course, we know that these agents are not just cardioprotective, but as Muthu mentioned, nephroprotective as well. So, not surprisingly, there was no access in renal events, there was no difference in hypoglycemia, and so on. Now, Muthu actually presented this data at ESE last year in 2022, trying to combine the data from delivered and preserved, and really understands the overall class benefits. Again, the results were very consistent, so the summary of these results across trials was very consistent as well. When you look at this kind of a harmonized primary endpoint, cardiovascular death and first hospitalization for heart failure, you see a very significant and large benefit. It's even larger when you look at hospitalizations for heart failure, about a 26% relative risk reduction. Again, much has been made about this cardiovascular death story in half-life trials, and I'll just give you my personal opinion of this, which is, first of all, the thing that I want to say much has been made of this is that there was no independent survival benefit, cardiovascular death benefit, ESE, and mpropreserved liver. But when you combine these trials, you see there is about a 12% relative risk reduction, with the p-value being right at 0.05. The point is, it's actually exactly the same between mpropreserved and delivered, and you got to keep a couple of things in mind. One is, if you look at half-life trials, actually the majority of patients, once they die, the majority of them die because of cardiovascular death, and it's mostly heart failure-related deaths or sudden death. But if you look at half-life populations, a very different patient population, and deliver only about half of the deaths were due to cardiovascular causes, and the other half were due to other things. So, showing a cardiovascular death benefit on half-life trial is extraordinarily difficult, and you need to do huge trials, and none of these trials, neither mpropreserved nor delivered, were independently powered for cardiovascular death. If they had to be powered for cardiovascular death, it would be trials that would be more than twice the size that they were. So, what you can actually do when you try to combine data across trials is actually get a number of events that allow you to understand the effect on cardiovascular death, and what you see here, it's clearly a power issue, because when you combine them, you actually get to very close to statistical significance. And if you actually look at the entire huge meta-analysis with tens of thousands of patients, in some cases, as many as 90,000 patients across all of the different trials that was due to hubris in people with diabetes, heart failure, and kidney disease, it's very clear that the overall effect on cardiovascular death is somewhere between 12 and 15 percent, and that's what we see in trials of patients with diabetes, that's what Muthu showed in people with HFRAF, and you see exactly the same thing. The point estimate is 12 percent relative risk reduction in patients with HFRAF. It's a very, very consistent message. These medications do reduce cardiovascular death. It's a modest effect, but it's absolutely there, and if you have enough events, it's going to be statistically significant. You combine the data across a range of rejection fraction, you clearly see between DAPA-HF and DELIVER, that the two goals of care, which is reducing cardiovascular death and heart failure hospitalizations, is clearly there. Across a range of rejection fraction, it doesn't matter if you have 15 percent or 75 percent. What about the effects on health status? Symptom function quality of life, measured by cancer, cardiomyopathy questionnaire. This is the data from the PRESERVE-CHEF trial, investigative trials that we did across more than 20 centers in the U.S., showing very large case Q benefits of nearly six points population of patients that were highly symptomatic and also actually an improvement in six minutes walking distance of about 20 meters. When you combine the data across an investigative trial done all within the United States across multiple centers between DEFINE-HF and PRESERVE-HF trials, you see exact same trend in symptom function quality of life as you see for CV death and heart hospitalizations and DAPA-HF and DELIVER. So we got a five-point benefit overall in cancer cardiomyopathy questionnaire. Whether your rejection fraction is 10 percent or 80 percent, it's essentially a straight line for all of these outcomes. Now, our European colleagues have taken this data very seriously, and as of just a few weeks ago at ESC, the new ESC guidelines were announced that now give us JLT2 inhibitors a class one level of redundancy recommendation. Whether it's in mildly reduced rejection fraction, heart failure, or completely preserved rejection fraction, heart failure. And my hope is that the U.S. guideline will be updated very, very soon. And we'll see similar class one level of evidence, a recommendation there as well. Now, couple of quick things just on the acute heart failure trial. So we're talking about half-path. Moose already showed you the data from SOLIST. I'm not going to rehash it just to say that a proportion of these patients had heart failure with PRESERVE-DF when they were randomized in a hospital within a few days of discharge, and the benefits were consistent regardless of rejection fraction. We did this trial with empagliflozin called EMPULSE, which randomized patients specifically only during hospitalization after a brief period of stabilization. And what we saw in EMPULSE was a statistically significant benefit on this composite hierarchical endpoints that included all comorbid mortality, heart failure events, and changes in KNCD cardiomyopathy questionnaire. But if you actually look at clinical events, even though it was a modest-sized trial, within 90 days, you actually saw a benefit on all-cause mortality and heart failure hospitalizations and within 15 days, just two weeks, for the symptomatic benefit as well. And in that hospitalized patient population, you saw a similar, very reassuring safety profile just as what you saw in a kind of a more combined patient population that included both hospitalized and non-hospitalized patients. So even when you do it in a hospital in patients that were decompensated for heart failure, you see very reassuring safety profiles. So the last thing that I'll cover is this whole issue of how do agility inhibitors actually do that and why is that the first class of agents to show benefits across a range of rejection fraction. I can't remember exactly whose quote it is, but it's something like, the less we know about something, the more we like to talk about it. We still don't understand the benefits and the mechanisms of benefits for agility inhibitors, but I think we can say a few things that we actually have data for. And one is that if you think about heart failure and how we find heart failure. So it's a clinical syndrome that we define based on symptoms and physical exam findings. So the symptoms are caused by congestion. So you've got to be congested in order for you to be diagnosed with clinical syndrome of heart failure. The idea is that you would be congested regardless of what your rejection fraction is. And so if you have an agent that effectively decongests the patient, it should be effective regardless of EF. And we clearly have data that says agility inhibitors do that. Not only is there increased diuretic efficiency and reduced plasma and blood volume, but if you look all the way to the bottom right, it's an EMBRACE-HF trial, an investigative shooter trial we did across 10 centers in the U.S. and patients with a cardiomyopathy device, where we randomized those patients regardless of rejection fraction to amplify the flows in the placebo. And we measured pulmonary pressures twice a day, every day for 12 weeks. And you can see that within a week, there is a reduction in pulmonary artery death. That pressure continues to diverge in favor of GIL-2 inhibitors. So they clearly are effective in congesting agents. And that should be relevant regardless of rejection fraction. There are also positive effects on LV remodeling, energetics, and thalamics, and of course, suffer protection, all of which arguably should be relevant for heart failure regardless of what your rejection fraction is. So again, very different from neurohormonal agents that predominantly work in half-ref, but less so in half-path. So to summarize, and you've seen a lot of this already, it's really across the range of rejection fractions that we see this triple benefit, which is reduction in CVF hospitalizations, improvement in symptoms, function, and quality of life, with a favorable safety profile across the range of rejection fraction, age, kidney function, background, therapies, or clinical setting. Muthu already talked about how easy it is to use SGLT2 inhibitors, one pill a day, no observation, no obligatory lab monitoring. Actually, I'll add to that, there are also no DDIs, no drug-drug interactions with other cardiovascular therapies like anticoagulants or statins or, you know, antiretinics or anything else that you can think of in our patients with cardiovascular disease. So with that, I will close and look forward to the LAMAS case. Thank you, Mikhail. So we'll wrap up with the last case, and this is a patient that I actually saw in CLIC. So she was a 68-year-old woman who presented with persistent dyspnea on exertion for the past six months. She had seen probably six different doctors before she was referred to me, and I think this is a very common scenario with patients like this, where no one can really give these patients a diagnosis, and they often say, oh, see, you're a lung doctor, oh, see, you're a primary care doctor, oh, see, this other doctor, and by the time the patient gets to see us in heart failure clinic, they're often extremely symptomatic but also extremely frustrated, which is not really understanding what their diagnosis is. She had a past medical history of obesity, hypertension. She had a history of atrial fibrillation and had a pulmonary vein ablation in the past. She came to me with about 400 pages worth of records from various physicians and outside hospital, and of course, as you know, we only have 20 minutes for a patient visit. So I had to go back and do some digging after I saw her, but again, sort of highlights the idea that these patients suffer, right? They're often sort of tossed around. They often have million-dollar workups, we like to say, which this patient did, and still no one had actually given her a diagnosis. So she had an echo before she saw me. Her ejection fraction was 60 to 65 percent. She had grade one diastolic dysfunction, which we often, you know, sort of hesitate to say whether or not that is HFPAF. She had mild left ventricular hypertrophy. She had normal feeling pressures, at least on her right echocardiogram, and she had had a left heart cath a few years prior that showed that her coronary arteries were normal. On physical exam, her BMI was 42, consistent with her diagnosis of obesity. She had a blood pressure that was elevated at 146 over 92, normal heart rate at 84. Her lungs were clear. She did have evidence of some algegular venous distension, tracelaric germaniedema, but otherwise her physical exam was relatively unremarkable. At the time that I saw her, medications included hydrochlorothiazide, amlodipine, as well as Apixan because of her atrial fibrillation. And her labs included a sodium of 139, normal potassium, low normal perhaps, as well as an EGFR of 49. So at this point, and I'm not sure that we have a way for you all to respond other than maybe just a show of hands, but, right, this is an SGLT2 inhibitor talk. So would you guys add to epiglottosin? Would you add spironolactone, right? That's an option. Would you add isosorbide mononitrate? Would you increase the dose of her amlodipine, or would you do none of the above? Anyone courageous enough to say, maybe I'll ask my experts, Mikhail, I'm calling you. So actually, I did none of the above. This was the first time that I saw her, because I wanted to feel confident that I had the right diagnosis, right? So I think that it's very easy to say, I'm just going to put her on dapligliflozin and see her back in two to four weeks and see how she feels. But again, because this is someone who had been to multiple doctors before she saw me. I wanted to feel confident that I was dealing the right diagnosis because there is a differential diagnosis for dyspnea, right? Not all patients are dyspneic because of heart failure. And I have been burned just like many of my colleagues have in the past. I thought this person maybe had heart failure, but when I did the appropriate diagnostic tests, I actually realized that wasn't the reason why they were short of breath. So again, I think it's important for us to ask ourselves as co-clinicians, could this be her obesity? Is she just physically deconditioned? Could you be having episodes of atrial fibrillation, perhaps a very matricular response that's undiagnosed? Could there be pulmonary veins stenosis? Right, this woman has had an ablation for her AFib in the past. We know she's a normal heart cath, but I don't think it's unreasonable to think about coronary disease, particularly in a woman, where we know that that diagnosis often is missed. But of course, because I'm a heart failure cardiologist and she's seeing in a heart failure clinic and short of breath, I wanna make sure this woman does not have half path. And again, this differential diagnosis for dyspnea is broad. It doesn't have to be cardiac or pulmonary. There could be other source. In fact, I can reflect on a patient who I put on diuretics and started, in fact, she had metastatic breast cancer. So again, it's important for us to be clinicians and make sure that we are attending to things that we do well in terms of working on patients for the reasons that they are short of breath. We also know, again, that there are sex specific differences in women where the half path presentation, as well as the diagnosis being more difficult to come by, there seems to be a greater attributable risk from risk factors like this woman had, hypertension, diabetes, obesity, that have sort of this cardiometabolic impact that contributes to a higher risk of half path in women as compared to in men. Again, there are unique factors that women have, including preeclampsia, as well as the impact of central obesity and visceral adiposity that, again, may presuppose to half path more in women. And these are things that we're still trying to understand. And we see a similar to half path as well as coronary disease that in half path women tend to be more symptomatic, a distinct symptom profile, tend to have more dyspnea and a worse health status independent of their ejection fraction or other factors. And finally, we see some sex specific findings, including more concentric remodeling, more impaired diastolic relaxation, as well as sort of our understanding that's continuing to evolve of what the actual EF thresholds may be in heart failure. Perhaps there should be sex specific ejection fraction thresholds that help us define heart failure better and differently in women as compared to men. So, colleagues, what would you do next? Sort of now knowing, are there any diagnostic tests or manures that you might want to get to help yourself feel confident that this woman has half path prior to initiating the GLT2 inhibitor? I'm happy to start. I'm happy to start too. I mean. Perfect. Well, for the purposes of learning. Yeah. Because we're at an academic conference. I did actually check a couple of things, again, to help myself feel confident. If I look at the guidelines, they do suggest to me that it's appropriate to check natripeptides, right? In someone who you're asking a question of whether or not they have heart failure, either in an ambulatory setting or an inpatient setting. So I actually sent her natripeptides. Her BMP was 53. She had also had to stress a cardiogram prior to seeing me to rule out ischemia. And it was relevant for the fact that she had very poor exercise capacity. She was actually only able to walk for two minutes before becoming short of breath. And they had to stop the test. Now again, I mentioned to you that this woman had seen multiple providers prior to seeing me and someone had actually not noted that the BMP being 53 was consistent with heart failure. But again, by the universal definition of heart failure, we know that this is consistent with heart failure diagnosis. Remember that in an ambulatory setting, we only have to see a BMP above 35 for it to be consistent with a diagnosis of heart failure. Of course, in a hospitalized setting, as many of these patients are seeing, we have a greater cutoff over 100. But again, I was seeing her in an ambulatory setting. We also know in patients with HFPAF, patients with obesity, we may not see an elevation in atrial peptides that may be as high as what we might think based on their symptom profile. So again, it's sort of important to put that BMP in context of A, what the universal definition tells us, but also in the context of her confounding comorbidities like her HFPAF and her obesity. We also know again that there's a stepwise approach to assess shortness of breath and edema in these patients. This is the HFAPAF score. HFPAF score, which again, encourage us to check atrial peptides, but also encourage us to do functional testing on these patients because as we know, many times the echocardiogram at rest doesn't give us the level of information that we need to feel confident about the diagnosis. So if we see a patient who has evidence of normal filling pressures at rest on echocardiogram, we can stress the system. And that's often when we see elevation of left atrial pressure, elevation of PA pressures that again, make us feel really confident this is indeed FPAF. So on her stress echo, as I look back to these records, I actually saw, again, sort of buried in this 500 page worth of documents that she did indeed have clear elevation of her right ventricular systolic pressure at stress, again, to me consistent with the diagnosis. So at that point, I felt very confident adding dapagliflozin in her to try to get her feeling better. So as you've heard from Mikhail, we know that the guideline-based recommendations in HFPAF have changed very, very rapidly, right? In 2022, when the U.S. heart failure guidelines came out, diuretics were still the only class one indication for HFPAF, SGLT2 inhibitors were a two-way. Now, of course, with the updated ESC guidelines that came out this past August, we now see that SGLT2 inhibitors, both DAPA and EMBA are a class one. Again, this is different than our U.S. guidelines. Just from a year ago, again, the indication for an SGLT2 inhibitor was a two-way. So again, we see this rapid evolution of the class of recommendation for these drugs, and Mikhail has shown you the evidence for why that is in patients with HFPAF. And of course, the U.S. guidelines still give us the opportunity to use the ARNI, the MRA, as well as the ARV, and there was expert consensus decision pathway that came out from the ACC, sort of helping us guide management of HFPAF, because ultimately in this patient, I actually did end up starting her on ARNI, because she continued to feel short of breath. So it's important to, again, sort of go back to the fact that many of our patients have symptoms that are quite severe and perhaps an SGLT2 inhibitor may not be the only drug that they benefit from. If we look at these guidelines, or at least the expert consensus decision pathway, it suggests that in women, that perhaps an MRA may be a perfectly useful second agent to add, and in men as well with an EF less than 55 to 60, or those who have evidence of fluid retention. For women, again, regardless of EF, or men with an EF less than 55 to 60, it's certainly reasonable to start ARNI. We know that the patient was very hypertensive when she came to us, so the addition of an ARNI may, again, help us with her blood pressure. And then, of course, for any ARNI eligible patient who cannot tolerate that due to cost or intolerance, ARBs are still very reasonable. So I think the last thing to say is it's important to involve the care team. Again, we oftentimes see that these patients have multiple clinicians. They see the nephrologist, the diabetologist, us as the heart failure clinician in the primary care, and we really see, again, sort of these drugs, the SGLT2 inhibitors in particular, have benefits across multiple comorbid conditions. So I think it's important for us to involve members of the care team. I often find myself sending notes, referring clinicians to other clinicians who might pull off the SGLT2 inhibitor that I've just initiated because of the EGFR dip or other reasons. So to make sure that people understand the rationale, because as Steven showed you, we see, unfortunately, that many of these patients are undertreated. They are not initiated on these drugs despite their comorbid profile. So I often find myself sort of sending my note to other clinicians, highlighting the benefits that we may give patients from these drugs as we study them. So I'll stop there. Although this is a common presenting symptom path, it's important to consider other diagnoses. But as you've seen this morning, there's a benefit of SGLT2 inhibitors across the spectrum of EF, including in this with mildly reduced as well as PEPF. And these should be initiated in all individuals, of course, if there are no contraindications documented. So I'll stop there. Thank you. So that was just a really beautiful summary of the efficacy and safety of the SGLT2 inhibitors across the spectrum of ejection fraction. I'm mindful of time, and I'd like to really focus on your questions because I think that will help us get into the practical elements of their use. We have six therapies now FDA approved and available for use, three of which are specifically labeled for heart failure. That's dapagliflozin, empagliflozin, and sodagliflozin. The totality of evidence suggests not only clinically important relevant benefits on heart failure hospitalizations, but also on mortality outcomes and how patients feel and function in their daily practices. This is the really first therapy across the full range of ejection fraction in men, women, regardless of their background comorbidities, these drugs actually influence heart failure status and are recommended as class one recommendations. And as Dr. Green showed, this is a very easy to implement therapy and it may even be the ideal cardiometabolic therapy. So once daily therapy that has limited need for titration or monitoring has meaningful benefits in days of initiation and has a very well tolerated clinical profile. So in putting this into context of the overall totality evidence, we see that patients, many patients that we commonly see in cardiovascular practice may benefit from SGLT inhibitors, whether they have heart failure, chronic kidney disease, or type two diabetes, and many individuals, they sit at these intersections of multiple morbidities. So seeking out those indications is of high priority. So let's move to some of the questions that you've asked us. So I'll start with a question to Mikhail, and it's a question about morbid obesity. And are there any unique issues that you consider when starting a drug like an SGLT2 inhibitor in a person who's morbidly obese or faces severe obesity? Well, thanks, Musa. So first of all, this is not very different from the case that you just presented on it. So that patient's BMI was quite high. I don't remember exactly. What is it? 42. 42, yeah. So we see that very commonly, right? So if you look at a preserved HF trial, which was an investigative trial we did, where we had no inclusion or exclusion criteria based on BMI. So patients could get on trial regardless of what their BMI was. And because of that, you actually get a pretty clear sense of what the typical BMI is in the patient's health path in the US. And the median BMI was 34 in that trial. So which tells you that its obesity is extremely prevalent in this patient population. Not only is it prevalent, but many of us, myself included, believe very strongly that obesity is not a coincidental finding. It's not an accident that the prevalence of obesity is so high, but in fact, obesity is what's causing heart failure in many of these patients. Now, what do we know about SGLT2 inhibitors? So it just so happens that preserved HF is the SGLT2 inhibitor trial that had the highest BMI of any heart failure preserved EF program with SGLT2 inhibitors. And it also happens to be the trial where the symptomatic and functional benefit was the largest one observed with any SGLT2 inhibitor program in terms of benefits on KCQ and 6-minute walks. So patients with a higher BMI, we know have higher burden of symptoms and physical limitations. And they appear to respond to SGLT2 inhibitors certainly as well as not better. And from a symptomatic and functional standpoint, probably even better than your average half-past patients. And there are no safety issues specifically in obesity to think about as far as SGLT2 inhibitor initiation is concerned. So yes, absolutely, in somebody with morbid obesity or obesity in general, not only SGLT2 inhibitors work and they're fine to use, but they actually work even better in terms of symptom and physical limitation improvements. The other thing I will say, and this is actually going back to Alana's case is that I would wholeheartedly agree in terms of what to do after an SGLT2 inhibitor if we were looking at this four, five, six weeks ago, but now with Step-Half-Path data, the other interventions that would need to be strongly considered in this patient would be a GLP-1 receptor and it's like somaglutide based on the Step-Half-Path result that we just presented to you a few weeks ago where there was a very large symptomatic and functional benefit with those agents as well. And GLP-1 receptor agonists, SGLT2 inhibitors work incredibly well together. We know that from a diabetes world and we're now increasingly learning that the heart failure world as well. Thank you. Dr. Morris, I'll ask you the next question. You're sitting with that patient in your clinic and they ask you about urinary tract infections. How do you initiate that discussion and what's that conversation look like? Regardless of the medication that I initiate, I always try to talk patients about the potential risks and side effects that they are aware, but I think Dr. Green made a very good point, which is it's important for us also to talk about the potential benefits. So I do tell patients that the most common side effects or adverse events that we see are certainly urinary tract infections as well as, and I think I probably also see, vulvovaginitis more commonly. If I do talk to women about that, if for some reason you have a UTI sort of out of the blue or a yeast infection to please call me and let me know, but I do not use that as a reason to stop the medication. So if that does occur, I certainly will give a patient a prescription for Diflucan or appropriately treat the UTI, but it is typically not a reason to stop the medication. I think of all the patients that I have, I might have one who has recurring UTIs because she has a neurodegenerative bladder, but again, those are few and far between. I would say anecdotally the data does not certainly support that recurrent UTIs are something that should limit our likelihood of starting these drugs in patients. I speak to that as well too, there were some other questions made on UTIs. I mean, when you look at actual clinical trial data, there's actually totality of evidence why no significant risk of urinary tract infections with the GLD2 inhibitor. I know it's a theoretical risk, it's actually in the label, but we need to distinguish that from genital mycotic infections. There is a small, absolute increased risk, but it comes up all the time. And I say to trainees and whatnot, older patients with multiple comorbidities, they get urinary tract infections and they get urinary tract infections whether you start on SGLD2 inhibitors or not based on data. So there's theoretical risk, it's in the label, monitor it, but again, distinguish from genital mycotic infections, urinary tract infections is a different story from the data. And just very quick practical tip. So, you know, fluconazole, single dose fluconazole, great way, if somebody does develop a genital mycotic infection, whether it's a woman or man, you know, one dose and you're done with genital mycotic infections, but you do need to keep in mind that fluconazole can prolong QT interval. So you've got to look at the med list, make sure if the patient's on dafetilide or sotalo, or one of the antirethmics that prolong QT interval, you got to keep that in mind. And maybe topical therapies in that kind of a patient would be a better option than fluconazole. We have a lot of questions. We're going to be, we're going to move through them quickly. We have a question about dosing. So these are general fixed dosing for the indication of heart failure. Dapaglifo is in 10 milligrams once daily, epiglifo is in 10 milligrams once daily, and sotaglifo is in 200 milligrams once daily. No need for titration, single dose that can be continued. This is a question for Dr. Morris about blood pressure control. So blood pressure control is the other class one indication that we have in heart failure preserve. You have a patient who has poorly controlled hypertension in front of you. How do you make that decision about using an SGLT2 inhibitor, or should we actually be controlling their blood pressure, or both? Yeah, I mean, I think it's both. So again, you saw data today that I think Dr. Green showed that, again, for the most part, these agents tend to be sort of titratable or sort of autotitrate to the situation. So even in someone who starts hypertension, we tend to see about a 46 millimeter lowing of the pressure that's been shown in the diabetes trials, as well as the CKD trials as well. So in this patient whose blood pressure was 146 over 92, I would not anticipate that adding the SGLT2 inhibitor would get her blood pressure under the 130 over 80 goal that I would like, which again, is why I showed the expert decision pathway, even though agents like ARNI, MRAs, or others are not necessarily a class one, they may be useful and to treat other comorbidities such as the hypertension. And we know that there are other benefits, again, in a woman that we may see an ARNI made more beneficial, perhaps, based on the PRR data. Thank you, thank you. And so, Dr. Green, I'll ask the next question. In many ways, heart failure has been called the embarrassment of the richest. We have many drug therapies, including now three FDA-labeled drug therapies that are SGLT inhibitors. So Empagliflozin, Dapagliflozin, and Sodagliflozin, how do you make the choice between these? It's a great question. And I mean, the bottom line is, practically speaking, do whichever their assurance and out of the costs are cheaper. That's the bottom line. I mean, we do have a heart failure perspective. We think this is a class effect, both in terms of heart failure prevention, but also in terms of heart failure treatment. So that's my short, simple answer to that. Mikhail, you talked about physiology and mechanisms as your last slide. And we have therapies that largely have the same mechanism of action. Sodagliflozin additionally inhibits SGLT-1. How do you incorporate that, if you do, into your own clinical practice? Well, I mean, I think from a heart failure standpoint, if you look at the clinical trial data, so the question is, does SGLT-1 inhibition matter, right? And it's a tough question to answer without doing head-to-head comparisons. And of course, those aren't coming anytime soon, if ever. So we probably won't have an answer to that question. With that acknowledged, it doesn't appear that SGLT-1 inhibition, on top of SGLT-2 inhibition, really changes signals that much when it comes to heart failure. Now, there may be some other reasons to think about SGLT-1 inhibition. There appears to be, even though it's not labeled for diabetes management, there appears to be, and physiologically, actually, it would make sense, that in people with kidney dysfunctions, there may be a bit more hemoglobin A1C lowering with SGLT-1 inhibition component than pure SGLT-2 inhibitor. There's also the centralizing data from four trials suggesting significant reductions in Lyme stroke, which we do not see with traditional SGLT-2 inhibitors. But that's a single trial. It has not been confirmed. It may or may not ever be confirmed. Another trial we'll see. Hopefully, it will be at some point. But I think it's very interesting. The question is, in patients with heart failure, how much does it actually matter to reduce Lyme stroke risk? Obviously, that's a bonus on top of heart failure events. But I don't think that data is quite definitive yet. Perfect. Last question. Dr. Morris, I loved your discussion of the practical approach to heart failure-preserved EF diagnoses. And perhaps, in most of our clinics, the most common presenting symptom is dyspnea on exertion. And most of our patients have preserved ejection fraction. So can you go through again, how do you actually triage that patient in terms of choosing whether to pursue advanced diagnostics like exercise, stress imaging, or exercise of an invasive hemodynamics? I think so. And for many of you, if you are into scores, I've had many of my colleagues sort of tease me, but I like to be very academic when I see these patients and use these scores. Again, we have two, the HFA-PEF score that I showed you, but also the H2-FPEF score. And I actually sat there in clinic and sort of added up her comorbidities, including her hypertension, her history of EFib, the evidence of pulmonary hypertension, her obesity. This is the H2-FPEF score. And so when I put all of those data in, it's very easy to do in a clinical setting. Her risk of having HFPEF, or her likelihood of having HFPEF, I should say, was over 90% based on the number of points that she had. So again, as a clinician, I always wanna feel confident with the diagnosis. And I think for HFPEF, as compared to HF-REF, for some of us, it can be a little bit more challenging. But I also think, again, she had evidence of systemic congestion. She had evidence of some lower extreme edema. Her neck veins were elevated. So I did, in fact, feel fairly confident that she had a diagnosis of HFPEF. I showed you the BNP, which many of my colleagues had missed, because, again, they were sort of unfamiliar with the fact that our new universal definition of heart failure has lowered those cutoffs for BNP that many of us are used to. And again, I think, as we see very commonly in the setting of other comorbidities, like obesity and HFPEF, we may not see natriuretic peptides that are as elevated as might be suggested based on the patient's symptom burden or clinical profile. So for me, I think it was a slam dunk that this woman had HFPEF based on multiple different factors. But there are certainly some patients where it's not a slam dunk. I think the other thing that's important to consider, we know that many of our patients with HFPEF actually have amyloidosis, for example. So there may be other conditions that may be sort of masquerading as HFPEF. And it's important for us to sort of pull those out. So I think if there's any sort of concern, if a patient sort of has an intermediate risk profile based on some of these scores, it's very reasonable to pursue some of this advanced diagnostic testing to make yourself more confident. Thank you. And so we are so, so very grateful for you to join us this early in the morning. I'd like to thank our faculty for just wonderful clinical insights and to all of you and in sharing our interest in this wonderful drug class. We will stay afterwards for a few minutes if you have any other questions. Thank you so much.

SGLT2 inhibitors

heart failure

ejection fraction

HFmrEF

HFpEF

HFrEF

efficacy

safety

adverse events

renal impairment

survival benefits