Dr. Ty Gluckman (Providence Health System): We will go on here and talk about cardiovascular-renal-metabolic or cardiovascular kidney metabolic syndrome. There is increased attention across many disciplines about talking about this condition. For all of you, I suspect, you know that there is a marked intersection for all of these conditions across one another. In fact, obesity is a common underpinning that exists in this patient population, but the presence of diabetes, chronic kidney disease, and various forms of cardiovascular disease, heart failure, ischemic heart disease, atrial fibrillation exists.

You can see, and I would not read through these, but the prevalence that exists globally of the respective conditions on the left side, with obesity again being a major driver of this condition. Very sobering statistics. If you look on the right-hand side, you can see the stages in the evolution from having no risk factors and the respective goals that go along with that, all the way to having overt forms of clinical cardiovascular disease or chronic kidney disease on the right-hand side. 90% of the population has stage I or greater forms of CRM or CKM. It is quite prevalent for the patients that you see.

Prevalence and Overlap of CRM Conditions in US Adults, 2015-2020

This is borne out a little bit by some data in US adults looking through between 2015 and 2020. You can see it is a weighted percentage of adults. On the Y-axis on the left, on the right is the estimated number of adults in millions. Then we start getting into the fact that these often will occur in concert with one another, where you will see cardiovascular and kidney disease as comorbidities for one another.

Future Prevalence of Adverse CV-Related Conditions in US Adults

This is sobering. I will tell you the only trajectory that is going down is that there is an anticipated decrease in the prevalence of high cholesterol. This is data through 2050 on the left and the respective various forms of adverse cardiovascular conditions. This comes as a publication from the cardiovascular community, looking at what effects are going to at least be associated with the rise in the prevalence of diabetes, hypertension, obesity conditions.

Incidence of HF, CHD, and Stroke Among Patients With or Without CKD

It is important to realize that the presence, in particular, of chronic kidney disease has a significant impact. These are unadjusted rates, but even looking at adjusted rates, we see increased rates of heart failure, coronary heart disease and stroke. They are high to begin with. Then when you add in the presence of chronic kidney disease, it further accentuates the potential for these adverse cardiovascular manifestations.

CRM Syndrome: Burden and Care Fragmentation

This is probably known to a lot of you. We can talk and we were highlighting some of the burdens associated with the multimorbidity associated with cardiovascular-renal-metabolic syndrome, the increased risk for heart failure hospitalization, cardiovascular death, and the presence of an increased prevalence of type 2 diabetes, cardiovascular disease, chronic kidney disease in these patient populations.

What stems a lot from this, and you all are often having to oversee a lot of this care, but the fragmentation that exists, particularly within the specialty community. I am a cardiologist, and I guess I think often about things through a cardiovascular lens, but not recognizing the intersection of other specialists and primary care and overseeing the care. This often gets to a challenge that Jennifer highlighted in one of the questions was waiting for endocrinology, nephrology to have concordant opinions about things. It is a challenge unto itself.

We are going to highlight with a quote towards the end, which I often like. I do not like the term ownership, but the reality is how do we all work rowing in the same direction for the benefit of patients?

SGLT2 Inhibitor Use for HF in US Ambulatory Setting

There are very sobering statistics highlighting the fact that we have effective therapies for this patient population. A lot of the theme tonight will focus in on SGLT2 inhibitors, but not at the expense of recognizing that there are other important therapeutic classes.

This is a data looking at over 750,000 individuals with heart failure. This is in the ambulatory setting. This is data through June of 2023. When you look at the rates of SGLT2 inhibitors being a Class I recommended intervention, a core pillar of therapy for those with heart failure with reduced ejection fraction. Yet fewer than one out of five in red people got that therapy. Less strong recommendation of Class IIa recommendation for those with mildly reduced or preserved ejection fraction heart failure, but again highlighting the fact that these therapies are significantly underutilized.

In some respects, as a cardiologist, my life is a little bit easier if patients do not have diabetes, because I fear this concern of what will my endocrinology colleagues think? Sometimes it is actually a little bit easier. The data does not bear this out nationally, but how do you better coordinate that care?

Underuse of GDMT: It Is not Only SGLT2 Inhibitors and HF!

We are highlighting here that the shortcomings and the care gaps are not unique to heart failure, and they are not unique to SGLT2 inhibitors, but SGLT2 inhibitors are underutilized in type 2 diabetes, in chronic kidney disease, where they have well-established benefits in those patient populations. Similarly, other effective pillars or therapeutic options, including GLP-1 receptor agonists are underutilized in patients with type 2 diabetes with chronic kidney disease or atherosclerotic cardiovascular disease.

You can see the sobering statistic there as the bullet point overall. Mineralocorticoid receptor antagonists, which have anti-fibrotic anti-inflammatory effects, underutilized but established benefit in these patient populations. It is easy to start inventorying either from a clinician perspective, a healthcare delivery system perspective, a patient perspective what may be the reasons for this? Does cost put up a barrier? Are there safety concerns?

We are going to come to a theme called clinical inertia in a second. Often patients come in. They are feeling well. There, for lack of a better word, stable gets tossed around as a word a lot. Yet the question is, what could happen if the therapy was not otherwise initiated? Often we are very much keen towards, “There is a problem, I am going to react to the problem.” When someone is doing well, how do we make them continue doing well as opposed to they may be well today but not well tomorrow?

Use of Glucose-Lowering Therapies in T2D Care

This is data at least just borrowing from some of the data for glucose lowering, or I should say more specifically those with diabetes. We have a wide array of different therapeutic options. We have recognized increasingly that certain comorbid conditions, the presence of atherosclerotic cardiovascular disease, the presence of chronic kidney disease, the presence of heart failure should inform our therapeutic decision-making, but often does not and the complexity for everyone in this room of how do you best manage all of these therapies?

I have never met patients that are actively moving their arm up to saying, “I want to be on more and more medications.” How do we prioritize those therapies that are most likely to be effective?

SGLT2 Inhibitor Underuse in Patients With HF With or Without Diabetes

This is data that a little bit I had highlighted previously, but is to look at the use of SGLT2 inhibitors amongst adults from 28 healthcare systems in patients with heart failure with or without diabetes.

Now, probably not surprising to a lot of you, given the fact that there is a well-established benefit for this class in diabetes, the rates are higher. I at least highlighted that it may even be easier for me. Across the board, whether patients had diabetes without diabetes marked underuse.

I know we have individuals, and we did not mention this earlier that this has been simulcast online. This look as who is responsible for this? I would again say that we have a shared responsibility, but sometimes our patients feel that way. We are going to show some videos that maybe highlight that as well.

Factors Contributing to Clinical Inertia

We are not alone on our own. We often live in an ecosystem where we work as part of a larger health system, a larger medical group. What are the factors that might contribute to clinical inertia? They are listed:

• Perhaps lack of access to tools that could support best practices;
• Lack of integration of that into clinical workflows or the Electronic Medical Record;
• Not using a team-based approach; and
• Unequivocally time constraints for all of us.

For the healthcare clinician, a more reactive approach to care, less so being proactive, but I am inundated with every one of the visits. A patient who has a specific complaint. I am trying to actually address the things that may be most important to them.

The amount of new science and knowledge that continues to come out, I have a very hard time just in cardiovascular medicine staying on top of it. It can promote knowledge gaps, difficulty in navigating or accessing what best practices exist overall, maybe disagreement with the evidence that is out there overall, and then being able to figure out confidently that you can measure certain indices that may drive decision making overall.

Some clinicians are particularly concerned about the safety of treatment intensification. Some of the therapies that we use can lower blood pressure, may have effects on kidney function to an advantageous way, but how do I assess whether or not there is any untoward effects overall?

Then unequivocally concerns about polypharmacy. The adherence implications associated with that, cost implications of some of our therapies. I can be all too certain that patients, this is top of mind for them. Again, we have some good videos that will highlight some of this for you overall.

Clinical Inertia and Implementation Delay

Clinical inertia and implementation delay. This concept of stability is one that is understandable, but we need to push on a little bit, is to say, the person that comes to see you, whether we are looking at their diabetes, their chronic kidney disease, their heart failure, it is largely chronic diseases that are progressive in nature?

How are we thinking two, five, 10 steps ahead in making sure that the patient who might not seem sick enough to warrant intensification of their therapy today, in fact, is the person that you want to double and triple down on by not only adding therapies proven to be beneficial and/or intensifying their regimen overall? It is really not an or, it is an, but recognizing that individuals may want to go slow, patients may want to go slow.

Sometimes individuals are perceived to be too sick. This is weird paradox of, “This patient is too sick. They are in the hospital. We will deal with this in the outpatient setting.” Someone saying they are stable in the outpatient setting. Unfortunately, it leads to a delayed initiation of therapy and/or the therapy never gets initiated at all.

In type 2 diabetes, individuals may focus more on glycemic control as opposed to recognizing the benefits that may differ from class to class in being able to provide renal protective, cardiovascular protective effects as well. Again, these misunderstandings often can perpetuate underutilization of therapy.

GDMT in HF Among Hospitalized Patients Who Are Frail

Again, this is just highlighting the concept of individuals that are hospitalized, perhaps the most vulnerable state, but also one of the most actionable times that you can initiate therapy. At least in the heart failure arena, we recognize that individuals are substantially more likely to fill a prescription being discharged from the hospital on that medication, as opposed to it being initiated de novo after discharge from the hospital.

Yet, I will tell you, as a cardiologist, most of our patients are admitted to our hospital medicine service who are fantastic, but they are unlikely to ever see the patient again, and they recognize and get pressure from the hospital. The goal is to keep short lengths of stay, get people stabilized, get them out of the hospital, and how do we use that moment that used to be seven, eight, nine days now for heart failure might be five or six days, or even could be two or three days as an opportunity to educate and get initiated on therapies as well. We know that outcomes are improved as a result.

Primary HCP-Reported Reason for Not Initiating GDMT in Patients With HF

This is a very interesting survey that looked at reasons that guideline-directed medical therapy was not initiated in the hospital for those with heart failure. Red is the largest segment, roughly half across the board, clinically stable. Their symptoms are adequately controlled. That meets the definition of clinical inertia overall.

It really reinforces across multiple drug classes that are key pillars of therapy for heart failure. In this case, this was all heart failure with reduced ejection fraction. We have some opportunity that even when they come in and they say, “Fine”, there is different gradations of what fine means, but they say they are doing fine or well, seize that moment. That is an opportunity to do better.

Unintended Harms of “First, Do No Harm”

I very much like this slide because we often think about the consequences of initiating therapy. Their blood pressure drops too much. Am I going to be affecting their blood sugars if I initiate a medication? They are on other medications already that may be attempting to optimize glycemic control. Are they going to have safety concerns? What are the costs?

We often do not think of a risk of omission. What would happen if I did not initiate this therapy? What are the consequences? Well, we know that in heart failure that means diminished survival, increased susceptibility to hospitalization, decreased quality of life, increased symptoms.

We are often very attentive to what are the consequences if I do something and something untoward happens. We often do not think from a framework of patients doing well today, if I do not initiate a therapy and I omit it, what are the consequences overall?

Patient Barriers in CRM Syndrome Management

We have talked about a lot of this, but recognizing that there are a number of social drivers or determinants of health that can impact a lot of this. We take for granted that patients can overcome a lot of these, but they have financial barriers or cost. Do they have transportation to a clinic appointment? Can they get blood work done? Can they make their outpatient appointment? What are the implications from insurance premiums? Polypharmacy. These are real that all of you know. We know and you all know every day in your practice.

Consequences of GDMT Underuse

To wrap some of this up, the consequences of guideline-directed medical therapy underuse. This is true in diabetes. This is true in chronic kidney disease. This is true in heart failure. It is certainly true in all those individuals who have all of that is underuse of effective therapies is associated with worsening of outcomes, increased morbidity and mortality.

In the end, it actually increases healthcare costs by actually engendering preventable hospitalization, preventable adverse consequences. You do have a window, where people can benefit even that much more from these therapies. Sometimes that early intervention window being missed perpetuates. Well, now they are too sick to initiate these therapies and those consequences.

This fragmentation of care is real. We are not going to come away with solving this. If we do, we got a lot more ahead of us to figure out with the healthcare system. Nonetheless, it is important to realize, how can I go home next week and figure out ways to break down these silos in care?

Who Should “Own” the Prescribing of SGLT2 Inhibitors?

Again, I do not like the word ownership, but it is this recognition of how do we work together? I would say we have largely a broken chronic care management system in the US today. For those of you that have figured it out, kudos to you. It is a very siloed system of care.

I know you all are front and center in this. How do we break down those barriers? How do we break down the fragmentation?

Base Camp Briefing 1

I am going to play this video now of Joe. He is going to tell his own story. It will resonate. Then I am going to ask Jennifer to go down. While you are talking just for a couple of minutes, we are going to let you say this resonates. Jennifer is going to be listening, summarize what she has heard. Come back out for the next section. This will be replicated overall.

For those of you that are online, I will actually be talking to you and share my views on Joe's story to keep you engaged while we are going along. Then we will do this with two other modules.

Joe: Thank you for letting me speak today. I am not a doctor. I am just someone who has been living with lots of health problems for a long time. I am 66 years old. I have type 2 diabetes, kidney disease and heart failure. I have also had high blood pressure most of my adult life, and I am overweight. I know those risk factors did not come out of nowhere. I worked long hours, did not exercise much, and I did not always understand how serious my conditions were until things started piling up.

I see a lot of doctors. My cardiologist manages my heart failure. My primary care doctor handles my diabetes, and I have seen a kidney specialist a few times. Most visits feel rushed. We focus on numbers. My A1C, my creatinine, my blood pressure, and on adjusting the medicines I have already been taking for years.

No one ever really talked to me about medications that protect more than one organ at the same time. I was not offered an SGLT2 inhibitor until recently. Honestly, I did not even know what that was. Looking back, I think there were a few reasons. My kidney function was not great and there was concern it might get worse. I was already on diuretics and I was told to watch out for dehydration.

I also complained a lot about having to pee a lot, so maybe people did not want to make that worse. From my side, I was hesitant too. I did not want another pill. I had had a genital infection once before and did not want to repeat that. No one explained clearly how the medication could help my heart and kidneys, even if my blood sugar was not that bad.

Then I ended up back in the hospital with fluid overload. That is when someone finally sat down and explained the bigger picture that this medication was not just for diabetes, and that starting it earlier might have helped prevent what I was going through.

I guess what I want you to hear is this. Sometimes we do not say no. We just do not get asked or we do not understand the question.

Base Camp Briefing 1

Dr. Gluckman: Great. This resonates a lot with me. I suspect it does with you all. Talk amongst yourselves here for the next couple of minutes, we are not going to take long, just some themes about does this resonate overall? Discuss the story. Do you see patients like this? Where did Joe's care fall short and what went well with Joe's care?

We will talk about this. Jennifer will report out in just a couple minutes and then we will pick up the next section. Thanks so much.

For those of you that are online, I am going to be talking to you. I will be honest with you, I think Joe's story is all too real for me and what I see and I suspect you all as well. It starts with the fact that there is multimorbidity. He has heart failure, he has chronic kidney disease, he has type 2 diabetes, his weight is higher than it should be. Almost certainly all of those are interconnected that term cardiovascular kidney or renal-metabolic syndrome.

The story of the fragmentation of care, the siloing of care. Not everybody necessarily beat on the same page. At the end of the day, Joe highlighted nicely that there were a number of missed opportunities to do better, to do better sooner, and not clear what would have made the biggest difference for him, but ultimately, not uncommonly, this culminates in the hospitalization, in his case, with heart failure. Then ultimately somebody sitting down and saying, we have a therapy. We in fact have multiple therapies that can be effective at helping to address multiple organ systems.

If you take nothing away from this, I would think about how do we begin to prioritize those drugs, those therapies that are able to address multiple different conditions? From an adherence standpoint, from a cardiovascular, renal and diabetes risk reduction standpoint, using those therapies that are able to provide benefit across multiple organ systems is really key. In this case, we are talking about an SGLT2 inhibitor.

We are going to give it about another 15 to 30 seconds for those that are in the room here to discuss the cases. We will have a brief report out and then we will move forward with the next section overall. We are going to give it about another 10, 15 seconds to just talk at your table. Then I will let Jennifer, as she walks back up, share thoughts of things that she has heard.

Okay. I am going to welcome Jennifer back. Just while you are walking back, any thoughts or themes that you heard about related to Joe's case?

Dr. Green: Dr. Jennifer Green (Duke University School of Medicine): Yes. I apologize if I did not get to your table. There will be other cases that we will be coming back to you to get your thoughts about. There was discussion about challenges and about ways to overcome the challenges. Some of the challenges that were mentioned were cost and access and others included fear of potentially overdoing it with the rapid implementation of guideline-directed medical therapy.

Those are fair. Some of the suggestions about ways to improve care of patients like Joe would be to improve communication and coordination between different subspecialists. That clearly was an issue in his care. Then also to make sure that you have a process in place where if you have initiated a new therapy that patients can be assessed by someone fairly soon afterwards to make sure that it is going well. Thank you so much for those wonderful thoughts.

Finding a Foothold: The Latest Evidence for SGLT2 Inhibitors in CRM Care

Dr. Gluckman: Awesome. I am going to pass things to you to do the second part.

Dr. Green: Okay, terrific. I am going to briefly go through some of the evidence that supports use of SGLT2 inhibitors, in particular in CRM care. Obviously, this is a very dynamic space, but just a little bit of a reminder before we discuss additional patients.

Poll 4

I do want to ask you, I have one poll, and that is, which of the following patients would not be an appropriate candidate for initiation of an SGLT2 inhibitor? You can select all that you think apply. Is it:

1. A patient with HFrEF and type 2 diabetes who is stable on guideline-directed medical therapy;
2. A patient with HFpEF without diabetes who has an eGFR of 45;
3. A patient with chronic kidney disease and albuminuria and an eGFR of 30;
4. A patient with HFrEF and chronic kidney disease currently on hemodialysis; or
5. A patient with HFrEF and well-controlled blood pressure.

Please select patients or a patient that you think may not be an appropriate candidate to start an SGLT2 inhibitor.

Okay. Thank you very much for that. The most popular answer, and I would agree, I do not think there were any data at the present time to support initiation of an SGLT2 inhibitor in someone who has already on renal replacement therapy, kidney replacement therapy. I agree. Certainly a patient on hemodialysis probably does not have an indication.

Some of you would not give the SGLT2 inhibitor to a patient with chronic kidney disease and albuminuria with an eGFR of 30. I personally would. That person is at very high risk for progressive kidney dysfunction and for associated cardiovascular complications. I would personally at least try starting an SGLT2 inhibitor on all of the other patients that are listed.

Meta-Analysis of 5 Large, Placebo-Controlled SGLT2 Inhibitor Clinical Trials

We all have our own comfort level. My job now is going to help provide you with a summary of information about why we should be thinking about use of SGLT2 inhibitors in really a lot of the patients that we see in clinic.

This slide shows altogether the results of many of the large outcomes trials in patients with heart failure, either heart failure with reduced, moderately reduced or preserved ejection fraction, testing the effects of different SGLT2 inhibitors compared to placebo on hard outcomes. In all these trials, the primary endpoint was a composite of cardiovascular death or heart failure hospitalization.

These data are pretty striking. When you look at the effects of SGLT2 inhibitors in patients with really any type of heart failure across the ejection fraction spectrum, you see a very significant reduction in the risk of, again, this composite of CV death or heart failure hospitalization. The number needed to treat to reduce the risk of one of these outcome events is 25.

I would point out too that SOLOIST-WHF was a trial that showed benefit in patients who were hospitalized with a heart failure exacerbation, and who started an SGLT2 inhibitor as soon as they were off of oxygen supplementation and off of IV diuretics. We can think about starting SGLT2 inhibitors when patients are hospitalized when they have been stabilized.

Association of SGLT2 Inhibitors With CV and Kidney Outcomes in Patients With T2D

In addition, SGLT2 inhibitors have demonstrated an outcomes benefit in many other populations of patients with manifestations of the CRM syndrome. These are the effects of SGLT2 inhibitors in patients with type 2 diabetes, with or without established atherosclerotic cardiovascular disease on cardiovascular and kidney outcomes.

You can see pretty consistently across the board a reduction in risk of adverse outcomes, really irrespective of whether or not these patients with type 2 diabetes had established atherosclerotic disease or had multiple risk factors for atherosclerotic disease.

Again, really pretty consistent effects across the board. Some variability in individual trials, but for the most part consistent evidence of benefit.

Composite Kidney Outcomes in Patients on SGLT2 Inhibitors Regardless of Their Underlying CKD Status

This slide is a little messier. It has got a lot of different trials listed. Before I jump into this, I would point out that all of the trials of the SGLT2 inhibitors in patients with chronic kidney disease have very clearly demonstrated an outcomes benefit in reducing the risk of cardiovascular events, cardiovascular death and progressive kidney disease.

This looks more broadly at those trials as well as the trials of patients with atherosclerotic disease, with heart failure. Again, you see in patients by eGFR status below or above 60 enrolled in those trials. Again, for the most part, the point estimates of those trials and the estimated class effect or population effect of SGLT2 inhibitor therapy in such patients really looking favorable when it comes to the effect of the intervention on kidney outcomes. Again, this includes a lot of people who were not technically considered to have chronic kidney disease, and they were patients who were not enrolled in a chronic kidney disease trial.

It just goes to show you that patients with cardiovascular disease, patients with metabolic conditions are at risk for adverse kidney outcomes. These are conditions that have the potential to adversely affect a wide array of outcomes and the SGLT2 inhibitors have been shown to reduce those risks.

Why Is Rapid Initiation Important in HFrEF?

I am always very impressed at the way that the heart failure specialists adopt data from these new trials as they emerge, and are willing to add new medication classes, demonstrating outcomes benefit to really what are considered the pillars of care, the foundational guideline-directed medical therapy approaches for patients with heart failure.

One of the really good reasons why that happens in heart failure patients or should happen in heart failure patients is because their prognosis is so poor. There is a tremendous amount of urgency related to the need to intensify guideline-directed medical therapy in patients with heart failure.

Now, that is wonderful, but I also feel that it is urgent to improve outcomes in people with diabetes who are at high risk or who have cardiovascular or kidney disease, or patients who have kidney disease without diabetes. These are urgent conditions, and these are patients who are going to experience events that compromise their quality of life and their duration of life. We really need to think about getting these beneficial agents on board as quickly as is individually appropriate for that person.

When we look at the HFrEF data, the reason why each individual pillar of care is so important is when you look, for example, at the effects of the individual medication classes on outcomes like death, cardiovascular death, or heart failure hospitalization, for example, the relative risk reduction conveyed by that individual intervention ranges from between 25% to almost 60%.

These are interventions that in this population work very quickly. The evidence of reduction in risk of these outcomes that we clearly want to avoid are evident certainly within 30 days of initiation with SGLT2 inhibitors, often much more quickly than that in the outcomes trials that have been conducted.

But the Creatinine Went Up!!!

What are some of the barriers? Well, when it comes to SGLT2 inhibitors or ACEs or ARBs or MRAs, we worry about the impact on creatinine or eGFR. These are data from EMPA-Reg, so the effects of the initiation of empagliflozin in patients enrolled in EMPA-Reg, patients with type 2 diabetes and established ASCVD.

You can see, we know this. I am going to try to do it so that it is the right way for you. When you start somebody on an SGLT2 inhibitor, you generally see a bit of a dip in the eGFR. Then over time, there tends to be a little bit of a correction. You often see a bit of an upward inflection in eGFR. The most important thing about what SGLT2 inhibitors do to eGFR is that after that acute dip happens and stabilizes, then the eGFR tends to stay much more flat over time, compared to, for example, patients in EMPA-Reg and many other trials, particularly the trials enrolling patients with CKD who got placebo, where you tend to see a steady downward march in eGFR over time.

I had to learn from the nephrologist how much is too much, what degree of reduction in eGFR is comfortable to you and is not considered evidence of an AKI.

Nephrologists are comfortable with a decline in eGFR with the initiation of these guideline-directed therapies of up to 30%. If it is a greater than 30% decline, then there could be something going on other than a favorable effects on kidney or systemic hemodynamics, and you need to reassess and do something different. Oftentimes, a greater-than-expected reduction in eGFR is related to volume depletion. We will talk about that throughout this program quite a bit.

What we want to do is remember that it is okay if the eGFR is reduced a bit by the initiation of an SGLT2 inhibitor. We see that with ACEs and ARBs in patients with kidney disease. That is an expected effect, and again is indicative of a favorable effect on kidney hemodynamics as long as it is not greater than 30%.

Is it Really AKI?

How do we know if it is an AKI? Well, one of the things I do want to remind you about is that in the SGLT2 inhibitor trials, as evidenced and as shown here in a meta-analysis including outcomes from over 90,000 individuals, they actually found that patients who were assigned to treatment with an SGLT2 inhibitor were 23% less likely to have an AKI event compared to the patients in the same trials who were assigned to placebo. In fact, we are probably reducing the risk of AKI in our patients whom we start on SGLT2 inhibitors.

Usually, again, this dip in eGFR is going to level out after several months. Again, many meta-analyses, including patients either solely enrolled in trials studying patients with chronic kidney disease or including patients at risk with a broader array of cardiovascular and kidney complications, consistently, the SGLT2 inhibitors have shown a reduction in risk of CKD progression, really irrespective of baseline eGFR and albuminuria.

2022 AHA/ACC/HFSA Guideline Updates for HF

Even patients with a little bit of albuminuria benefit. Sometimes it is hard to tease that information out from an individual trial. The meta-analyses allow us to look more carefully and be more confident that we understand the effects of SGLT2 inhibitors in those populations.

I have to tell you that it is a little bit hard to see the red boxes here, but if you can pick out the red boxes surrounding these, it is easy to remember that the AHA/ACC/HFSA guideline updates for heart failure from 2022 really suggest that we think about using SGLT2 inhibitor therapy from the outset, even in patients at risk for the development of heart failure, and that includes patients with type 2 diabetes. Do not forget that people with type 1 diabetes are also at risk, but we do not use SGLT2 inhibitors in them.

In patients with stage C and D heart failure, so symptomatic and/or advanced heart failure, those patients all have indications for use of an SGLT2 inhibitor as foundational therapy to improve outcomes in addition to the other indicated foundational therapies.

KDIGO 2024: SGLT2 Inhibitors in First-line CKD Treatment

The KDIGO guidelines. This is small print, I apologize. If you can see after lifestyle modification at the top, again in patients with chronic kidney disease, the SGLT2 inhibitors, along with ACEs along with RAS inhibition, are now considered to be foundational first-line drug therapy for most patients with chronic kidney disease, and that includes people with chronic kidney disease that is not due to diabetes or in patients who do not have diabetes.

Use of Glucose-Lowering Therapies in T2D Care

You have seen this slide before. I do not think I have the circles. I will tell you that across the categories, again, it is very easy for me to remember. If you look at the columns on the left-hand side, patients with type 2 diabetes are at high risk for atherosclerotic disease, with heart failure, with chronic kidney disease.

You can use an SGLT2 inhibitor to reduce the risk of adverse outcomes in patients with all those conditions. I have to say, years ago, what I used to do when I was seeing a patient with diabetes in clinic is I would run their list of meds and make sure the statin was there. Right? That was the best I could do at the time, maybe an ACE or ARB in addition to that, to improve or reduce their risk of adverse cardiovascular and kidney outcomes.

Now, I am also looking for often an SGLT2 inhibitor in patients who have type 2 diabetes who are with or at risk for these additional conditions, because I consider those to be foundational therapy for my patients. I have to say, we were talking earlier, I practice largely at a VA clinic, and almost all of my patients with diabetes have or are at high risk for these complications. It really is something that I expect to see on the list. If it is not there, if the SGLT2 inhibitor is not part of the care that I am delivering, there needs to be a reason why, and I need to have documented it in my note.

STRONG-HF: Uptitration of GDMTs for Acute HF

I am going to very briefly talk a little bit about the evidence to support use of uptitration of guideline-directed medical therapy in patients with acute heart failure. This was a trial that enrolled patients with heart failure who were currently hospitalized and not yet on full GDMT. They got randomized either to high intensity GDMT care or their usual care and then they look to see what happened to them at 180 days.

The primary endpoint was over that 180-day time frame, how often were they readmitted due to heart failure? Or how often did they die for any reason? They also looked at patient-reported outcomes.

STRONG-HF: High-Intensity vs Usual Care GDMT for Patients With Acute HF

This slide is a summary of what they found. Shown in red are the effects of high intensity care, where you can see compared to the group in blue that received usual care for patients with heart failure, the group that received intentional intensive therapy, starting from the time of their hospitalization were far less likely to experience these outcome events.

Also the patients reported improvement in their PROs, their NYHA class, and they had fewer signs and symptoms of congestion with the high intensity therapy compared to usual care.

Treatment Approaches for T2D ± CKD

We have a variety of different approaches that can be taken. We have talked about the traditional approach. The traditional approach where you take a long time to add each pillar of care takes a long time and is not rapidly reducing risk in our high-risk patients.

We can consider alternatives, including, what some people advocate is a rapid sequence approach where you think about initiating combinations of drugs and perhaps rapidly uptitrate. Then alternatively, what many heart failure docs recommend is the accelerated risk-based approach, where perhaps for your most at-risk patients, you try to start as many pillars of care as possible at the same time, or as close to the same time as possible.

We do not have a lot of time to talk about it. The good news is that many of these therapies have been proven to improve outcomes at low doses, the lowest therapeutic dose. We do not have to do a lot of uptitration. That makes our job easier.

Accelerated, Risk-Based GDMT Implementation for T2D ± CKD

Again, this is just another figure that shows this potential alternative strategy. Think about and identify your very highest risk patients. If you are going to ease this into your usual practice in patients with chronic kidney disease, look at that KDIGO heat map. See which patients are in those red rectangles, indicating that they are at the highest risk for progressive kidney disease and cardiovascular complications.

Maybe work on their care first. You do not neglect the care of other patients. If you are going to try out this rapid implementation of guideline-directed medical therapy, they are the patients who are clearly going to benefit the most. They are at highest risk fundamentally.

Interprofessional Workflow Challenges

There are a lot of challenges. We have talked about who owns it. We will get back to that. I do not even see endocrinology here, but we are doing it too. We can think about educating ourselves. We are doing that here today. Think about if you are fortunate enough to have other team members, like pharmacists or educators or trained nurses, who can help with dose titration or nurse navigators. Think about using your EHR to identify the most at-risk patients and maybe survey in a very objective way the care that you are providing to your patients. We do not know until we look.

Practical Strategies for Overcoming Clinical Inertia

If you are lucky enough to have an integrated cardio-kidney-metabolic clinic in your area, that is a nice opportunity to send your highest risk patients to see a bunch of specialists at once. That is not really practical everywhere, so we need to learn to do the best that we can.

Practical strategies for overcoming clinical inertia. Please communicate the need, for example, to use an SGLT2 inhibitor not just for diabetes but to protect organs.

Practical Strategies for Overcoming Clinical Inertia (Cont’d)

Talk about the potential for adverse events ahead of time. We do not want to take our patients by surprise if they start urinating more, or they have a genital mycotic infection. If they know that it might happen and they know that we want to hear about it, if it happens and it is a problem, it is going to be far better than them just having something bad happened, being taken by surprise and stopping the medicine and never starting it again.

Practical Strategies for Overcoming Clinical Inertia (Cont’d)

We do need to take ownership as best we are able. One of the ways that we can think about communicating with other specialists is, for example, I staff diabetes quick consult that is an e-consult and people will send me their cases and they have questions, for example, about whether or not they can safely implement or intensify guideline-directed medical therapy.

I provide them with very rapid turnaround. It is not a lot of work for me to do, but I can provide feedback to get them past a point at which they might be stuck, because they are not sure whether or not they are doing something good or not good for that person.

Think about whether or not those kinds of avenues of feedback might be available to you from other types of physicians whom you have questions for about patient management.

Base Camp Briefing 2

This is our second case. This is Angela. I am going to play her story, and then Ty will be talking with you about what you think could have been done better, or maybe what was done well in this example.

Angela: My name is Angela. I am 62 years old, and for the last few years I have been living with what I now know is cardio-renal-metabolic disease. No one ever told me that until very recently.

I was diagnosed with type 2 diabetes in my late 40s. At first, my primary care doctor focused on my blood sugar. We talked a lot about my diet, A1C, and eventually insulin. I also have high blood pressure and high cholesterol, but those felt like background problems. A few years later, my lab showed worse kidney function. My doctor said it was something to watch, probably related to diabetes and blood pressure.

I was referred to a kidney specialist who adjusted my blood pressure medications and told me to avoid some medicines and drink plenty of water. Because my kidney numbers were not terrible yet, it did not feel urgent. Then I started getting short of breath. I could not keep up on stairs and my ankle swelled by the end of the day. I went to a heart doctor. After some tests, I was told I had heart failure. I was started on a diuretic and we talked about salt restriction.

The visits were short and focused on whether I was retaining fluid. I assumed that meant my treatment was complete. About a year later, I was hospitalized for excess fluid. That was scary. During that time, different doctors came in and out. Medications were adjusted.

When I was discharged, I left with a longer medication list, but it was mostly higher doses of things I was already taking. No one really explained what this meant, or whether my treatment plan needed to change in another way.

It was not until another visit, this time with a different heart doctor, that someone sat down and explained how my heart failure, kidney disease, and diabetes were all connected. She talked about guideline-recommended medications that protect multiple organs, not just treat symptoms. She mentioned things that could have been started years earlier when my diabetes was first diagnosed, when my kidney function started declining, when heart failure was diagnosed and even at hospital discharge.

Hearing that was frustrating, honestly, not because anyone meant to withhold care, but because it made me realize how many chances there were to change the course of my disease. Each doctor was doing their part, but no one was looking at the whole picture. If I have learned anything, it is that timing matters. Sometimes the best moment to start the right therapy is earlier than it feels.

Base Camp Briefing 2

Dr. Green: Okay. Now if you could, like we did the last time, let us please talk amongst each other about Angela's story. This is a very common scenario in my clinic. Talk about whether or not you see similar patients in your clinic. Let us talk about what some of the missed opportunities for the application of guideline-directed medical therapy to her care might have been, and what we might be able to do to improve to improve the delivery of care to similar patients.

Ty is going to come around and, like last time, get some opinions from you. We will sum that up in just a few minutes. Thank you.

Hello to everyone joining us online. We are very glad that you have tuned in. I have to say I am an endocrinologist and I do see many patients like Angela in my clinic. I will say that the type of care that she received was probably the best that we could do perhaps 15 years ago.

As we have been talking about this evening, care for patients with diabetes and kidney disease has been completely revolutionized with the advent of data from the cardiovascular outcomes trials in patients with type 2 diabetes at high risk for cardiovascular disease, in patients with chronic kidney disease, and in patients with heart failure.

Unfortunately, as we have seen, Angela has been affected by all of those conditions. They have been diagnosed at different times? She probably was at risk for both kidney disease and heart failure from the time that she was diagnosed with type 2 diabetes. We need to start thinking about the risks posed to our patients,, again in this example, to patients with diabetes and hypertension in particular. We need to think longer term and not focus just on glycemic control.

Most practitioners recognize that. We now have the opportunity to intervene early. I will say that some have, in fact, recommended that we begin screening for preclinical heart failure in patients with diabetes from very early stages, for example, by measuring N-terminal proBNP or BNP to identify patients with elevated levels who in fact might have evidence of structural heart disease on echocardiogram before they become symptomatic. For those patients, we know that the use of medications such as SGLT2 inhibitors can reduce the risk of incident clinically apparent heart failure.

Of course, from the time that patients are diagnosed with type 2 diabetes, we should be screening for evidence of chronic kidney disease with both, the eGFR and the UACR. If the patients have an eGFR less than 60 or any elevation in their UACR that is sustained for at least three months, they clearly have an indication for SGLT2 inhibitor therapy.

Now we are going to take it back to the rest of the group. Thanks for joining.

Okay. I hear everybody deep in conversation, and I hate to interrupt. I am going to have to ask Ty to come back and summarize what he has heard. When I go down next time, I need to go over to that side of the room. We have neglected you a bit.

Dr. Gluckman: I did not get to enough tables. We were talking about some of the challenges that exist here. There was a focus around heart failure. Many in the room raised good discussion about the fact that this is proactively trying to get people on these therapies. We spent a lot of time actually talking about what it is like for people who have been hospitalized.

If you work in a hospital medicine, comfort level of initiating therapy that ultimately you are not responsible for not having necessarily, I might even call it a safety net, but a transition plan where they are going to be able to be seen as an outpatient. We live in this rainbows and unicorns world, where everybody is immediately seen in the outpatient setting. They can get an appointment, they can be seen. The transition of laboratory testing, starting a medication that they are not going to be accountable for when they leave, it raises a lot of concern.

We need a better systems way to transition patients out of the hospital to alleviate at least some of those concerns, which are concerns.

Dr. Green: Yes. They are probably not going to be able to see a cardiologist within a week of being discharged from the hospital. This is a nice opportunity to think about coordination of care, maybe the creation of new pathways for follow-up of patients who have been hospitalized, in particular with a heart failure exacerbation.

All great points, but points that we all need to work together to try to overcome. I am going to hand it back to Ty for the next module.

Plotting a Course Through the Crags: Practical Approaches to AE Management With SGLT2 Inhibitors

Dr. Gluckman: This last module is really about practical troubleshooting as it relates to SGLT2 inhibitors.

Poll 5

We are going to start with a poll. When a patient on an SGLT2 inhibitor expresses concern about potential or early side effects, how do you typically manage therapy?

1. Reassure the patient and continue therapy with education and monitoring;
2. Temporarily hold the medication and reassess after symptoms resolve;
3. Discontinue the medication and switch to an alternative therapy;
4. Individualize the approach based on severity and patient preference;
5. Refer the decision to another specialist.

Please key in your answer.

Interesting. We have a split here between the two. This to me reinforces, and this was actually brought up in the discussion as well, how you do effective shared decision-making and wanting to respect patient preferences. The more education we can have up front about potential side effects, the more they are going to be proactive in reaching out to you. Also the importance of sometimes some of the concerns may just require reassurance. Therapy can be continued through. Sometimes patients will feel strongly about adjusting therapy and it has to be individualized.

Concerns in Patients With and Without T2D When Using SGLT2 Inhibitors

I am going to break this down in three areas. This really is an incomplete way of talking about operationalizing SGLT2 inhibitors. We are going to talk about:

• Infection;
• Hypoglycemia; and
• Euglycemic DKA.

We will go and first talk about infections.

SGLT2 Inhibitors and GU Infections in Patients With HF

This is a lot of data. It is busy data, and I apologize for that. Just trying to highlight that in trials that enrolled patients with SGLT2 inhibitors or placebo in heart failure trials, none of them excluded patients with a history of genital mycotic infection or urinary tract infection. We do see a small but increased risk of infection associated with the use of SGLT2 inhibitors. This really reinforces the importance of proactive education, making sure that they are aware and know what to do in terms of surfacing complaints and also addressing them when they come up.

GMI and UTI Risk Factor Assessment Prior to Starting SGLT2 Inhibitors

I like this slide a lot because it just gives the practical advice about what you should be doing relative to an infection initiation or treatment through. At the top in pink, it talks about someone who has an active infection. You are seeing them for the first time. They are actively dealing with an infection. Please do not initiate an SGLT2 inhibitor at that time. Initiate after they have completed their treatment for their urinary tract infection, their genital mycotic infection.

If they have had a series of recurrent infections, those individuals, for me, often require input from another specialist to help guide decision-making about whether that class should be initiated. In those that do not have an active infection, an SGLT2 inhibitor can be initiated. In individuals who subsequently develop an infection while on therapy, often, if it is uncomplicated, you can treat through with continue the SGLT2 inhibitor without interruption while treating the infection.

Obviously, for those that have a complicated infection, stopping their SGLT2 inhibitor, addressing the underlying infection.

GU Infection Prevention With SGLT2 Inhibitor Use

This is all about raising awareness, setting expectations. We had this a little bit at our breakout, to manage expectations and promote early intervention. Part of the problem is just being made aware that they are actually dealing with the infection.

Providing practical hygiene advice to patients, their partners about how best to mitigate the risk of infection. Then topical treatments or appropriate oral treatments can be used to treat most people who have mild to moderate infections overall.

Hypoglycemia Rates With SGLT2 Inhibitors in Those Without T2D

I am going to pivot over to hypoglycemia. The bottom line is, is that similar proportions of patients with SGLT2 inhibitor and placebo in those groups without type 2 diabetes experienced hypoglycemic events. You really did not see much in the way of difference overall.

Rates of hypoglycemia were not increased in those with using SGLT2 inhibitors in heart failure with or without type 2 diabetes. However, as Jennifer knows probably even better than I do, certain classes of medications can potentiate an increased risk of hypoglycemia, sulfonylureas and/or insulin. Those medications may need to be adjusted in concert with you all, in concert with endocrinologist if they are being followed as well.

Proposed Insulin and Other Diabetes Medication Adjustments When Initiating SGLT2 Inhibitors

This is that same flow diagram in thinking about where you might need to adjust background therapy when you are initiating SGLT2 inhibitor. Certainly in those individuals who have a history of hypoglycemia, feelers want to go up to say, “this is a person I want to even be more proactive about reducing one or more of their hypoglycemic agents.”

Classes listed with the SUs, repaglinide or insulin in terms of potentiating increased risk of hypoglycemia and making decisions based upon their estimated GFR and A1C overall. The bottom line is, in those individuals that have lower estimated GFRs, those who have lower but not by any means low A1Cs, you may want to adjust your hypoglycemic regimen when initiating an SGLT2 inhibitor.

Dr. Green: Do you mind if I just add?

Dr. Gluckman: No, please.

Dr. Green: You can always add it back, right? If you have a patient in whom you are very concerned that the addition of an SGLT2 inhibitor might cause hypoglycemia, hold their SU when you start it and see how things play out. Have your nurse call them, have someone get in touch with them about how their blood sugars are doing. If their blood sugars go up off of the SU, you can always add it back, maybe at a lower dose than they were on before.

As long as there is follow-up, you can always make adjustments in the name of safety.

Ketoacidosis Concerns With SGLT2 Inhibitors

Dr. Gluckman: Great points. Lastly, ketoacidosis and euglycemic ketoacidosis in particular to be aware of with the SGLT2 inhibitors. This is a rare potential effect, but it is a potentially life-threatening effect or condition. The symptoms are listed on the left, and I would recognize and acknowledge that these may be non-specific symptoms. They also can be potentiated by conditions where people get dehydrated, nausea, vomiting, poor oral intake.

We are going to come back to surgery in a second, but people being made NPO for a surgery increases the potential for this occurring overall. Patients may present with this condition with normal or only modestly elevated blood glucose levels. Nonetheless, if this is in your differential or this is something that is suspected, the SGLT2 inhibitor should be discontinued immediately and they should be seeking medical attention.

Serum ketones should be measured to help detect rare cases of a normal anion gap acidosis.

Diuretic Considerations With SGLT2 Inhibitor Use

Overall, in a meta-analysis of eight SGLT2 inhibitor cardiovascular outcomes trials, volume depletion was observed in a low proportion of individuals and really was no different than placebo overall.

In DAPA-HF, there was an excess of volume depletion in those that were taking higher doses. These are not high by my definition, but higher doses of furosemide or equivalent doses of diuretic. In most cases, the diuretic dose does not need to be adjusted.

In individuals where someone has tenuous volume status or you are adding multiple agents that may affect their volume status, then a reduction in their maintenance dose of their loop diuretic may need to be done. To your point you brought up, there is no reason you cannot add it back in the event that volume overload becomes a condition.

Surgery Considerations With SGLT2 Inhibitors

Just pausing briefly to talk about surgery. This is a condition obviously in which individuals may frequently be asked to take nothing by mouth. In those conditions where you are leading to restriction of food or liquid intake, or they are dehydrated or have a change in insulin requirements, these individuals may be predisposed or at higher risk for ketoacidosis. Generally, treatment with their SGLT2 inhibitors should be interrupted. Monitoring of blood ketones if it is felt to be appropriate for that individual with the reinitiation of the SGLT2 inhibitor once they are resuming their normal diet overall.

It is an acknowledgement that in patients with diabetes, blood glucose may be higher as a result for a day, and you can make adjustments or compensate during that period of time.

When Should SGLT2 Inhibitor Therapy Be Paused?

Just briefly, in summary, when should you pause an SGLT2 inhibitor and the therapy? If they have an acute serious medical illness. In particular, I am thinking about people that may be predisposed and have intravascular volume depletion, an acute illness where they may be hospitalized and not taking in their normal intake of food or liquid.

A condition, as is listed here, that leads to volume depletion. They are having a gastrointestinal illness with vomiting, diarrhea, insensible fluid loss because of fever, a major infection or hospitalized for major surgical procedures.

General Patient Counseling Points for Possible Adverse Effects Related to SGLT2 Inhibitors

Just some key points reinforcing what we had talked about. Good hygiene. It was brought up to me during the break. Again, really being proactive about preparing people for the potential. Even though the prevalence is low, people who are informed of this are less likely to be spooked or surprised, and therefore probably more likely to go back on therapy if they require temporary cessation.

Being attentive to orthostatic hypotension, a marker of intravascular volume depletion. Looking for symptoms of DKA. Again, these individuals may be euglycemic or only have modest elevation in their glucose. Avoidance of excess alcohol use which can promote intravascular volume depletion and holding before surgery.

Emerging Therapies Targeting the CRM Axis

There are a number of emerging therapies. We do not have sufficient time to go through all of these. Each of these in themselves could be future talks unto themselves. As Jennifer and I were talking about, this field is blowing up. You all appreciate that as well. We have a wide range of not just monotherapies, but combination therapies that are intended to help people improve heart outcomes.

Our challenge in the future is how do you sequence these? How do you combine these? How do we get over the hurdles of polypharmacy, of affordability and access issues?

Strategies for Better GDMT Care

Strategies for better GDMT care. These are broad, and I am not going to read through them. You have access to all of these slides. How do we overcome clinical inertia?

Really being a supportive environment for ongoing continuous education. I have a very hard time trying to stay up to date. If you can create forums where new trials, new data is brought out, new guidelines are brought out to be able to share. Pearls for navigating insurance barriers, how you can overcome that? Then practical adjustments for minimizing adverse effects. A lot of this is just education awareness.

Base Camp Briefing 3

We are going to come back. These are small snippets just to have individuals talk about their experiences. I will ask Jennifer to go down briefly just to share what she heard. I will preface this enrolling with the audience as well.

Angela: I have been reading about this medication, and I am honestly worried about the risk of infections. I have had issues like that before, and I do not want to start something that might make it worse.

Joe: My biggest worry is that it makes you pee more. I already feel like I get dehydrated easily, and I am concerned about how this could affect my kidneys.

Speaker: I am already taking several medicines every day, and I am not sure I want to add another one unless it is absolutely necessary. I worry about keeping track of everything.

Speaker: I am nervous about feeling dizzy or having low blood sugar. I live alone and I do not want to risk falling or passing out.

Base Camp Briefing 3

Dr. Gluckman: I am going to ask you just to take about 30 to 60 seconds to talk amongst yourself, do these items resonate with you? What can you do with your colleagues to address or mitigate some of the concerns that patients have? I suspect that the concerns that have been raised are ones that you all see, if not daily, at least weekly overall. Come back in about 30 seconds or so.

For those that are online, just highlighting the importance of listening to our patients, understanding the concerns that they have, the frustrations. I want to come back to the fact that often we are, I dare say, unduly influenced by acts of commission. We do not want to cause an infection. We do not want to result in hypoglycemia. We do not want to contribute to one more medication that they are at odds with having to take, amongst the many others that they are on. Yet the act of omission of not prescribing such therapy can create a big challenge overall.

We will give it about 15 more seconds, and then I will welcome Jennifer back up. Then we are going to be closing out with post-test questions. Then we are going to hopefully open it up for time for Q&A as well.

I am going to ask Jennifer if she is coming up. Anything stand out for you about this?

Dr. Green: Well, one very broad and useful recommendation is communication, which we talked about before, is making sure people are not taken by surprise if they have one of these more common side effects. Someone suggested frequent visits. Maybe after you start a new medicine, have a follow-up appointment, maybe by phone fairly soon afterwards to make sure you know if it is going well, that is fine. If it is not going well, it is good to know about that early when something can be done about it.

The genital mycotic infections. One of the suggestions that was made, which I do in my own clinic, is you actually do have to have a conversation about personal hygiene, because we may assume that everyone is showering or bathing every day, and that may in fact not be happening. That is a fairly straightforward way to minimize the risk of a GMI.

Those were all excellent suggestions and I am sorry that I could not get to everyone.

Postactivity Survey

Posttest 1

Dr. Gluckman: Really helpful points. I am going to let you close things out with the post-activity survey. Then I think we have time for Q&A. I would encourage people to pose questions if you have not already and you do have some.

Dr. Green: Yes, I see a lot already come in. Thank you. Okay. These are cases that you have seen before. You did a great job. Let us make sure that that remains the case. This is a 67-year-old man with HFpEF, type 2 diabetes and CKD, started on GDMT after being hospitalized 18 months ago. Blood pressure, glucose near targets. Feeling okay, but he has not had additional guideline-directed therapies started or intensified because he has stable and there are general concerns about polypharmacy. Which of the following is most likely to be the outcome for this patient if the current approach to care is continued? Is it:

1. An increased risk of symptomatic hypotension without reducing the risk of adverse long-term outcomes;
2. Favorable long-term outcomes as long as his blood pressure and glucose management stay near target;
3. A higher likelihood of medication-related adverse effects if therapy is later intensified during a clinical decompensation; or
4. A missed opportunity to reduce future heart failure hospitalizations and slow kidney disease progression.

Pick your preferred answer.

Okay. Great job. Look, you already were awesome at this.

Posttest 1: Rationale

Now, I will say, before we move on from this, the second most popular answer was making sure that he is going to do well if glucose and blood pressure remain a target. We cannot forget that those are also important modalities of risk reduction. We do not do new therapies instead of those things, but all of these newer therapies have shown an outcomes benefit added to what is already standard of care for high-risk patients. We need to do all of those things. We do not pick and choose. We build and use these newer therapies on top of the foundational ones.

Yes, if we just leave him where he is, it is a missed opportunity to reduce the risk of future heart failure hospitalizations, and his kidney disease is likely to worsen.

Posttest 2

Okay. Second case. A 58-year-old woman is hospitalized with newly diagnosed HFrEF. She has been diuresed. She is hemodynamically stable. Her eGFR is 55. She getting to the day of discharge, and she is on a low-dose beta-blocker and a loop diuretic. Based on current evidence, which of the following approaches would be most appropriate to optimize her outcomes soon after discharge from the hospital? Would it be:

1. Start low-dose initiation of the remaining foundational therapies prior to hospital discharge with rapid outpatient titration;
2. Gradually introduce one additional medication every four to six weeks to minimize adverse effects;
3. To initiate all the remaining guideline-directed therapies at target dose before discharge; or
4. To wait to make sure her EF is still abnormal on repeat echo before you decide whether or not to start those additional therapies.

Okay, pick your best path forward.

We see starting low-dose initiation of the remaining indicated therapies before hospital discharge, and then uptitrating them as quickly as possible in the outpatient setting, becoming more popular.

Posttest 2: Rationale

That probably is the best correct answer. If you are adding a new therapy every four to six weeks that the patient should be on, then that is a month, for example, that the patient has not benefited from use of a drug that, for example, may have been shown to reduce the risk of death in someone like her.

Yes, so we want to try to get all these drugs on board, at least at low doses, as quickly as possible. I probably would not start at the highest dose all at once. You can certainly start giving lower doses of as many as possible.

Posttest 3

Okay. The third case is a 64-year-old man with HFpEF, type 2 diabetes, chronic kidney disease, talking about starting an SGLT2 inhibitor. He had a bad experience with a different diabetes medicine in the past. He is worried about urinary symptoms, cost, and taking something forever. He also does not want to be hospitalized again in the future or to reduce the risk that that is going to happen. Which would be the best counselling strategy for him taking all of this into consideration? Should we:

1. Reassure him that adverse effects are uncommon and focus on guideline endorsement to help him make a decision;
2. Support his perspective for not starting an SGLT2 inhibitor because he is too old and he did not tolerate a different drug;
3. Explain the multiorgan benefits of the new drug and talk about how we are going to monitor for side effects and reduce the risk of those that are most common; or
4. Are we going to consult nephrology and endocrinology and start the SGLT2 inhibitor if they all agree as well?

Okay. Again, the third answer remains most possible to really have a conversation about why and how.

Posttest 3: Rationale

The final answer option after getting him to talk with nephrology and endocrinology about it, depending on where you are, that is going to take a minimum of six months to see either or both of those.

Dr. Gluckman: If you get agreement.

Dr. Green: Yes, if the nephrologist will see them. Yes. That is probably not a meaningful approach. It does take extra time to discuss the rationale and how patients can use new drugs safely, but it is worth those extra minutes.

Poll 6

Do you plan to make any changes in your practice based on what you learned here today?

1. Yes;
2. No; or
3. Not sure.

Poll 7

Okay. We would also like you to take a minute to enter one key change you plan to make in your practice based on the program today.

Questions and Answer Session

Okay. I do not know how much time we have. Maybe five minutes for Q&A.

Dr. Gluckman: While you are looking, I have a couple of questions that came up. Thank you all for feeding questions online and here in the room. One was a question again about when somebody gets initiated an SGLT2 inhibitor in the hospital, this could apply to the outpatient setting. Do we cut back on the diuretic?

For most individuals who are at an equipotent dose to 40 milligrams of furosemide or less, the rates of essentially intravascular volume depletion are so low, you do not need to. For patients that are on particularly high doses of diuretics, it may require a modest dose reduction of their loop diuretic because there is both a natriuretic and diuretic effect of the SGLT2 inhibitor.

Another question that somebody asked about, which is a great question, but it is a lead in for me of something else. Older adults – could be younger adults. Older adults who are frail were dealing with end of life issues. Clearly, this is about shared decision-making and aligning with goals of care. Sometimes less is really more in that patient population.

I am going to extrapolate two quick things from this. Age alone is not a consideration for me. We have all seen individuals who are in their 90s who look like they are in their 70s, and individuals in their 70s who look like they are in their 90s. Age is not a reason that I would choose to initiate therapy or particularly not initiate therapy based on that.

Then one other related issues about prognosis. You brought this up beforehand. For any individuals that have been hospitalized with heart failure, their five-year mortality rate is 75%. This matches or exceeds some of the worst malignancies that we have. It is all the more reason to try and get people on effective therapies that improve heart outcomes.

Dr. Green: Yes. Great. Wonderful questions here. One of them is, is it better to start an SGLT2 inhibitor alone in the hospital, or with a non-steroidal MRA and/or GLP-1? I am assuming this is prior to discharge.

Let us say it is a patient with chronic kidney disease, then they have an indication for an SGLT2 inhibitor and a non-steroidal MRA, you could probably start both of those at low doses. There are data to suggest too, that if a patient is being started on an MRA, that if they are on an SGLT2 inhibitor, in addition, their risk of hyperkalemia is in fact a bit reduced. There may be a benefit to simultaneous initiation in the CONFIDENCE trial that was studied and was safe and effective intervention to start both empagliflozin and finerenone at the same time. That was not in hospitalized patients, so a little bit of a different patient population.

Many patients will also, for a variety of different reasons, have an indication to start a GLP-1 receptor agonist. I will say it is a little bit hard to start that in the hospital. I find sometimes there are issues related to access in the outpatient setting. They are a little bit hard to uncover. If you give them a dose in the hospital, they are not allowed to take the rest of the pen home with them anymore. If it is a multi-dose pen, you end up wasting it.

Then there is a long uptitration period that somebody is going to need to follow up to make sure they eventually get on a therapeutic dose. Sometimes starting a GLP-1 receptor agonist in the hospital, I would say, would be the trickiest of those three. Not impossible, but it sounds like we have a lot of opportunity to start indicated therapies other than that.

Dr. Gluckman: Somebody had asked, and this is just the thread of following through, and we are getting into the last minute or so is, when you start looking at classes of medications that have a common benefit across these conditions, it ends up being SGLT2 inhibitors, GLP-1 receptor agonist-based therapies, and MRAs.

Someone had asked about combination of those therapies at the same time in individuals in the ambulatory setting. We do, do that. These are effective therapies. These are pillars of therapy. GLP-1s right now, we have data for but have not been incorporated into guidelines for heart failure with preserved ejection fraction or mildly reduced ejection fraction. We anticipate seeing yet another class that is shown to be effective, but it really gets to this root of underlying treatment of this condition really goes a long way across multiple organ systems.

Dr. Green: The other comment I would like to make, because there was the woman who was worried about how many medicines she needed to take, which is a very common concern. I look for opportunities to make substitutions. If I am starting guideline-directed medical therapy, and I can reduce their dose of an antihypertensive that does not have a demonstrated outcomes benefit, I will do that.

If I can stop their sulfonylurea, if I can maybe even decrease the dose of mealtime insulin, I will do that. Look for opportunities to make swaps of medications that can limit the pill or injection burden, maybe limit costs, but at the end of the day, improve their outcomes beyond what they are already taking.