Okay. This is something that Dr Greene published a little while ago, and we talked about it. Actually, the figure came out of a bunch of jokes between us on emails and stuff like that about how sort of the different specialties view the risk differently. The problem with heart failure is that we started with such an incredibly high risk, and then we got these effective therapies and the risks started coming down that our mental model is still pegged to what was happening in the 1990s that we just think that we have fixed heart failure, even on good medical therapy, optimal medical therapy, the average risk that the patients incur.

I am talking about patients who are on quadruple therapy in outpatient with NYHA II Class. We are talking about an annualized event rate that exceeds over 10%. So more than 1 in 10 percent will die or get hospitalized within a year. Then you go to these high dose lipid trials and all that sort of ASCVD world and if you have 5% annualized event rate, it is considered high risk. If it is 7% annualized event rate, that is considered a very high risk.

I think the problem is with us, not that 5% and 7% is exaggerated. I think that is exactly true, that if you have 5% risk of dying or getting a heart attack, I mean, that seems like a pretty high risk, especially when you are in your 40s and 50s and something like that. We just need to be a little bit more careful in not thinking that the patients with heart failure, we have just solved the problem.

Now, this is when you give good therapy. Obviously, if you do not give good therapy, those risks are escalated. Then when patients start developing worsening heart failure, edema, shortness of breath, more need for diuretic. That risk starts escalating into 20%, 30% annualized event rate overall.

[00:38:52]

Heart Failure Has a Prognosis Like a Cancer

This again, not to be juvenile and say that my disease is more important than your disease. But the fact is that heart failure outcomes, again, are comparable to many, many forms of cancer. We would not be having these discussions in cancer, right? I mean, you do not talk about whether the oncologist appointment is available and can we see you in 3 months or whatnot? Or if you have something light up on the PET scan or you find a mass on, I do not know, colonoscopy, you are in the oncologist office right away and the world stops even if you are completely asymptomatic. Here in heart failure, we, again, just a little bit too complacent despite of this.

[00:39:26]

2022 HF Guidelines: 4 Pillars of GDMT for HFrEF

Now, the good thing is that we are not in the 1990s of the digoxin diuretic era. We have these 4 therapies, ARNI, beta blocker, MRA, SGLT2 inhibitors in patients with heart failure, reduced ejection fraction. They are all on equal footing.

The guidelines have moved away from that hierarchy and algorithm. The whole idea is to get these 4 drugs on board as soon as possible, at least at some low doses. Again, if you are hospitalized, at least get low doses prior to discharge. If it is a new onset outpatient diagnosis, try to get these drugs on board within a matter of 4-6 weeks. This is what the guidelines are saying.

[00:40:01]

SGLT2 Inhibitors in HFrEF: DAPA-HF/EMPEROR-Reduced

This is based on really solid data. If you look at SGLT2 inhibitors, pretty much all the outcomes if you combine the data. Again, these are EMPEROR-Reduced and DAPA-HF, the 2 large outpatient trials. We have inpatient trial, worsening heart failure trial with SGLT2 inhibitors as well. As you add the cumulative data, you look at the heart failure data and the CKD trials, the benefit is just completely consistent where we are looking at mortality benefit, hospitalization benefit, recurrent heart failure, hospitalization benefit, or quality of life benefit.

[00:40:34]

What About Heart Failure With an Ejection Fraction >40%?

EMPEROR-Preserved: Outcomes

Now, I grew up in an era where we had actually almost given up on HFpEF. Nothing is going to happen, and no matter what you do that you will never improve the outcomes of these patients. We are pretty much given up with after about 10, 15 years of multiple negative trials, but we are not in that world anymore, like we have positive trials. Again, SGLT2 inhibitors led to this revolution.

Now we see that we have moved beyond SGLT2 inhibitor to nonsteroidal MRA. Now more and more interesting data are coming out with GLP-1 receptor agonists. We are again having a series of success.

But moving into SGLT2 inhibitor, again, we have solid data with multiple large outcomes trial showing substantial benefit in terms of quality of life, in terms of heart failure, hospitalization and the combined endpoint of cardiovascular death, heart failure hospitalization.

[00:41:31]

Heart Failure Outcomes With Empagliflozin

If you put the data for HFrEF and HFpEF right next to each other, what is interesting is that not only do you see the benefit, the benefit is almost the same across the entire spectrum of EF. This is meaningful not only in the sense that now you have therapies that improve outcome in patients with HFpEF. But think about it from a practical management perspective how important that is as well.

In the past, when you have got a heart failure diagnosis, you have edema, you are not feeling well. Clinician is pretty convinced you would give somebody a diuretic and then wait for an echo, which if you are in a rural setting and a primary care setting, should be 4, 6 weeks before you get an echo and you had no disease modifying therapy given.

Now that has gone away, right? If you are clinically suspecting diagnosis of heart failure, you can start an SGLT2 inhibitor or at least start 1 therapy, which can improve the outcome of the patient while you are waiting for their evaluation of the patient.

[00:42:27]

Meta-analysis: DELIVER and EMPEROR-Preserved

Again, this is the pooled analysis looking at EMPEROR-Preserved and DELIVER. I showed you the pooled analysis in HFrEF population before. These are the HFpEF. Again, no heterogeneity.

Again, I think at this point, this was really a point of debate and discussion 5 years ago. I think we have moved well past that, that these are good drugs for diabetes, but their cardiorenal risk modification has nothing to do with diabetes. The point estimate looks exactly the same whether you have diabetes or whether you do not have diabetes, you see the benefit.

[00:43:01]

SGLT2 Inhibitors: Cornerstone of HFpEF Treatment

Now the US guidelines are a little bit lagging behind. They have not updated the guidelines since more evidence for SGLT2 inhibitors have come out in HFpEF. However, to remedy this, the American College of Cardiology has these documents called ECDP, Expert Consensus Decision Pathway. They at least want to take all the knowledge and tell the clinicians what to do while they are waiting for the guidelines to be updated.

As you can see, SGLT2 inhibitors, the only reason to not give it in HFpEF patients is if there is a contraindication. Otherwise, patients are eligible and should get an SGLT2 inhibitor overall.

[00:43:42]

GDMT for HFrEF in US: Prescriptions at Discharge

Having said that, that is all great. We have multiple trials, large trials, regulatory approvals, indications and guideline recommendation. The bottom line is that clinical use of these drugs continue to lag behind the so-called 15 years of implementing from trial being positive to widespread use in clinical practice, unfortunately still persist.

If you look at the combination quadruple therapy, it is still 1 in 10 or so if you look at triple therapy. Remember, we have shown that this triple therapy. I think Dr Greene was the first author on that paper from CHAMP-HF, is that even if you take triple therapy, that is all generic ACE inhibitor, beta blocker, and MRA. So no ARNI, no SGLT2 inhibitor, no cost issue, all generic. Triple therapy is still not given in 70% of the patients. There is a lot of inertia and a lot of these things.

We will never not treat hypertension, diabetes or dyslipidemia because a person is doing okay, right? I mean, these conditions are asymptomatic by definition, but you treat aggressively to prevent complication. But we still have this mindset in heart failure, “Oh, my patient is doing okay. Maybe I will wait, treat later.” I will have Dr Greene get into some of those details.

Then if you look at what components of these therapies are used the least, no surprise that the components that are used the least are the ones that are later evidence generation, which is ARNI and SGLT2 inhibitor. Those things that have been there for 15 years, 10 years are slowly picking up.

[00:45:24]

Real-world Uptake in US: SGLT2 Inhibitors for HFrEF

Again, if you look at the SGLT2 inhibitors in HFrEF population, you start dissecting that 20%. Is there some group that gets nothing and some group that gets 90%? Unfortunately, the answer is no. No matter what combination you look at, including those patients, there have some alternate indications like they have CKD or they have diabetes or whatever, they use continues, unfortunately, to be incredibly suboptimal. That is on us how to translate all of these clinical trial results into our patients as well.

I will stop here. I will hand it over to Midge for the case and we will take it from there.

[00:46:03]

Patient Case 1: Mr. Harris, 64 Yr of Age

Midge Bowers: Now we are really going to count on you to be interactive. Our 3 clinical experts up here will be going down into the audience while you discuss amongst yourselves at your table the case of Mr. Harris, who is a 64-year-old gentleman. Folks, do you want to go down toward the audience? That would be great. Our online audience, I will be working with you to have a case discussion.

Mr. Harris presents to your outpatient clinic with progressive exertional dyspnea, orthopnea and lower extremity edema over the past month. He has a history of hypertension, type 2 diabetes. He is currently taking an ACE inhibitor and metformin. His physical exam and vital signs, blood pressure 118 over 72. Heart rate 82, O2 sat is 97% on room air. His JVP is elevated. He has bilateral lower extremity pitting edema and bibasilar crackles.

You can see his labs here. He has a mildly elevated BNP, a potassium of 4.5 and an LVEF of 35%. At your small tables here, go ahead and discuss Mr. Harris's case, including his diagnosis, and develop a treatment plan.

Okay, so we are back in the room. I want to thank everybody for your active engagement. I am going to ask my colleagues here, going to call on them 1 at a time while they are still on the floor, to go ahead and say. Dr Greene, what are some things you heard from the people discussing the treatment plans?

Dr Greene: Yes. Well, thanks, Midge. I think we all recognize the different tables I went to that he is only on really 1 GDMT and ACE inhibitor, not even an ARNI. So we have a lot of gaps here. Also, he is hypervolemic. But after we gave him some diuretic in the clinic, people seem to be unanimous on that. There was some debate over what is the next GDMT to start? What is the order of operations here? One table actually talked about beta blocker, SGLT2 inhibitor. And said we will hold off on ARNI and MRA.

Another table, again, without hearing what they had to say was like, let us do SGLT2 and MRA first and we will hold off on the other drugs. It was just some different conversations about which drug sequencing to go with.

Midge Bowers: Dr Gluckman, did you hear some other things here?

Dr Gluckman: Thanks, Midge. I would say 1 of the other themes that we talked about is, on the acute care setting, when we talk about the importance of GDMT in this patient population, you have the benefit of very close titration. You are seeing blood pressures. The question is now in the outpatient setting. Exactly to Steve's point. How do you sequence these? How closely do you follow up at a comfort level in being able to start medications, and how do you prepare patients for that acceptance of, I am going to be making a lot of medication changes. I do not think we came to a conclusion, but those are some of the themes that were brought up.

Midge Bowers: Great. How about you, Dr Butler?

Dr Butler: This table wins this round.

Midge Bowers: We are all winners here. Everybody gets a prize.

Dr Butler: The discussion here was go ahead, let us stop the ACE inhibitor. Move to an ARB, so that you can eventually move on to an ARNI. So just start planning in the future. Right now, start low dose loop diuretic with an SGLT2 inhibitor. Avoid beta blocker. He is congested. New onset. Let us just do it. Hypertension. Diabetes. We need to rule out ischemic heart disease. Probably low dose diuretic. SGLT2 inhibitor, MRA combo. Then slowly ease into that discussion. So in complete agreement.

Midge Bowers: Perfect. Okay. For our virtual audience, I want to recognize them as well. They talked about IV diuretics, SGLT2, then MRA. Again, switching over to an ARNI with those caveats. While we have our next speaker, Dr Greene, coming up, what is 1 change in this patient's care that you should implement or can implement as a result of this patient case discussion?

[00:54:23]

Section 2: Overcoming Clinical Inertia: Initiating GDMT and SGLT2 Inhibitors With a Need for Speed

Dr Greene: Well, I am honored to keep the train moving here. We are going to be talking about section 2. This is Overcoming Clinical Inertia: Initiating GDMT and SGLT2 Inhibitors With a Need for Speed.

[00:54:41]

Poll 4

First, we have a polling question. When initiating guideline-directed medical therapy for HFrEF, which setting do you believe offers the greatest opportunity for optimal initiation and titration of therapy? Is it:

1. The inpatient setting either during hospitalization for acute decompensated heart failure;
2. The outpatient setting, such as a follow up appointment in clinic;
3. Both settings are important and should be used strategically;
4. Neither initiation and titration should be deferred to specialized heart failure clinics only; or
5. Not sure.

Please enter your answer. We have a clear winner. Not 100%, but 90% said both settings are equally important and should be used strategically.

[00:55:42]

Traditional Serial vs Selective Approach to GDMT

Dr Butler just gave a great presentation setting the stage about the risk of the patient population we are dealing with. Remember that figure that heart failure compared to ASCVD truly is an extreme risk condition. But paradoxical to heart failure being an extreme risk condition, what is our standard approach with taking care of heart failure patients? It is one where we take our time. We go slow and steady, 1 move at a time.

Despite being very well intentioned, if you just do the math of all the different steps that would be required could take 28 to 56 weeks before GDMT is fully implemented at the maximally tolerated or target dose. Again, while very well-intentioned, many patients are never going to get all the way through this path. Things come up. There is missed clinic visits, there is clinical inertia that creeps in when you are in a rush and you say, “Oh, I will just do it next visit.”

Hospitalizations. Needless to say, when patients are on this long, circuitous pathway to optimal GDMT, they are needlessly exposed to excess risk of death and clinical worsening the entire time.

[00:56:51]

Minimal Titration of GDMT in Outpatient Setting

What is this status quo serial 1 move at a time approach get us? Well, it gets us what we see in the real-world evidence. This is data from the CHANP-HF registry, which showed that when you look at outpatient clinic visit after outpatient clinic visit, there is minimal titration of GDMT over time. That is despite the patients coming in with a median blood pressure of 120, median EGFR around 60, strongly suggesting that had we been paying attention, we could be optimizing GDMT. But instead we have this pervasive culture of set it and forget it. People get started on some drug regimen and we just let it ride over time. That is what the status quo unfortunately is.

[00:57:31]

Primary Reason Why HCPs Did Not Initiate GDMT From HCP-Reported Survey

When people though look at those data, they are like, “Okay, yes, we understand that GDMT gaps are huge and there do not seem to be getting that much better. But then we start debating, “Well, what is the why?” And some people will say, “Well, it is because the medicines are too expensive”, and other people will start saying, “Well, it is because the drugs are not tolerated.” Then you have folks like me who are talking about clinical inertia, and we just go round and round in circles. How are we actually going to figure out what is our number 1 target for closing these gaps?

I think we need to ask the clinicians that are taking care of these patients. To do this, this was a kind of innovative study that I am proud of from a year or so ago. We had US clinicians in this study, about 90 of them or so, and they take care of HFrEF patients, and we had them refer back and audit their own patient charts of randomly selected patients in their clinic and report on the GDMT use.

Also when the gap was there, when a GDMT was not prescribed, they had to figure out the number 1 reason why they did not prescribe it. Now, the study design here is unique in that yes, we are having clinicians as part of this study. One, they are picking their own randomly selected patients in their clinic, so they cannot pick their favorite patient or the patient that was the easiest to take care of, randomly selected. But also we are having them audit their own charts, because a lot of times we do not document why we do not do things.

If we do not think of an SGLT2 inhibitor, we are going to have the chart blank, and I am just going to be guessing, “Well, what is the reason that Dr Butler di not prescribe an SGLT2 inhibitor?

What I am saying here is we have people audit. They can use their own memory of why they did not prescribe GDMT, and they know their own practice. Well, lo and behold, when you look at the top reasons, small contribution from the drug was too expensive. That is why I did not prescribe it. Small contribution of patient preference was the reason. Small contribution of kidney dysfunction.

For all 4 pillars of GDMT, the number 1 reason why clinicians admitted to not prescribing the drug, clinical inertia. The patient was clinically stable and currently stable on the current regimen. No need to rock the boat. I think we can all agree that is uniformly the wrong answer. That is our number 1 target for correcting these gaps.

[00:59:42]

4 Pillars of GDMT for HFrEF

To overcome what I would call, again, a widespread culture of clinical inertia, myself, Dr Butler and colleagues for a few years ago now have been proposing the concept of simultaneous or rapid sequence initiation of GDMT for HFrEF. The key concept would be that we start all 4 mortality reducing drugs without delay on Day 1, or in rapid sequence within maximum 1 week or by time of hospital discharge.

Also, key concept here is that we prioritize at least a low dose of all the medicines. There is only 1 dose of an SGLT2 inhibitor. After you achieve at least a sprinkle of all 4 medicines, then you focus on titration over the coming days to weeks. But another key concept here is we need to be willing to do more than 1 thing at the same time. If we say there is some unwritten rule in the heart failure handbook where I can only make 1 medication change per clinic visit. We are never going to get there.

[01:00:36]

3 Pillars of GDMT for HFpEF and HFmrEF

Now, similar. I would argue we have pillars in HFpEF. We have 3 classes of agents: SGLT2 inhibitor, nonsteroidal MRA, and GLP-1s that have definitive outcome trial and/or patient-reported outcome trial results. They make people either feel better or they reduce hard outcomes definitively. That includes SGLT2 inhibitors, nonsteroidal MRA, and again GLP-1s.

We need to have the same sense of urgency. I would argue, start all 3 disease modifying agents without delay or in rapid sequence.

Key Point: Clinically and Statistically Significant Benefits With SGLT2 Inhibitors Appear Early After Treatment Initiation

But when we are thinking about, well, why do we need to rush? I already painted the picture of yes, this is an extreme risk situation. So it then makes sense to have some urgency. But another key point why we need to rush with our GDMT is that clinically and statistically significant benefits appear with our GDMT, particularly SGLT inhibitors, early after treatment initiation.

[01:01:33]

Clinical Benefit Within Days of Initiation

Here are data from EMPEROR-Reduced, for example. Just 12 days after starting the drug, you see early separation of event curves, statistically significant, clinically significant reduction in hard clinical events such that you can easily understand that if you kick the can down the road, even a couple of weeks, you are exposing that patient to needless excess clinical risk.

[01:01:56]

Rapid & Sustained Improvement in Patient-Reported Symptoms Within Days

But it is not just about how hard outcomes. The patients also feel better when you start an SGLT2 inhibitor and they feel better quickly. These are data from the EMPULSE study that show just within 15 days, you see that separation of the KCCQ curves, for example. Again, even if you are talking about your older patients, frailer patients where there is so much clinical inertia and we are like, “Oh, well, they do not necessarily care about survival as a top priority. Well, they care about feeling better and you feel better quickly based on the clinical trial evidence with an SGLT2 inhibitor.

[01:02:43]

Deferring Initiation = Never Initiating or Substantial Delay

But not only when we kick the can down the road do we expose patients needlessly to excess clinical risk. The real-world evidence would say, unfortunately, we also destined them to never getting the therapies at all, or at best, after only a substantial delay.

These are data from Get With The Guidelines Heart Failure. These are US nationwide registry of patients hospitalized for HFrEF. These data show patients eligible for the different GDMTs and what their chances are of filling a prescription if you prescribe the therapy to that eligible patient at discharge vs you do not prescribe at discharge.

You say, “Yeah, it is just the outpatient doctor. I am the diuresis and discharge clinician, I will let the outpatient team handle it.”

Take for example ARNI and MRA. If you have that eligible patient in front of you at time of discharge, but you defer, more than a 75% chance that patient does not fill a prescription over the entire 1 year after you leave the hospital. That is another underestimated consequence of this slow and steady kick the can down the road approach.

[01:03:33]

Addressing Hesitation: Does Initiating Multiple Agents Simultaneously Increase Risk of Intolerance?

But whenever we are talking about starting multiple medicines quickly or in rapid sequence, a lot of people say, “Whoa, whoa, Steve, you are going to cause a lot of side effects and medication intolerance.” The first thing I say to that is, “Well, first of all, there is no objective evidence that starting these drugs simultaneously or rapid sequence increases risk of intolerance. There is no evidence you can point to in a study, for example.

I will also highlight that tolerability is enhanced when you prioritize the low doses of these medicines. Point number 2 is that 2 of the 4 therapies, SGLT2 inhibitors or MRAs, they rarely cause symptomatic side effects in and of themselves. That is 2 out of 4 pillars you do not really need to worry about.

Third, which is probably the most important, is that HFrEF disease progression may be misinterpreted as a treatment-related adverse event.

What do I mean by that? Well, take for example data on the right-hand side from EMPEROR-Reduced. You have a data here that showed that the odds of your NYHA class getting better or getting worse go in completely different directions, whether that patient gets empagliflozin vs placebo.

To think of this in a more clinical context, you have a patient in clinic today. They are feeling fine. They are eligible for an SGLT2 inhibitor, but you defer. You are like, “Oh, they are doing fine. I do not need to rock the boat.” By essentially giving them a placebo, you are now increasing the chances essentially that 4 weeks from now they come back with worsening fatigue, shortness of breath, etc. Then what happens is we tend to blame the GDMTs they are already on. We are like, “Oh, well, you must be fatigued because of the beta blocker. We have to titrate that dose and get all the medicines off. And it is a slippery slope, when in fact, if you had a time machine and you can go back to that visit when the patient was feeling well and you promptly started the therapy, you decrease the chance you got in the situation to begin with.

Again, that is why timely initiation is so important.

[01:05:22]

Addressing Hesitation: How Can HCPs Start so Many Agents at Once?

Also, people say, “Well, I cannot start all these medicines because it just seems totally unreasonable and practical.” What do we do with acute MI? Patient hospitalized for acute MI with new LV dysfunction? It is in our culture. Dual antiplatelet therapy, statin, ACE inhibitor, beta blocker, MRA. We think nothing of it. Whereas the patient hospitalized for worsening heart failure for example length of stay 4 days. We make few, if any, changes in their disease modifying therapy.

[01:05:49]

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

STRONG-HF now, a randomized controlled trial, body of evidence that further supports the concept of simultaneous rapid sequence optimization of GDMT prior to discharge. Major benefits on hard clinical outcomes. But the patients also felt better, improvements in decongestion. For those that were so worried about side effects, no significant difference in serious adverse events vs usual care, slow and steady vs high intensity rapid sequence.

[01:06:17]

Unintended Harms of “First, Do No Harm”

I joke a lot of times that my major is cardiology. If I was a college student, my minor is psychology. When we think about this, we are all very well intentioned. When you start a new medicine, the first thing that comes up in the conversation with a patient is usually about side effects. What could go wrong? But while I am not saying do not talk about that, but we also need to talk about is the evidence-based consequences of not starting medicines, or at least not trying medicine.

These are the risks of omission, and these risks of omission are heavily evidence based. Higher chances of dying, higher chances of going to the hospital, higher chances of feeling worse when we defer or delay GDMT.

With that, I will turn things over to Dr Bowers.

[01:06:56]

Patient Case 2: Ms Morrison, 72 Yr of Age

Midge Bowers: Here we are on our second case, and you are going to do the same thing. We are going to have our facilitators walk around. Patient case number 2 is Ms Morrison, a 72-year-old person. They come in to clinic reporting increasing fatigue, exertional dyspnea, 2 episodes of paroxysmal or PND over the past 2 weeks. She has a history of obesity, hypertension, type 2 diabetes and AFib.

She is currently taking a thiazide diuretic, beta-blocker, oral anticoagulant, and metformin. Her blood pressure is 132 over 78. Heart rate 92, irregularly irregular, O2 sat is 95% on room air. JVP is elevated with mild bibasilar crackles and trace pedal edema.

As far as her labs and echo go, her potassium is 4.3, EGFR of 58. BNP is elevated and her most recent echo with an LVEF of 58% with concentric LVH and biatrial enlargement.

Okay. We are going to go back. Hopefully you have had a chance to engage with our physician leaders. Let us get some thoughts. This time, we will start with Ty. Dr Gluckman?

Dr Gluckman: Yes. Perfect. There has been discussion about adjustments in therapy potentially changing her thiazide over to a loop diuretic, adding in ARNI and an SGLT2 inhibitor. Then we started talking about a nonsteroidal MRA and a GLP-1 receptor agonist a lot.

The 1 thing that came about around this was what Dr Greene had highlighted, the behavioral psychology from a clinician or clinical delivery standpoint. But also how do you prepare the patient that if not today, there are 5 medication changes that we want to make in the near term. We are really talking about near term and getting them on the stage for that, as opposed to each time just adding potentially another medication and someone says, but 1 more, etc.

Midge Bowers: So setting the stage.

Dr Gluckman: Exactly.

Midge Bowers: Okay. Javed?

Dr Butler: We had a similar discussion. I would not repeat what Ty said, but a couple of other points that came up. One was, there is a lot of issues about stopping beta blockers in patients with HFpEF. But then this person has atrial fibrillation and the rate is on the higher side. We thought that maybe leaving the patient on beta blockers, certainly changing diuretic would be important.

Then the other question sort of a theoretical discussion came up. Well, I mean what about this is not HFpEF and just AF? You can get BNP elevation in edema and whatnot, but it looks like it is chronic AF. The heart rate is not that out of control, is already on anticoagulation. So there is probably not the case. That person, as was discussed in the other table, be more appropriately treated for HFpEF.

Midge Bowers: Great. Steve?

Dr Greene: Yes, I echo a lot of those points. I think from a medical therapy perspective, a lot of people bought into the rapid sequence right away, and partly because this is a Duke table too, as they are used to [inaudible] from me.

Yes, SGLT2 inhibitor, nonsteroidal MRA. And we will also think about GLP-1 because they have a history of obese HFpEF phenotype.

But then both these tables really were thinking about like the holistic picture of this person, or an AFib. Have they ever had a rhythm control strategy for example that can be a way with. So think about cardioversion. Also sleep study for example. That can be a driver of both AFib and HFpEF and whatnot. A lot of good conversations about the holistic approach. But again, GDMT front and center.

Midge Bowers: Excellent. We are going to go on. What 1 change in this patient's care could or should you implement as a result of this patient case discussion? Go ahead and type your answer. Dr Gluckman is going to go on.

[01:14:20]

Section 3: Keeping It Practical: Understanding Safety and Tolerability With an SGLT2i in Heart Failure

Dr Gluckman: Awesome. I will let you type in while we are going along here. I have more of the practical operational perspectives on this. A, are there myths and misperceptions as it relates to SGLT2 inhibitors? Then, frankly, what are the things that may slow you down, or very practically, things you need to be aware of from a safety and tolerability standpoint?

[01:14:47]

Poll 5

We will start with a polling question. A patient with heart failure is on an SGLT2 inhibitor and presents for their first episode of a mild, uncomplicated genital mycotic infection. What is the preferred management approach?

1. Discontinue the SGLT2 inhibitor permanently;
2. Hold the SGLT2 inhibitor temporarily and resume after resolution of the infection;
3. Treat the infection and continue the SGLT2 inhibitor without interruption;
4. Switch to an alternative class of a glucose lowering agent; or
5. Not sure.

Please key in your answer. I like the variability here. We are going to cover this as we go through here. This is 1 of the situations where variability is a good thing. We are going to talk through this overall. But likely the answer for this would be C, you could treat through. We are going to talk through this here.

[01:15:50]

SGLT2 Inhibitors and GU Infections in Patients With HF

As most individuals probably in the room know that SGLT2 inhibitors are associated with a small, low single-digit but increased risk of urinary tract infection or genital mycotic infection. It is important when beginning these therapies. Dr Greene had highlighted the importance of initiation. But just as important is what is the education that complements that to be aware of potential symptoms or side effects that may individuals may have. The reality is it happens infrequently. But when it does happen, what do you do about it?

[01:16:25]

GMI and UTI Risk Factor Assessment Prior to Starting SGLT2 Inhibitors

This is nicely illustrated here. It is a little bit of a flow diagram. I am going to start on the left side. But essentially if you are seeing a patient who actively has an infection today, while you are seeing them, whether in the hospital or in the outpatient setting, do not initiate therapy. Wait until their urinary tract infection or their genital mycotic infection has resolved before initiation of therapy. Obviously, for those individuals that have had recurrent infection, this becomes a more difficult conversation.

On the right-hand side in green. If in fact they do not have an active infection, you can initiate therapy. If they do develop a urinary tract infection or a genital mycotic infection, often, if it is an uncomplicated infection and the patient is doing well in terms of managing that, you can continue their SGLT2 inhibitor through their infection, obviously, while they are being managed for their infection.

In individuals that have a complicated infection and/or they continue to have recurrent infections, getting counsel from a urologist, someone who is responsible for evaluating and managing that infection is going to be a key importance.

As part of the reinitiation of therapy, it is reevaluating all risk factors, making sure that they obviously have an indication for therapy, optimizing all modifiable risk factors, pre-educating about the importance of hygiene. We will talk about that in a second. Then practicing shared decision making with the patient to make sure they understand the risks and benefits.

[01:17:46]

GU Infection Prevention With SGLT2 Inhibitor Use

When it comes to prevention of this, it is raising awareness at the start of their initiation of therapy. So they are not surprised should they develop an infection. The risk of infection again is low. But preparing people for that is important.

Practicing hygiene. Optimal hygiene is important for all patients, their partners. In some cases, those individuals that may help in managing individuals to prevent infection, including rinsing and drying the genital area after using the toilet and before going to sleep.

Topical treatments usually are most effective from a mycotic infection standpoint, and then oral therapies most often are used to manage uncomplicated urinary tract infections.

When candidiasis occurs, it is usually mild and it responds to treatment and does not require, again, medication discontinuation, getting back to our initial patient. Recurrent infection, despite doing optimal things to mitigate the risk of infection, should invite a question about reinitiation of therapy, at least in advance of someone being seen by another specialist.

[01:18:49]

What Other Potential Concerns Should You Educate Patients About When Starting an SGLT2 Inhibitor?

What are the other concerns that may be top of mind for all of you or your colleagues who initiate an SGLT2 inhibitor?

[01:18:56]

Hypoglycemia Rates With SGLT2 Inhibitors in Patients Without T2D

Well, the first that comes up often but is probably way overstated, is the risk of hypoglycemia. This is evidence from the respective clinical trials that were highlighted by Dr Butler showing similar proportions of individuals on an SGLT2 inhibitor vs placebo without type 2 diabetes, and the risk of hypoglycemic events. In general, the rates of hypoglycemia were not increased amongst those individuals receiving an SGLT2 inhibitor with and without type 2 diabetes, but in particular without type 2 diabetes.

We are going to come back to in a second on the risk, but concurrent use, in particular from a drug class standpoint of oral sulfonylureas and/or insulin in those with diabetes can precipitate increased risk of hypoglycemia. In those individuals that you are beginning an SGLT2 inhibitor, principally a priori for their heart failure. If they have concomitant type 2 diabetes and are on 1 of these other drug classes for managing their blood sugars, we should have a discussion for those individuals who are managing their diabetes, endocrinologists, primary care, clinician about adjustment of their medical regimen for that, because there is an added benefit for the SGLT2 inhibitor in lowering their blood sugars.

[01:20:09]

Proposed Insulin and Other Diabetes Medication Adjustments When Initiating SGLT2 Inhibitors

This is a brief flow diagram about how to approach it. Again, coming back to the fact that for an all comer patient population risks of hypoglycemia are low. But in those on insulin and/or secretagogues, it can potentiate hypoglycemia. You may want to adjust their therapy. So ask the question first, do they have a history of hypoglycemia? If they do, when initiating the SGLT2 inhibitor, strong consideration to reduce other hypoglycemic agents.

This includes the sulfonylureas, repaglinide or insulin. Then looking at their renal function in verifying possibility of hypoglycemia for those individuals that may have lesser degrees of renal function. For those individuals whose blood sugars are particularly well controlled at baseline, adjustment of other agents that are used to lower blood sugars.

[01:20:56]

Ketoacidosis Concerns With SGLT2 Inhibitors

Ketoacidosis comes up. We think of ketoacidosis with elevated blood sugars. But you can have euglycemic ketoacidosis as well. This is accentuated by those individuals that may have intravascular volume depletion. They are dehydrated. They are put in a position where they may actually develop dehydration will come to surgery in general and management around people who may have bigger surgeries that involve them receiving nothing by mouth for hours in advance, and potentially not being able to eat in follow up as well.

The reality is this is a rare condition, but it is potentially life-threatening. You should caution individuals that if they were ever to get into a state like this, or present with symptoms that are included on the left-hand side, confusion, nausea, difficulty breathing, vomiting, you really worry about ketoacidosis. Those individuals need to be seen immediately, and in those individuals you should be measuring serum ketones to guide decisions.

I will say, do not be dissuaded by the fact that they have normal or normal-ish blood sugars because, again, euglycemic ketoacidosis can carry the same risks as those individuals that have elevated blood sugars. If you suspect ketoacidosis, stopping the SGLT2 inhibitor is of key importance immediately to minimize complications that may ensue.

[01:22:14]

Surgery Considerations With SGLT2 Inhibitors

Surgical considerations around SGLT2 inhibitors. In general, those conditions that result in decreased oral intake, food or liquids can increase the risk for ketoacidosis, and this has to be a game time decision depending upon the type of surgery and how long you think individuals may be without access to food or liquids overall. If you are concerned, major abdominal procedures, major thoracic procedures. These individuals may be without food and water, withholding the SGLT2 inhibitor temporarily in advance of surgery and then restarting it once they have resumed a more normal dietary intake for food and liquids is a reasonable strategy, as listed at the bottom. In patients with diabetes, their blood glucose may be elevated as a result, acceptable around that perioperative setting.

[01:23:07]

When Should SGLT2 Inhibitor Therapy Be Paused?

When should an SGLT2 inhibitor therapy be withheld or paused? When I say withheld, I am talking about temporarily acute serious medical illness, that can even include acute worsening of their heart failure, particularly if you are concerned about their ability to maintain normal intake if they have a condition that leads to volume depletion, dehydration, if they have a major infection and including infection of the kidney or urinary tract. But even in the absence of that, as infection can be a predisposing factor to ketoacidosis. Then they are hospitalized for a major procedure, namely a major surgical procedure.

[01:23:46]

Dosing Considerations in Patients With HF

Dosing considerations. I am not going to spend a lot of time. You all have access to the slides, but this show notes for empagliflozin, dapagliflozin and sotagliflozin, how these drugs are initiated, and at least for sotagliflozin, if you are going to be doing titration, how you do that titration.

[01:24:03]

Diuretic Considerations With SGLT2 Inhibitor Use

Diuretic considerations with SGLT2 inhibitors. As all of you have mentioned, the respective tables that at least I have been able to go to, there is a diuretic and natriuretic effect. But that being said, in a meta-analysis of these 8 SGLT2 inhibitor, cardiovascular outcomes trials, volume depletion was observed just as frequently in those randomized to an SGLT2 inhibitor and those receiving placebo. It does not mean that you should not be attentive to volume status. It is required when initiating any of these agents, SGLT2 inhibitors, ARNIs, loop diuretics, as it can have a synergistic or concomitant effect with their diuretics overall.

[01:24:43]

Minimal to No Overall Effect on Systolic Blood Pressure

This is noting the effect on blood pressure, hemodynamic effect. This is data from the DAPA-HF trial on the left-hand side, EMPEROR-Reduced on the right-hand side, noting that in general you may see a very modest reduction in systolic blood pressure. As you can see on the left-hand side, very early, a 4 mm drop. Most people, when you talk to them, most clinicians think it is a much more exaggerated effect in terms of the hemodynamic effect of an SGLT2 inhibitor. But this is just highlighting amongst individuals with systolic blood pressures as low as 95 mm Hg. You do see a flattening out as you go just in a matter of several weeks.

[01:25:20]

Safety of SGLT2 Inhibitors in HF and Comorbid CKD

What about the safety of SGLT2 inhibitors in those individuals who have heart failure while we are all here and comorbid chronic kidney disease? This is highlighting the risk of serious adverse events, renal events you can see, respectively, in DAPA-HF on the left, EMPEROR-Reduced on the right. Pretty much the same rates occurred in those individuals randomized to the SGLT2 inhibitor vs placebo, highlighting the safety and tolerability of these therapies when initiated in individuals who have coexisting chronic kidney disease.

[01:25:57]

Financial Toxicity in HF Management

Finally, perhaps the most challenging thing for a lot of us in medicine more broadly is the financial toxicity that occurs in healthcare in general. I do not want to be naive to this because we can come talk about the clinical benefits.

Dr Greene nicely highlighted that even when clinicians who were asked to self-reflect the financial toxicity or the out-of-pocket cost represented a small slice of the pie that dissuaded most clinicians. Although we talk about it an awful lot, it does not necessarily inform our treatment or decision making as often. This just highlights that the various factors that can influence that decision overall.

[01:26:34]

SGLT2 Inhibitors: An Ideal HF Therapy

Lastly, I will let you read through this. But there are a lot of levers or bars or check marks where we can say that SGLT2 inhibitors are really ideal heart failure therapies and SGLT2 inhibitors almost across the board, if not across the board, satisfy all of these criteria, making it an ideal therapy.

With that, I am going to pass things back to Dr Bowers to talk about this third case, and then we will circle again as we are doing this. Thank you.

[01:27:00]

Patient Case 3: Mr. Kennedy, 68 Yr of Age

Midge Bowers: Our final case this morning is Mr. Kennedy. He is 68 years old, admitted to the hospital with worsening dyspnea and fluid overload. He has a history of hypertension and CKD. You can see his EGFR is 52. He was diagnosed with HFrEF with an LVEF of 30% just about 2 weeks ago and has not, I repeat, not started on therapy for heart failure.

His vital signs include a blood pressure of 110 over 70. Heart rate 78. O2 sat of 96% on 2 liters. His JVP is elevated and he has 2+ pretibial pitting edema.

During his hospital course, he was initiated on an IV diuretic with a good response and he is now euvolemic, eating, and ambulating on the ward.

Okay, folks, so we are wrapping us up. This is our last case. Hopefully, it sounds like the volume has gotten higher. So we are having more vibrant discussions here. I am going to ask Steve, go ahead and give us some feedback on how your patient was treated.

Dr Greene: Yes. We want to take advantage of the hospital stay and get this patient on quadruple medical therapy by time of discharge. We also were talking about some of the real life challenges they faced with the patients getting pushback of, “Oh, gosh, I am already on so many medicines, now you want to start 4 new medicines. And even if they are affordable, do I really need all these?”

We kind of talked there is no easy answer per se. Patients are always in charge. But we got to make sure they are well informed. I think it is just to be open and honest with patients on the well informed risks of not trying these medicines. I think that is what we have to just really be clear about.

Midge Bowers: Very clear. Javed?

Dr Butler: I never thought that I will see this day, that I will sit with a bunch of folks and I will be the most conservative person in terms of aggressive medical therapy. Basically pretty much the same. We actually started getting into a little bit into the weeds at sure. SGLT2 inhibitor, this is not at the time of discharge, even if the person getting IV diuretic. Great idea. Go ahead and get start with that.

Then the other least hemodynamic affecting agent would be spironolactone in combination with an SGLT2 inhibitor. Then the question is the real decision is what is the third drug, ARNI or beta blocker? People for a while you are going to diuresis the person, maybe low dose ARNI. Although we were cognizant of the blood pressure, so we did not want to start both at the same day and then start an ARNI and then transition into a low dose beta blocker predischarge. But then please, please have a follow up post-discharge relatively very soon.

Midge Bowers: That is great. And Ty?

Dr Gluckman: Beyond all the great comments that were made, there was a little bit of a systems of care discussion about a couple of things. Number 1, having a systematic check to review the therapies that people were on and trying to get over the clinical inertia, figuring out justification about why they are not in therapy.

There was an acknowledgement that quadruple therapy notwithstanding what Dr Greene shared can be a challenge even for some clinicians and patients to sort of that pill to swallow, no pun intended, before they leave the hospital.

The last piece, and I would encourage all of you in the room is, at least at my institution, these patients may be admitted to a hospital medicine physician or clinician. They may never even see cardiology. How do you share that this learnings here more broadly to systematically consider, and if not initiated in the hospital at discharge, how do you prepare people? The last piece is some of the financial toxicity pieces meds to beds programs or working with your pharmacist, perhaps to even assess what the out-of-pocket costs could be before they left the hospital might help prepare for what they could tolerate financially as an outpatient.

Midge Bowers: I am so glad you brought up to our pharmacy partners, because I have 2 of my colleagues here, and I think that is it. We heard earlier from my other colleagues about prior authorizations. I think that has helped us, if they can be done earlier, for those of us that work in the ambulatory setting, and I think about my primary care colleagues as well of what do they know? They have 15 minute visits. What can they do? What can they add? So being clear in our discharge summaries, or if they are already seen by cardiology, being clear of what is the next step kind of teeing them up.

Go ahead and type your answer. What is the 1 change in his care that you can implement as a result of this patient case discussion. Then we are going to circle back to our initial cases.

[01:35:53]

Posttest 1

Okay. If you recall from way in the beginning, your patient is a 62-year-old person with hypertension, CKD and a recent diagnosis of HFrEF with an EF of 30%. They came to the ER or emergency department with worsening dyspnea, vital signs were stable. O2 sat is normal on 2 liters of O2, but they were volume overloaded with an elevated JVP and lower extremity edema. They received IV diuresis and are now euvolemic and eating well. What is the answer? When would you consider an SGLT2?

1. During follow up with his PCP in the next 2 weeks;
2. During his first follow up with his cardiologist in the next month;
3. Before hospital discharge once the patient is clinically stable; or
4. At the time of discharge, so prescriptions can be discussed during discharge planning.

Go ahead and enter your response.

Dr Butler: If the answer is less than something, then we made things worse.

Dr Greene: There is a lot of pressure here. A lot of pressure.

Midge Bowers: I remember how well you did. There you go.

Dr Butler: Thank you.

Midge Bowers: Okay, so see how smart you were? Still smart at the end of the talk.

[01:37:09]

Posttest 1: Rationale

Okay. The rationale for this, as we have heard discussed many times is recommendations or current guidelines recommend that 4 pillar or quad therapy, as we say, for patients with HFpEF. We have heard from all of my physician colleagues here about clinical trials that demonstrate not only the significant reduction in mortality, but also hospitalizations, and that implementation of these quad therapies should be started early and never be delayed.

[01:37:41]

Posttest 2

Next question, and we are almost done. Which of the following best summarizes the evidence from major RCTs regarding the use of SGLT2 inhibitors in patients with heart failure, regardless of their ejection fraction?

1. They reduce cardiovascular death and heart failure hospitalization across a broad spectrum of ejection fractions, with early benefits observed within weeks of initiation;
2. They improve glycemic control and reduce hospitalization risk in patients with diabetes, but show minimal benefits in patients without diabetes;
3. Long-term use of SGLT2 inhibitors is associated with a high incidence of hypotension and risk of dehydration, limiting their use in patients with HFrEF; or
4. There is limited evidence to support SGLT2 inhibition use in HFpEF, with benefits predominantly confined to advanced HFrEF.

Go ahead and enter your response, please. These are a lot of words. Okay. Here we go. Everybody is doing very well as the educator in the room, so I can say, yay, you are all getting A's.

[01:39:04]

Posttest 2: Rationale

Really the response A is that the reduced cardiovascular death and heart failure hospitalizations across a broad spectrum. I think you heard earlier, Dr Butler really talking about we finally have something for HFpEF. I have been doing heart failure care for a really long time, and it was joyful when we finally had something.

We know that from DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved and DELIVER, SGLT2 significantly reduced the risk of cardiovascular death and hospitalizations in patients with both HFrEF and HFpEF, regardless of whether or not they have diabetes. These benefits, Dr Greene really pushed and told us early, early, often, underscoring the importance of early and sustained use.

Finally, Dr Gluckman brought us home talking about the safety profiles, really favorable safety profiles with a low incidence of serious adverse events and acute kidney injury. These agents are now should be are incorporated into the guideline-directed medical therapy but should be part of our practice.

[01:40:08]

Posttest 3

Finally, a 74-year-old woman with a history of hypertension and obesity presents with worsening fatigue and exertional dyspnea over 3 months. She has CKD with an EGFR of 48. She does not have diabetes. She is on amlodipine and hydrochlorothiazide. Her echo shows an EF of 56% with mild atrial enlargement and moderate diastolic dysfunction. Her NT-proBNP level is elevated, and she has NYHA Class II functional status. Which of the following is the most appropriate approach as it relates to SGLT2 inhibitors?

1. Defer starting an SGLT2 inhibitor due to the absence of diabetes and a preserved LVEF;
2. Avoid an SGLT2 inhibitor unless she develops NYHA Class III or IV functional status, or develops left ventricular systolic dysfunction;
3. Switch her HCTZ to furosemide prior to considering an SGLT2 inhibitor to minimize overlapping diuretic effects; or
4. Recommend an SGLT2 inhibitor now to reduce the risk of hospitalization for heart failure and improve her quality of life while monitoring her renal function.

Go ahead and enter your response, please.

Okay. Well, we can see that everybody once again understands that patients with HFpEF and Class II symptoms with CKD and an elevated proBNP would benefit from starting an SGLT2 inhibitor as part of their personalized evidence-based care.

[01:41:57]

Posttest 3: Rationale

Again, EMPEROR-Preserved, DELIVER demonstrated that empagliflozin, dapagliflozin both, not together, but significantly reduced the composite outcome of heart failure hospitalization, and cardiovascular death in patients with HFpEF, regardless of diabetes status. These benefits extend to individuals with also mild to moderate renal impairment, with an EGFR of greater than 30, with effects that emerge early and persist.

[01:42:25]

Q&A

Midge Bowers: Any final questions here from our audience or online? Dr Greene, do you know are there GDMT utilization registries for quad therapy in the outpatient setting? One of our online learners asked about that.

Dr Greene: Yes. It is a great question. Nationwide we have the Get With The Guidelines Heart Failure Registry, which is a hospitalized for heart failure registry, both rEF and pEF. There is been a lot of past work and ongoing work on uptake of quadruple medical therapy.

In terms of outpatient registries in the US, we historically had the CHAMP-HF registry from a few years ago, and I think that really gave us the alarm bells with how we were doing with triple therapy. Less than 1 out of 4, we are getting triple therapy, only 1% were getting triple therapy at target doses.

I am not aware of a US outpatient registry ongoing right now, although there is lots of real world evidence from claims databases and whatnot show really horrifically low outpatient use of quad therapy. Usually single digits is unfortunately what we see.

Midge Bowers: Dr Butler, any thoughts on why only 1 SGLT2 inhibitor showed a mortality benefit?

Dr Butler: Well, that is not that 1 SGLT2 inhibitor showed mortality benefit. One SGLT2 inhibitor trial was about 4,700 patients. The other one was 3,700 patients with the size was different. On average, the follow up was different between the 2 trials as well.

If you look at the meta-analysis, there is no heterogeneity of the effect. It is an issue of power that you saw the difference that while the magnitude was pretty similar, 1 was statistically significant and sneaked a p value of less than 0.05 vs not the other. If you look at overall consensus and the meta-analysis, there is no difference between the 2.

Dr Gluckman: Can I ask a quick question of my colleagues here. I have found from talking with individuals that often in the heart failure realm, there may be less of a barrier to adopting an SGLT2 inhibitor in patients without type 2 diabetes, in part because you are not having to worry about coordination of care with anyone else rather than I am not the endocrinologist, I am not managing their other medications for diabetes. Do you see that in the real world? Has there been any data to support that, or do you see that in your own practice?

Dr Greene: Well, I will say from a real world evidence perspective, use of patients with heart failure in comorbid diabetes have higher use of SGLT2 inhibitors. So real world evidence, as Dr Butler showed the slide. I mean, no matter what subgroup you look at, they are all variations of low. But there was a little bit of a bump among people with heart failure and diabetes compared to heart failure without diabetes.

Again, from a coordination standpoint, collaborative care is critical, obviously. But I also want to make sure sometimes when you get, I do not know, overly collaborative, we almost think we need to ask for permission to do every little thing and then we all get paralyzed. That is the unintended consequence of being overly collaborative. I think we need to take ownership and initiative and not be timid. Then sure, update the other clinicians. But again, do not be timid and kick the can down the road.

Dr Butler: Completely agree.

Midge Bowers: Yes. I think 1 of the things that I noticed, I just saw a patient last Tuesday that was on multiple medicines for their diabetes, including already a GLP-1 agonist. I just tag teamed with the endocrinologist and got my answer. I wanted to start the SGLT2 inhibitor and I said, “Which 1 of the other medications can we take off?” I was a little assertive in my approach, I will just say that. But I put links to the guidelines here.

Let us go on here. Dr Gluckman, any concerns about wound healing? Someone is asking about SGLT2 effect on wound healing.

Dr Gluckman: Yes. I mean, we have not seen any higher predisposition from that perspective that I am aware of. Again, you want to be conscientious of the risks of infection from a genital mycotic infection, urinary tract infection. But absent a scenario where somebody has an active wound that is requiring surgery and an interruption of their therapy, one would not anticipate that.

Midge Bowers: Okay. I am going to ask this to the group. The virtual audience was missing seeing urine creatinine in all 3 cases. Do we need to know what their creatinine level is vs GFR?

Dr Butler: I am so glad that somebody raised this issue, because this is just a public service announcement right at the end that that you cannot manage your heart failure as well without managing their CKD well. If you look at the 3 cases, all 3 of them had some degree of CKD. Two of them had diabetes. There is a lot of undiagnosed diabetes and heart failure as well, or at least insulin resistance.

Whether HFrEF, HFpEF, it really does not matter. The average GFR in most heart failure trials is like 58, 60, sort of in that range. But remember that the earlier form of CKD is actually start leaking the protein before the GFR goes down considerably. If your GFR is 45, yes, there is definitely additional prognostic value that comes with UACR. But if your GFR is 65, you may still be missing out on CKD without assessing the UACR.

This is for the cardiology community to check UACR more carefully, more commonly. Then giving appropriate CKD therapy is we should really consider it like an integral part of heart failure management.

Dr Gluckman: At the risk of being over collaborative, I will say that the growing discussion about cardiovascular, kidney and metabolic disease, it is validating that SGLT2 inhibitors among several different drug classes, not surprising that they actually provide and convey benefit across multiple different conditions and organ systems. These are often systemic conditions. I think there will be, out of necessity, greater collaboration, but do not need to ask for permission to necessarily get people on effective therapies that show improvement in outcomes.

Midge Bowers: I think that is a great time. We thank you for your time and attention to this session.