How Do We Practically Do This? Expert Guidance and Interactive Practice on SGLT2i Integration Across the Spectrum of Heart Failure

Thursday, 14^th November 2024

“How Do We Practically Do This?” Expert Guidance and Interactive Practice on SGLT2i Integration Across the Spectrum of Heart Failure

Start: [00:17:46]    

Dr Ty Gluckman (Providence Health System): And I always think it is great to have a patient case to bounce ideas off of. It actually sets up our entire discussion today. So this is a fictitious but all too real case that I suspect we all may see in the hospital or ambulatory settings.

This is Barbara. She's a 67-year-old woman who was recently discharged from the hospital after being diagnosed with new onset heart failure with reduced ejection fraction, or HFrEF. Her left ventricular ejection fraction is 35%, and she's found to have a non-ischemic cardiomyopathy. During her hospitalization, treated with intravenous diuresis, and she has a net loss of 12 pounds. She feels much better as a result, and she started on multiple new medications during that hospitalization.

At the time that she's being discharged, she denies any chest discomfort, but still notes that she has mild shortness of breath with exertion. Her past medical history is relevant for obesity, high blood pressure, high cholesterol, type 2 diabetes mellitus, sleep apnea, and hypothyroidism. She's a lifelong non-smoker with social alcohol use, and she's a retired business analyst. And she has no family history of heart failure.

Medications at the time that you are seeing her in follow up to discharge from the hospital include atorvastatin at 10 mg a day, furosemide at 40 mg a day, glyburide at 10 mg a day, levothyroxine at 125 mcg a day, losartan at 50 mg a day, metformin 1000 mg twice daily, metoprolol succinate at 50 mg a day and spironolactone at 12.5 mg a day.

Her exam is notable for an elevated systolic and diastolic blood pressure. She's in a regular rhythm with a heart rate of 78 beats a minute. Her BMI is listed there at 34.8. She is saturating well on room air. She has an elevated jugular venous pressure with a positive HJR. She has got no third or fourth heart sound, and again, is in a regular rhythm. There are no murmurs, and she has got faint by basilar crackles. There is no hepatosplenomegaly. And she has 1+ pretibial pitting edema bilaterally. I will let you know that this is improved compared to where she was in the hospital, but still has findings of volume overload.

Pertinent labs include a serum sodium of 137, potassium of 3.9. Her creatinine is 1.0. That gives her an estimated creatinine clearance of 62 moles per minute, and her NT-proBNP level is 912 picograms per mil.

[00:20:20]   

          Points to Ponder

I am going to ask a rhetorical question to myself and my colleagues, actions to take today. Obviously, the focus of today's discussion is around SGLT2 inhibitors, and this is at least notable that she is not receiving that medication.

I am going to pass things to Javed in just a moment to go through the evidence that supports the onboarding of a medication like that. But in addition to thinking about what is missing or what could be done to optimize her treatment regimen, for me at least, there are a number of questions that I ask out loud, or at least in my head that are important, I think, to address as we think about onboarding an SGLT2 inhibitor, namely:

• Would the decision to initiate an SGLT2 inhibitor differ if she did not have type 2 diabetes? Again, she has it.
• What if she was already prescribed and taking an ARNI?
• What if her left ventricular ejection fraction was not 35%, but was 45% or 60%? As was evidenced by some of her symptoms, she has more or higher than Class 1 functional status.
• What if she was asymptomatic and had Class 1 functional status?
• What if her creatinine clearance was even lower, less than 60 ml per minute or less than 45 mL per minute or less than 30mL per minute?

So these are just a number of questions that at least we all should be asking ourselves as we are approaching patients for initiation of an important medication class, namely SGLT2 inhibitors.

And I am now going to pass things over to Javed to walk us through the clinical trial data and real world evidence that substantiates the use of SGLT2 inhibitors in heart failure today.

[00:21:56]

Latest Clinical Trial Data and Real-world Evidence in Support of SGLT2 Inhibitors in Heart Failure

Dr Javed Butler (University of Mississippi Medical Center): Great. Well, thank you very much, Ty, for those introductory comments on the case. Always helps to anchor the discussion. So I very much appreciate the opportunity to talk to you. And thank you very much for taking the time out from your busy days on this learning opportunity.

So we will talk a little bit about the data on the basis of which SGLT2 inhibitors have the recommendation that they have right now. And then we will talk a little bit about the guidelines and practical management tips as well, along the course of the program.

[00:22:29]

          Poll 2

So let us start with another polling question. I am familiar with available clinical evidence for safety and efficacy of SGLT2 inhibitor use in patients with heart failure. See if you have the response.

Okay. So we have a fair amount of split. We have some folks that are very familiar, some not too much. So that is good. We will have a good discussion on that. And let us start with our discussion.

[00:23:18]

EMPA-REG OUTCOME: CV and Renal Benefits in People With Established CVD and T2D

So first let me just give a little bit of a historical background as a refresher. Many of us know these data from the past. But just again, a quick refresher. Why are we talking about using a “diabetes drug” for the management of heart failure?

So that all started with the EMPA-REG OUTCOME trial, when the FDA had mandated that all new diabetes drugs should be tested in long term clinical outcome study, so that we know what is their effect on clinical outcomes beyond just glycemic control.

So the first SGLT2 inhibitor trial that came out was the EMPA-REG OUTCOME trial. And very pleasantly surprising, this trial was associated with substantial reduction in MACE and cardiovascular death and heart failure hospitalization, regardless whether somebody had baseline history of heart failure or not, and substantial improvement in kidney outcomes as well.

So there were all of these benefits. But it was a little bit confusing when these data came out. No doubt that these are good anti-diabetes drug and that we should be giving it for glycemic control and for diabetes. But the question is, what was driving all of this cardiovascular benefit? Because in the past, with other therapies, when we have gotten glycemic control, just the glycemic control in itself has not translated into improvement in cardiovascular outcomes. More so, even in this trial, the starting hemoglobin A1C, the ending hemoglobin A1C, the delta changes over time. None of those things correlated with the outcomes. In other words, the outcomes were being driven by something other than glycemic control.

Well, in parallel to this trial and subsequent to this trial, we found a lot of mechanistic data in humans and in animals and patients with or without diabetes, that these drugs are associated with improvement in cardiac structure and function, and vascular structure and function, and kidney structure and function. And obviously, kidney is intricately involved in the cardiovascular disease development and progression. That it became pretty evident why these drugs would will be associated with such a good clinical outcomes on cardiovascular system.

But then the question was, well, if a drug can have favorable effect on cardiac, vascular and renal structure and function, then what does this have to do with diabetes? That maybe what we have is both. It is not this or that, it is both that these are good anti-diabetes drugs, but they are also cardiovascular risk modifying agents, irrespective of whether you have diabetes or not.

So that led to clinical development program in heart failure. There were multiple large scale OUTCOME trial and heart failure were started both in HFrEF and HFpEF, but with one distinction as opposed to all the previous SGLT2 inhibitor trials, and that is that these trials were completely agnostic of whether somebody had diabetes or not. These were truly heart failure studies, does not matter whether you have diabetes or you do not.

[00:26:37]

          Clinical Trials of SGLT2 Inhibitors in Ambulatory Patients With HFrEF: DAPA-HF and EMPEROR-Reduced

The first 2 trials that read out were in heart failure with reduced ejection fraction, that DAPA-HF and EMPEROR-Reduced, a pretty comparable trial. Comparable populations. EMPEROR-Reduced was a little bit of a sicker population. One important point to note is that prior to EMPEROR-Reduced all the data that we had on GFR for inclusion criteria and heart failure trials was pretty much GFR of 30, which is a little bit of a problem, because over the course of development of heart failure patients life journey, invariably they develop chronic kidney disease.

So the worse the chronic kidney disease, the worse the prognosis, the higher the need for therapy. Unfortunately, the least likely they are going to get the therapy, right? MRAs are contraindicated for GFR less than 30. And even without that, the RAS inhibitor use goes substantially down below a GFR of 45. So that was an enriched population for outcomes without a lot of therapeutic options.

So in EMPEROR-Reduced, the GFR was all the way down to 20. And in DAPA-HF it was 30. But again it was the same mindset that during treatment, if the GFR falls, you basically just continue the therapy till end stage kidney disease.

[00:27:52]

          SLGT2 Inhibitors in Ambulatory Patients With HFrEF

Here are the results of these 2 trials. I mean talk about getting validation, right? I mean, if I were to take out all the numbers, letters and words from this slide, you would not know which is EMPEROR-Reduced, which is DAPA-HF. Identical results. Early separation of the curve not only highly, highly statistically significant benefit, but a very clinically relevant benefit, 22% to 25% relative risk reduction in the risk of cardiovascular death or heart failure hospitalization.

[00:28:18]

          DAPA-HF and EMPEROR-Reduced: Reduction in CV Death/HF Hospitalization With or Without T2D

Well, what about our experiment that with or without diabetes does not matter. So this is the summary of those data. And as you can see, if you look at dichotomously, whether somebody has diabetes or not, not shown here, but we have published those data. If you look at as trichotomous, diabetes, prediabetes and no glycemic abnormality, or we just do not categorize and look at hemoglobin A1C from four to 12 or 11, whatever the inclusion criteria was, no difference at all.

In other words, truly, these are cardiorenal risk modifying drugs irrespective of diabetes, in addition to the type 2 diabetes benefits known with these therapies. So diabetes or no diabetes made no difference.

[00:29:09]

          DAPA-HF and EMPEROR-Reduced: Adding SGLT2i to ARNI

Now one question always comes up is that we are developing multiple therapies in heart failure simultaneously. So the ARNI results had just come out. And the question was what about if somebody is on ARNI versus ACE !inhibitors. Does that make a difference? And again the answer is no difference whether you are on ARNI or ACE inhibitor.

And this is not something novel for SGLT2 inhibitors. We have learned from pretty much every therapy that if a therapy works, it works irrespective of what the other baseline medical therapies are.

[00:29:43]

          Left Ventricular Remodeling Trials

Okay. So part of the question that folks always ask is what is the effect of these therapies on remodeling overall? So now there are 3 studies that have looked at HFrEF with remodeling, 2 with echo, 1 with MR, including both patients with diabetes and without diabetes.

And the bottom line is that there is significant LV remodeling that has been replicated, reduction in LV volumes and improvement in ejection fraction. We saw that EMPATROPISM and Empire HF Echocardiography Substudy and in SUGAR-DM-HF study as well. So there is substantial evidence for remodeling as well.

[00:30:22]

Clinical Evidence for SGLT2 Inhibitors in HFpEF

Okay. So that's about HFrEF. We were very happy because of the residual risk, despite of all the therapies. And that these drugs improve the outcomes in addition to the other therapies. But now the bigger question was that up until now, there was not a single therapy that had conclusively proven to be of benefit in heart failure with preserved ejection fraction. In 2018, 2020, we were with HFpEF, where we were in HFrEF in 1985, 1990. Right. No therapy just give diuretics sort of a situation.

Till SGLT2 inhibitors came out, showed benefit for the first time in patients with heart failure, with preserved ejection fraction making at least one therapy now available that works across the spectrum of ejection fraction.

[00:31:14]

          EMPEROR-Preserved: Empagliflozin for Treatment of HFpEF in Addition to SoC, Regardless of DM Status

So similar to the HFrEF story, there were 2 trials that started with empagliflozin and with dapagliflozin. EMPEROR-Preserved and DELIVER. Again, large outcomes trial, 6000 patient trial. Same thing GFR all the way down to 20. And if during the trial if the GFR falls to less than 20, no problem. Just continue the therapy till end-stage kidney disease randomized to empa 10 versus placebo followed for long-term clinical outcome.

[00:31:45]

EMPEROR-Preserved: Effects of Empagliflozin on Composite of CV Death or HHF in HFpEF

Again, not only were the DAPA-HF and EMPEROR-Reduced trial results pretty comparable, EMPEROR-Reduced and EMPEROR-Preserved results were also pretty comparable. If you look at the inset here, early separation of the curve, 21% relative risk reduction in cardiovascular death, heart failure hospitalization. A highly, highly statistically significant result.

So now we truly have a therapy across the spectrum of EF. Does not matter.

[00:32:13]

          DELIVER: Dapagliflozin for Patients With HFpEF

And soon following this was the DELIVER trial that came out, again, heart failure with preserved ejection fraction in one place where DELIVER stands out is that they also included people with heart failure and recovered EF. So if your EF used to be less than 40, but now it is greater than 40, those patients were included.

Again, same result as we have been seeing with all the other trials. Highly statistically significant reduction in cardiovascular death, heart failure, hospitalization, including those group of patients that had recovered EF. So truly across the spectrum of the disease process.

[00:32:48]

          DELIVER and EMPEROR-Preserved Meta-analysis

Then the meta-analysis was done for EMPEROR-Preserved and with DELIVER, showing again about a 20% relative risk reduction in cardiovascular death, heart failure hospitalization. Cardiovascular death by itself, there was about a 12% relative risk reduction. Probably did not have enough power to meet a p value of less than 0.05, but this is about as close as it is going to get 0.052 as we can see on the left bottom corner.

[00:33:17]

          DELIVER and EMPEROR-Preserved Meta-analysis

And this is the result on ejection fraction 40% to 50%, 50% to 60%, greater than 60%. No heterogeneity if you look at the orange box. They literally just line over top of each other. And a drug works across ejection fraction.

[00:33:33]

          Posttest 1

Okay. So one post-test question. In a meta-analysis of DELIVER an EMPEROR-Preserved use of SGLT2 inhibitor in patients with HFpEF showed significant reduction in cardiovascular death or first heart failure hospitalization in;

1. Only 40% to 50%;
2. Only 50% to 60%;
3. Only greater than 60%; or
4. All above 40%.

Okay, great. So most of you got the right answer. All above 40%. Now 41% to 49% and 50% to 59% obviously is not the wrong answer. The trick here was the word only, and I think some of our readers may have missed the word only. So yes, they definitely work in 40% to 50%, 50% to 60%. But it is not exclusive in that group. Everybody over the EF of 40%, DELIVER and EMPEROR-Preserved showed that these drugs had significant beneficial effects.

[00:34:48]

          Answer: Rationale

And this is the rationale, basically showing the results of the clinical trials that we just discussed.

[00:34:56]

          KCCQ Summary Scores and Domains

Okay, so moving on. Our patients not only want to have the traditional clinical outcomes of mortality, hospitalization risk go down. But they also want to have a better health status and quality of life. Both of these trials tested the quality of life assessment using KCCQ, Kansas City Cardiomyopathy Questionnaire. For some of our friends who may not be totally aware of KCCQ questionnaire, it is a 23 questionnaire basically divided into 3 scores.

One is symptoms, frequency and burden that is called TSS or total symptom score. If on top of symptoms, you include physical limitation, that's called clinical summary score. And if you have the overall quality of life and social limitation and sexual function and interaction and going out and bring all that, that's called OSS or overall summary score.

[00:35:53]

          Effect of Empagliflozin on KCCQ Over Time

In the interest of time, I will just show you the data from one of the trials. Again, you can see that at the first time when these scores were measured at 12 weeks, there was already a significant benefit in favor of the treatment with improvement in scores and across the duration of the trial, that improvement was maintained.

[00:36:14]

          Clinically Meaningful Improvements and Deteriorations in KCCQ-CSS, -TSS, and -OSS Over Time

Now, this is a complicated slide and at the same time a very simple slide. It is complicated because what it is doing is looking at the degree of improvement in quality of life scores, 5 point, 10 point, 15 points. So a little improvement, a moderate improvement, a lot improvement. It is looking at 3 by 3 by 3. So small, moderate, large improvement at 3 month, 8 month, 12-month improvement.

And the 3 domains I talked about, symptoms, CSS and OSS. The reason why this is a very simple slide is that we just don't need to go into details. Does not matter when we measure it, does not matter which scale we measure it, and does not matter what threshold we measure it at, the data were in favor of SGLT2 inhibitor for improvement and worsening with placebo.

[00:37:10]

          Acute HF: The Missing Link

Okay. So that is all on the outpatient side. What about acute heart failure, worsening heart failure in the hospital side.

[00:37:19]

          SOLOIST-WHF: Primary Outcome

So one of the trials that addressed this question was the SOLOIST worsening heart failure study. This was limited to patients with diabetes and with a drug which is a little bit different. Empagliflozin, dapagliflozin that I have discussed so far are SGLT2 inhibitors, whereas sotagliflozin is SGLT1/2 inhibitors. So it has a little broader spectrum of receptor function.

And the bottom line is again, substantial reduction at 33% reduction in patients who were worsening heart failure. So hospitalization or soon thereafter so, really enrich high risk population, showing substantial benefit in the risk of mortality, hospitalization.

[00:38:01]

          EMPULSE: Primary Endpoint

And another trial that looked at it was EMPULSE trial. So they did something called a win ratio, which is a hierarchical endpoint where you stack on all 3 domains into one endpoint looking at mortality, hospitalization and quality of life scores. And as you can see in the blue box on the top, the win ratio statistics was positive 1.36, highly statistically significant, showing that this composite of mortality, hospitalization, and quality of life going in favor when people were started during hospitalization for worsening heart failure.

You just had to be stable. In other words, you were in the hospital at least for 24 hours, not requiring inotropes, blood pressure was not labile. You were not on IV vasodilators. You could still be on IV diuretics Day 2 and you could be randomized. And this early in-hospital initiation was safe, and there was a 36% higher chance of winning on this composite endpoint if you were taking an SGLT2 inhibitor, empagliflozin.

[00:39:08]

          EMPULSE: Reduction in Time to All-Cause Death or HFE

And although it was a smaller trial, not powered for clinical outcomes, just in short, in 3-month follow-up, there was a nominal statistically significant reduction in all cause death and heart failure hospitalization by 35%.

And as one might expect because of the diuretic effect of these drugs in combination with WHO diuretic, there was better decongestion of these patients that was also persistent.

[00:39:43]

Clinical Evidence for SGLT2 Inhibitors Across EF Spectrum        

So bottom line, we have now data on in-hospital out of the hospital, worsening heart failure, HFrEF, HFpEF, Recovered EF, which sets us up for a good meta-analysis of the overall field.

[00:39:50]

          Meta-analysis of 5 Large Placebo-Controlled Trials

And if you put all of these data together, we can see an impressive 25% relative risk reduction in cardiovascular death, heart failure, hospitalization requiring a very modest number needed to treat to start seeing a clinical benefit of 25%.

So I will now turn it over to my colleague Ty, to start talking about a little bit now that we have all the data, what to do with it, how to implement it, and what the guidelines are saying. Ty?

[00:40:19]

Guideline Incorporation of SGLT2 Inhibitors

Dr  Gluckman: Javed, that was phenomenal. So I get to catch the baton and now run with it. We have been very fortunate to have both international outside the United States and US guidelines that have been produced since this data. Much of this data has come out. We've had some consensus statements or other forms of guidance that have come out that I am going to attempt to review and summarize overall.

[00:40:43]

          2022 AHA/ACC/HFSA HF Guideline Updates

This is a pictorial display about key therapies that we would use in heart failure. I am going to walk you through this briefly, but this comes from the most recent US American Heart Association, American College of Cardiology, Heart Failure Society of America Heart Failure Guideline that was put out in 2022.

I will just call attention to in contrast to how we normally might include in some of our guidelines. Class 1 recommended interventions are colored blue here, 2A are colored green, 2B are yellow. I will change on the next slide, so I will just call that out.

And for those that are less familiar, we talk about heart failure, and I would say least commonly will assign people by stage of heart failure. So Stage A are people who have a risk factor for heart failure, but have not developed structural or functional abnormalities in their heart.

Stage B takes it a step further that they have a risk factor, and they have structural or functional abnormalities, but have never developed symptoms or signs of heart failure. Stage C is what we spend the greatest amount of time talking about. These are individuals who are currently symptomatic or who have been symptomatic in the past. And stage D is advanced heart failure.

And it is a box around it in red calling out that SGLT2 inhibitors are given a Class 1 recommendation in patients with diabetes, who have Stage A heart failure, or Stage B heart failure. And clearly based on the preponderance of data that Javed highlighted before, in patients with heart failure with reduced ejection fraction, less than or equal to 40%, this is sort of the middle column that has the greatest top to bottom list of tiles there, SGLT2 inhibitors are listed down fourth, but they are part of our core 4 pillars of therapy for heart failure with reduced ejection fraction and have been assigned a Class 1 recommended intervention in our guidelines.

If we move rightward in Stage C and D, it moves to a Class 2a indication for SGLT2 inhibitors in those with heart failure with mildly reduced ejection fraction, that fourth column. And then lastly, the heart failure with preserved ejection fraction, those with an ejection fraction of the left ventricle greater or equal to 50%, a Class 2a indication as well.

So this is where our guidelines sit as of today. And we look forward obviously to future data further informing them going into the future.

[00:43:10]

          SGLT2i: Cornerstone of HFpEF Treatment

The American College of Cardiology put out in 2023 an expert consensus decision pathway related to heart failure with preserved ejection fraction. And not inconsistent with what we saw in the 2022 guideline document, a Class 1 recommendation is assigned to loop diuretics for those individuals who have Class 2 or greater functional limitation, symptoms and signs related to volume overload. But at the top of our other therapies sits SGLT2 inhibitors as a cornerstone therapy as a Class 2a indication.

Interestingly, in the original document, it was assigned to Class 2a. This was actually prior to the data from DELIVER being published. And so this was based solely on EMPEROR-Preserved. And so there was speculation by the authors of this document as to whether the availability of a second, large scale randomized controlled trial, whether or not it may move future guidelines to even raise it to a higher class overall.

Needless to say, consistent with what we see in our 2022 heart failure guidelines, this expert consensus decision pathway for HfpEF puts SGLT2 inhibitors above other therapies that we may consider in these patients, like mineralocorticoid receptor antagonists and MRA and ARNI, or an ARB with the latter 2 groups based upon, in fact, their ejection fraction or whether or not they can afford an ARNI overall.

[00:44:34]

          Major HF Guidelines Strongly Recommend Foundational Use of SGLT2i Across the LVEF Spectrum

This is a busy slide, but I think it actually very helpful slide. And it reinforces, as Javed shared earlier, the consistency of the clinical trial data and therefore the consistency of different guideline writing groups arriving to similar conclusions about where SGLT2 inhibitors should be prioritized relative to other therapies that we may use broadly in heart failure.

So if you look to the far left, you will see heart failure with reduced ejection fraction. SGLT2 inhibitors are given a Class 1 recommendation in the 2022 US heart failure guideline that I referenced. Similar, it is given a Class 1a recommendation in the 2021 European Society of Cardiology heart failure guidelines. They do specifically call out drugs by name and dapagliflozin and empagliflozin in that document.

And then even more recently in the 2024, this year, the American College of Cardiology put out another expert consensus decision pathway focused on HFrEF or heart failure with reduced ejection fraction, a similar order as well. This is actually a topic that we are going to come back to in our Q&A session about whether these apply to the therapies that Javed reviewed in the specific clinical trials, or whether we should be expanding this more broadly to SGLT2 inhibitors as a class.

In terms of moving to the middle panel and the right word, this is sort of combining heart failure with mildly reduced ejection fraction, with heart failure with preserved ejection fraction, and in fact, both in the SGLT2 inhibitor space, but in other classes of drugs, we see increasingly sort of this bifurcation of those that have reduced ejection fraction less than or equal to 40%, and then those with an ejection fraction greater than 40%, as sort of encapsulating these latter 2 categories.

As was stated previously in the 2022 Heart Failure US guidelines, SGLT2 inhibitors are assigned a Class 2a recommendation. In the European guidelines, the SGLT2 inhibitors spelled out as dapagliflozin and empagliflozin, are given a Class 1a recommendation in this group for mildly reduced and preserved ejection fraction heart failure. And then in that heart failure with preserved ejection fraction document put out by the American College of Cardiology, given the equivalent of a Class 2a recommendation, it is not a formal guideline, but it was given a level very similar to what we see in the 2022 US heart failure document. So a large degree of consistency both in the US and outside the United States.

[00:47:12]

          Case Study: Barbara

So I am going to come back to our case, Barbara. And you have seen her. You recognize based upon everything that Javed shared with you, that this is a patient that would benefit from being on an SGLT2 inhibitor.

After she returns from her visit, she lets you know in a follow up visit through your electronic medical record that you can afford an SGLT2 inhibitor and would like to start one, you appropriately send in a prescription to her pharmacy. But this begs some of the operational questions about what kind of instruction, information guidance should be provided to her from a practical perspective to ensure that she is able to get on the therapy, derive all the benefits that Javed outlined, and mitigate any of the risks associated with the use of the drug.

And so rhetorical questions that you should be asking yourself, and I ask myself, is what are the instructions that we should be providing to her? Are there any precautions that we should give her as it relates to taking an SGLT2 inhibitor? Is there any adjustment of any other drug therapy that she is on that, in fact, you may not have prescribed, but in coordination with her primary care clinician or endocrinologist may be best suited for her to mitigate the risk of complications while on an SGLT2 inhibitor.

Are there things that you should inform her of to watch out for while she is taking an SGLT2 inhibitor, and appropriately to notify you of should they occur? And under what circumstances should you consider stopping an SGLT2 inhibitor in Barbara?

[00:48:44]

Approaches for Integration of SGLT2 Inhibitors Into Treatment Plans

So this latter portion, before I turn it to Lauren, to give us even further practical information about how to onboard an SGLT2 inhibitor and overcome some of the barriers that may exist in practical day in and day out work, I want to walk through how to integrate this into the treatment plans and address many of those rhetorical questions that I just posed to all of us.

[00:49:06]

          Poll 3

So before we do that, I am going to pose another poll. And if you practice in an inpatient setting, what percentage of the time do you prescribe an SGLT2 inhibitor upon hospital discharge to a patient with heart failure who is otherwise not already taking one?

1. 0% to 10%;
2. 11% to 25%;
3. 26% to 50%; and
4. More than 50%.

Please type in or key in your answer. This is interesting because we have a relatively even split of individuals who will do it in the single-digit percentage of the time, some that will modestly increase beyond that, and some that are even doing it more than 50% of the time. So really helpful broad split.

[00:50:06]

          SGLT2i Underuse in Patients With HF Being Discharged From the Hospital

This next slide nicely highlights the level of variability that exists. Now that is not necessarily good variability, but it is a reflection of what we see throughout the United States. So this is a observational cohort study of nearly 50,000 patients. And in this case, I do want to call out that these were patients with heart failure with reduced ejection fraction that were part of enrollment in the get with the guidelines heart failure registry put on by the American Heart Association.

And it looked at the degree of hospital level variation in the percentage of patients discharged with a prescription for an SGLT2 inhibitor at the time of discharge from the hospital. And importantly, I want to call out the fact that only 1 in 5 patients were discharged on an SGLT2 inhibitor. This is despite some of the acute heart failure, as well as, obviously, chronic disease heart failure data that Javed shared previously overall.

Of note, rates were similar in this analysis of being discharged on an SGLT2 inhibitor, whether or not a patient had type 2 diabetes or not, and whether they had concomitant chronic kidney disease or not. And it really reinforces the need to overcome this clinical inertia. Pictorially, this is a display of essentially the equivalent of a waterfall plot of showing individual hospitals, grouped by the types or the different categories in which they have rates of SGLT2 inhibitor prescription at discharge.

The darkest color is reflective of people doing it more than 50% of the time. This was only 19 hospitals, and there was a split, perhaps not too dissimilar-ish from what we observed in the poll, where as you step leftward along the x-axis, you have hospitals that are doing this less and less and such to the point in the dark red color, we had 20 hospitals where there were no discharges of any patients with heart failure with reduced ejection fraction being discharged on an SGLT2 inhibitor.

And this is really a call to action to figure out what are the systems based approaches where we can be prompted to or motivated to get people on this very favorable, risk reducing therapy overall.

[00:52:15]

          Challenging Traditional GDMT Initiation

So this opens up a whole broader discussion about guideline-directed medical therapy. And the traditional approaches we have taken in heart failure not unique to SGLT2 inhibitors, and the challenges in realizing many of the benefits that Javed outlined by using a traditional approach. And our old tried and true was starting people on vasodilators to unload the ventricle, titrating people to the maximally tolerated dose of one drug before conceivably even adding other drugs. You might add a beta blocker afterwards, start at a low dose, titrate slowly, but in a methodical way upward, or in some cases not titrate at all.

You would be checking a box saying they're on a beta blocker, but they may not be at the target doses that were in the clinical trials. And in fact, some approaches may even consider only adding additional medications, if needed.

They are having ongoing symptoms, blood pressure challenges, heart rate control. And this is a very common. And at least in my career, this was a way that was more commonly taken for heart failure. And we've seen a wealth of data countering this approach overall.

[00:53:19]

          Consequences of Traditional Sequencing

So what are the consequences of this more traditional sequencing? It takes a long time to get people on guideline-directed medical therapy, now our 4 core pillars of therapy, at least if we are talking about heart failure with reduced ejection fraction. And some people may even beg the question, are there clinical benefits of having multiple agents on board? Having multiple agents on board does have an impact, even at relatively low doses, and the benefits of morbidity and mortality may be not realized for a longer period of time if you do not take that approach.

Collectively, there is a missed mortality benefit. There is a missed morbidity benefit by this traditional sequencing approach.

[00:54:00]

          The Need for Speed

So this begs the question about the need for speed. And this is a pictorial display of a fictitious but all too real approach that may be taken by certain clinicians on the conventional sequencing approach. You may start with an ACE inhibitor or an angiotensin receptor blocker, add a beta blocker, add an MRA, potentially switch their ACE inhibitor ARB to an ARNI and then potentially add an SGLT2 inhibitor.

And I want to call out the fact that there are various different permutations or approaches that may be taken on that traditional approach, but it may take weeks, months, and in some cases, it may never come to fruition that people are on core therapies at target doses.

And on the right-hand side is one of several approaches that can be taken even over short periods of time as little as 6 weeks, 8 weeks, 10 weeks to be able to rapidly sequence people either to get on a drug, yes or no. And for drugs that have target doses beyond the initial starting dose to titrate people to those doses. And this is just 1 example of a proposed schema to be able to facilitate rapid sequencing.

What we lack is the timeline along the equivalent of the y-axis, with the rapid sequencing happening much, much faster.

[00:55:13]

          Why Is Rapid Initiation in HFrEF Important?

So why is rapid initiation in HFrEF? And I would argue even more broadly in heart failure important is because many of the benefits observed with key pillar therapies, beta blocker, ARNI, or angiotensin receptor neprilysin inhibition, mineralocorticoid receptor antagonism, and SGLT2 inhibitors. These benefits are realized by the outcomes in the middle column here, many of which were outlined with regard to SGLT2 inhibitors by Javed.

But there is substantial relative and absolute risk reduction in these patients as a result of getting on these drugs and clinical benefits, not the full magnitude, but clinical benefits associated with these drug classes are apparent even as short of a time frame as one month, 30 days of initiation.

So essentially, the faster you get people on these therapies, the faster they realize the cumulative benefits, either up front or over time with these therapies.

[00:56:09]

          Posttest 2

So another post-test question. This is the same question you saw earlier. How often do you plan to use a rapid sequencing approach when initiating medications in patients with heart failure?

1. Never;
2. Rarely;
3. Sometimes;
4. Often; or
5. Always.

Please key in your answer. Fantastic. And I do remember the very brief showing of the pretest question. It looks like we have been able to shift substantial numbers of people, regardless of which category. Maybe they are even jumping to a even lower category, doing it more often overall.

[00:56:51]

          STRONG-HF: Uptitration of Guideline-Directed Medical Therapies for Acute Heart Failure

So is there data for rapid titration of medications? There in fact is. And this is the STRONG-HF trial. For those less familiar with this, this was a trial that looked at comparing in individuals with heart failure, not yet on full doses of guideline-directed medical therapy. Could you facilitate randomization to in blue treatment intensification with a beta blocker, ACE inhibitor, ARB or ARNI and MRA?

And I want to call out the fact that this trial was conducted largely in an era when we had not fully incorporated SGLT2 inhibitors into our treatment armamentarium as much as we should today. And this was done essentially in a very rapid sequence with a goal of looking at endpoints 180 days versus just usual care left to the discretion of the managing clinician.

The primary endpoint in this trial was 180-day composite of heart failure readmission or all-cause mortality and other endpoints. Secondary endpoints are listed below that as well in this trial.

[00:57:50]

          STRONG-HF: Target GDMT Doses in High-Intensity vs Usual Care

So this looks like a busy slide, but I think it will become clearer very quickly. The high-intensity care group or that intensive treatment approach of getting people on core therapies as quickly as possible is shown in the spectrum of orangish reddish colors, with the darker colors getting into a magenta reflective of getting to optimal doses. And the usual care is more in the bluish color, with the darker blue getting to full or optimal doses of these medication classes.

On the rightward side, ACE inhibitor, ARB or ARNI is grouped together as one category, evidence-based beta blocker in the middle and MRA to the far right. And what you can see in this pictorially, but also in terms of the numbers, more patients in the high intensity randomized arm receive target doses or getting on drug therapy with regard to guideline-directed medical therapy at 90 days compared to those in the usual care group.

And that was super demonstrable with the ARNI/ACE inhibitor, ARB group, beta blocker group, and the MRA group as well, and is striking in terms of the rates of use of MRAs in this trial, in those in the intensive or high intensity group compared to what we see as background therapy in many heart failure trials today.

[00:59:02]

STRONG-HF: All-Cause Mortality

What was the cumulative effect of that? More patients in the high intensity group felt better and lived longer. On the right-hand side, you'll see the probability of event-free survival out to 180 days comparing the usual care group and the high-intensity care group with a substantial effect size, both in terms of absolute and relative risk reduction in this trial.

There was a higher likelihood in the intensive group to shift to a better functional class, Class 1 or 2. That primary end point reduction had a delta of about 8% in terms of the cumulative effect of death or heart failure hospitalization. And heart failure readmission was essentially almost cut in half by day 180.

So essentially this trial was terminated early because of a larger-than-expected effect size. But the bottom line is getting people on these therapies as quickly as possible, and that includes, at the time of discharge, will realize those benefits early on. And if you are working at hospitals, as I suspect all of us are, that are keenly focused on reducing 30-day readmission, let alone other key outcomes, this can be a key tactic in facilitating that overall.

[01:00:06]

Concerns in Patients With and Without T2D When Using SGLT2 Inhibitors

So I'm going to close out this session with a sort of a hodgepodge of the concerns in patients, regardless of whether they do or don't have type 2 diabetes when using SGLT2 inhibitors focused on genitourinary infections, both bacterial and fungal. Hypoglycemia risk, and then diabetic ketoacidosis that may be associated with either hypoglycemia or euglycemic states overall.

[01:00:30]

SGLT2 Inhibitors and GU Infections in Patients With HF

So let us dive in really quickly with SGLT2 inhibitors in genitourinary infections in patients with heart failure. This is a busy analysis, but it highlights what is listed there as genital mycotic infections, as GMI either uncomplicated or all group versus complicated urinary tract infections, and then sort of the cumulative effect that led to discontinuation of the drug.

And at least numerically, you can see across the different groups whether we are talking about reduced or preserved ejection fraction, there are greater rates overall of urinary tract infection. Small absolute differences in some respects, but there is a numerically greater rate of these types of infections for people being on an SGLT2 inhibitor.

In these trials, we will talk about tactics that should be taken, but it is really important to inform patients of this. And patients being initiated on SGLT2 inhibitors should be made aware of the potential risks of either bacterial urinary tract infection or genital mycotic infections. And then we are going to talk in a second about how to mitigate that overall.

[01:01:32]

Mycotic Genital Infection and UTI Risk Factor Assessment Prior to Starting SGLT2i

So how do you approach an SGLT2 inhibitor in somebody that may have a current infection, either urinary tract, bacterial or mycotic infection? And then what do you do if they develop one?

So I am going to start at the top of this flow diagram. And if somebody has an active fungal or bacterial infection, they have had recurrent infections and/or they have autosomal dominant polycystic kidney disease, you really in those situations should not be initiating a SGLT2 inhibitor. Certainly in those that have an active infection, you want to wait until that infection abates. But for those that have demonstrated in the absence of an SGLT2 inhibitor, recurrent infections to begin with, or polycystic kidney disease, this class should be avoided.

On the right-hand side, if they do not have that, initiate the SGLT2 inhibitor and you want to assess and mitigate risks overall.

On the left-hand side, just if you did not initiate an SGLT2 inhibitor because of an active infection, you should consider initiation after they have been treated for their infection and their infection is resolved. And if you are uncertain about the pros and cons about an SGLT2 inhibitor in someone who has had recurrent infection, really reassess with specialist infectious disease input to help guide that decision making.

On the right-hand side, if in fact someone gets initiated on an SGLT2 inhibitor and they develop a mycotic infection or a bacterial urinary tract infection, but it is an uncomplicated infection in general, you can continue their SGLT2 inhibitor with close observation of that patient and their infection status.

Obviously, if they have a complicated infection, you should stop the SGLT2 inhibitor, treat the infection. And as is shown in the dotted or dashed line to the right, you should plan to re-initiate. And so, in your mind, looking forward when this infection is resolved, you want to reevaluate all the risk factors. Obviously, optimize all modifiable risk factors to mitigate the risk of recurrent infection, re-educate about proper hygiene, and then really have a shared decision making discussion with the patient about this.

[01:03:32]

          GU Infection Prevention in SGLT2 Inhibitor Use

So how can you prevent genital mycotic infections, urinary tract infections in this patient population? It starts with raising awareness and making it clear that patients are at risk for this, and therefore should be made aware about tactics to prevent it. That is listed in the sort of the second bullet here is providing practical hygiene advice to patients and their partners about preventing genital infections, including rinsing and drying the genital area after using the toilet and before going to sleep, and topical treatments or appropriate oral treatments can be helpful in mild to moderate infections.

When candidiasis occurs, it is usually mild. In the vast majority of cases, it is usually responsive to treatment. It is uncomplicated, and you can continue the SGLT2 inhibitor throughout. Recurrent infections, despite appropriate hygienic approaches, may necessitate reassessment of therapy and consultation with a specialist.

[01:04:25]

          Hypoglycemia Rates With SGLT2i in Patients Without T2D

I want to pivot to hypoglycemia with SGLT2 inhibitors. And in contrast to what I just talked about with genital mycotic infections and urinary tract infections, we really observed similar proportions of rates of hypoglycemia in patients in these trials randomized to an SGLT2 inhibitor versus placebo, especially in those without type 2 diabetes.

So it reinforces the fact that the likelihood of experiencing hypoglycemia in these patients is low, and there are no appreciable differences between those getting an SGLT2 inhibitor versus those who were not.

In general, because those rates were low in patients without type 2 diabetes, what about in patients with type 2 diabetes? And this speaks to the potential for potentiating hypoglycemia in those that may be on background therapy that they are receiving to lower their blood sugars, namely the use of oral agents like a sulfonylurea and/or insulin. And concomitant use with these classes when adding an SGLT2 inhibitor to it can potentiate hypoglycemia and involves, importantly, a discussion with whoever is managing their insulin, their oral sulfonylurea to adjust their medications.

[01:05:39]

Proposed Insulin and Other Diabetes Medication Adjustments When Initiating SGLT2 Inhibitor Therapy

So how do you about approach implementing this in practice? Again, I want to reinforce in the absence of type 2 diabetes, in the absence with diabetes of an oral sulfonylurea or insulin, SGLT2 inhibitors rarely cause hypoglycemia. But if they have a history of hypoglycemia, you should consider reducing the dose of those alternative hypoglycemic agents. If they are on a sulfonylurea, repaglinide or insulin, there is a potential risk for hypoglycemia. Their estimated GFR, A1C, may all inform decision making about decreasing the doses of these other drugs that are intentionally used to lower blood sugars. And you can see, based on an estimated GFR or an A1C, what recommendations may be put forward overall.

[01:06:26]

          Ketoacidosis Concerns With SGLT2 Inhibitors

And I am going to round this out with talking about ketoacidosis. And for those of you less familiar, ketoacidosis is a rare but potentially life-threatening condition. Its risk seems to be potentiated by those that restrict or have poor food intake, have severe dehydration, acute medical illness, surgery, or alcohol use.

And I will acknowledge these things can go hand in hand. Somebody who develops a case of gastroenteritis is having vomiting doesn't feel like eating. That's their acute medical illness may be a setup for this overall.

Importantly, we have traditionally thought about diabetic ketoacidosis as occurring in the setting of very, very high blood sugar levels. But patients can present with ketoacidosis even in the presence of only mildly elevated or even normal blood sugar levels. So simply finding out that the patient does not have significantly elevated blood sugars in a patient suspected of having diabetic ketoacidosis should not dissuade you of the diagnosis. And serum ketones should be measured to help detect rare cases of a normal anion gap acidosis.

On the leftward side, you can see a number of the symptoms that can be at least hallmarks of diabetic ketoacidosis or even euglycemic ketoacidosis, confusion, nausea, excess thirst, difficulty breathing, vomiting, abdominal pain, fatigue. And importantly, on the right-hand side if ketoacidosis is suspected or diagnosed even before you have confirmed the diagnosis, the SGLT2 inhibitor should be discontinued immediately. Immediate medical attention should be initiated for this patient to get appropriate treatment for their diabetic ketoacidosis.

Attention to directing that with reinitiation or consideration of reinitiation of the SGLT2 inhibitor, particularly if it was playing a more innocent bystander role, but was contributing insofar as something else triggered the event, but they were on the SGLT2 inhibitor.

[01:08:21]

          Dosing Considerations in Patients With HF

From a dosing considerations, I am not going to read through all of this, but it lists for empagliflozin, dapagliflozin and sotagliflozin what the recommended doses are for heart failure patients overall. I do want to call out and distinguish this from the fact that doses used for lowering of blood sugar do differ between these different agents. And so the recommended doses are listed here for you.

[01:08:48]

          Diuretic Considerations With SGLT2 Inhibitor Use

From the standpoint of diuretic considerations, many patients, an overwhelming majority of patients with heart failure across the left ventricular ejection fraction continuum are often on a diuretic, most often a loop diuretic. The SGLT2 inhibitors can have a diuretic effect. And so as a result of that, should you be adjusting their diuretic dose? This shows a brief report out of a meta-analysis of 8 SGLT2 inhibitor cardiovascular outcomes trial, and noted that volume depletion was observed in essentially an equal percentage of people on an SGLT2 inhibitor compared to placebo.

There was in DAPA-HF an excess of volume depletion in patients taking an SGLT2 inhibitor with doses of diuretic equivalent to or greater than 40 mg per day of furosemide, or an equipotent dose of an alternative loop diuretic overall.

And attention to volume status is required, and this is true not only for SGLT2 inhibitors, but ARNIs and loop diuretics, as they may potentiate each other's effects in driving a pronounced diuretic effect. And one wants to just make sure that one's attentive to that in adjusting, in particular, the dose of a loop diuretic when warranted.

[01:10:00]

          Diuretic Dose Adjustments

This is just a look at the frequency of adjustment of diuretic dose in EMPEROR-Reduced reduced and EMPEROR-Preserved on the left and right, respectively. And it is just important to call out, and I think Javed made at least some comments about this is to say, in most cases with these trials, it did not require any protocol mandated diuretic adjustment overall.

Overall, in the vast majority of cases, particularly for people that have a net excess of volume, you derive the added benefit of a diuretic effect of SGLT2 inhibitors in patients that are euvolemic, and certainly on multiple medications that may potentiate a diuretic effect, you want to follow their volume status very closely.

[01:10:41]

          Surgery Considerations With SGLT2 Inhibitors

Lastly, I think surgery considerations with SGLT2 inhibitors. When people go to the operating room, they may be nothing by mouth. They may have restricted food intake or dehydration. They may have changes in their insulin requirements. And therefore, collectively, the patient undergoing in particular general anesthesia is at higher risk for ketoacidosis. These patients should be closely monitored, and in some cases, monitoring the blood ketones may be warranted. For these individuals, there is recommendation that treatment with SGLT2 inhibitor be interrupted and use of blood ketones as dictated by the managing team to monitor for ketoacidosis obviously on the back end of reinitiation normal fluid and food intake, reinitiation prudently for the SGLT2 inhibitors there afterwards.

You can see on the right hand side, in most cases, after their condition is stabilized, blood ketones have returned to normal, and it has been at least 24 hours consider reinitiation overall.

[01:11:34]

          When Should SGLT2 Inhibitor Therapy Be Paused?

So when should it be paused? This is sort of a summary slide just highlighting acute medical illness, acute worsening of heart failure or other illnesses, having a condition that could potentiate volume depletion or dehydration, a setup for ketoacidosis, having a major infection, whether that's a urinary or a genital mycotic infection or an infection elsewhere, or they're hospitalized for major surgical procedures.

[01:12:01]

          Case Study: Barbara

And I am going to revisit Barbara just as a tee up for Lauren, who is going to be coming on in a second here. All of this helps to frame the discussion, and I know it is a lot to cover when educating Barbara after you have written the prescription, but some questions that one may come up against with a patient like Barbara or other patients is what would one do if she is unable to afford an SGLT2 inhibitor?

Barbara told you she could, but what if she could not? And what approaches should be considered as part of discussion if she were hesitant to start an SGLT2 inhibitor?

And importantly, these drugs are only as good as patients remaining on them. So how do we ensure adherence to these therapies, not unlike all of our other heart failure therapies, to derive the benefits that Javed so nicely summarized.

So with that, I am going to turn things over to Lauren to round out this final section and we will be sure, I am just going to call out, have lots of questions, put them in the chat in the Q&A section because we will have time for Q&A. Lauren, I am going to get to you.

[01:12:57]

Strategies for Patient Counseling About the Benefits and Adverse Effects of SGLT2 Inhibitors

Dr Eyadiel: Thank you, Ty. I really appreciate Javed, you laying a foundation, and then Ty, you layering even further data for practical implementation and the importance of implementation of SGLT2 inhibitors for our patients with heart failure.

So now we are going to change gears and talk about how do we counsel our patients on the benefits and adverse effects of SGLT2 inhibitors with some practical tips on how to get these from the bench to the bedside.

[01:13:28]

          Poll 4

So a fourth polling question here. When discussing the use of an SGLT2 inhibitor with a patient, which topic do you address first?

1. Rationale for use in patients with heart failure;
2. Mechanism of action;
3. Guideline recommendations;
4. Implications from a cost perspective;
5. Potential adverse effects; or
6. Something else.

All right. Let us take a look. So it seems like the overwhelming majority here is really kind of honing in on the rationale for why we use these in patients with heart failure, as well as what our guidelines say.

[01:14:13]

          Shared Decision-making

So let us talk a little bit more about that. I think many times we have thought of delivering or recommending something for a patient historically as like this is our recommendation, this is what you should do. But there is really a shift now regarding the importance of shared decision making.

So when we think about having our patients use an SGLT2 inhibitor, I think what is really important is that we involve them in the process. So we want our patients to be engaged and empowered in the decision-making. I always tell my patients that it is fundamentally my job to give you all the information that you need to make the best decision for you in terms of your medication and your treatment and heart failure.

So ultimately, I am not the one that is living day in and day out with implications from a cost perspective or adverse effects, things like that. And so I think it is really important that we collaborate with our patients.

So we want to empower them to make the decision. We want them to have all the tools that they need, translate it into a way that they can understand, regardless of their health literacy and making a decision for what is best in their care.

So we also want to tell them what are their alternative agents, and then what is the data that supports the use of those agents. Are we giving them the option between SGLT2 inhibitor and loop diuretic from a heart failure, hospitalization, reduction perspective. And then what is the additional benefit to using that SGLT2 inhibitor that makes it so superior to a loop diuretic alone?

And then we need to really work with our patients to incorporate what are their visions, their goals, and their needs from a treatment plan perspective into our overall care and our plan for them.

[01:16:02]

          Utilize Educational Infographics

So one thing that we can use that is really helpful with patients, I think, in really introducing and focusing on these new and oftentimes more expensive tools in our toolbox for the management of heart failure are things like infographics. So we have provided you with one that you can use, that is really helpful in talking with your patients and reading through together when you are talking about initiating an SGLT2 inhibitor.

So I would encourage you to use the QR code on the screen that translates into a PDF. And then consider copying these, keeping them in your clinic. Because oftentimes with some of these newer or more novel therapies for heart failure, even though the data is overwhelming for their use and for their benefit, patients like a minute or some time to think about that. So oftentimes you can send a patient home with this as well as a prescription and have them either follow up with additional questions, or let you know if they are ready and open to considering that therapy.

[01:17:08]

          SDM Is Not the Typical Way Healthcare Professionals Make Decisions With Patients

So we as healthcare professionals usually do not use this shared decision making model, right? So we have Gen Z now, right, in the millennials who have a great desire for transparency and to be involved in their care.

So before the year 2000, about 50% of people preferred a shared decision making model. But now we are seeing from the 2000 on. So in the past 24 years, that has increased by 1.5 times to 71%, give or take. So this is the wave of the future. And so it is a good opportunity for us to practice and get accustomed to using this model.

So people want us. Our patients want us to listen to them. They want us to do more than to just hear them. They want us to really listen. But we are not as good at that as we might think we are. And so I think at times, too, we think or go in with biases about what we think patients can do and what we think is feasible for them or reasonable.

But our patients really want the truth, and clear terms that they can understand. And then some autonomy in the decision making for their own healthcare. So we have a great opportunity to do that in initiation of treatment of heart failure across the spectrum with SGLT2 inhibitors.

[01:18:32]

          Talking Points for Discussing SGLT2 Inhibitors in Patients With Heart Failure

So what are some talking points? I usually like to start the conversation with the data, right? So, yeah, this drug, just like Javed told us about, was originally created for people with diabetes. But in the big heart safety trials for diabetic medications, we actually found that patients with heart failure got better with this. So then we did some big studies for patients with and without diabetes. And we found that this medicine was good for all comers with heart failure.

And helping you live longer, feel better and stay out of the hospital with heart failure, which are all really compelling reasons to take a medication.

In addition, we can talk to them, especially in patients who have pre-existing low blood pressure. This is a drug that has minimal to no effect on blood pressure. And it is something that you can add, pretty easily for these patients.

We can talk about what is the mechanism of action. So sometimes I talk about how this medicine was created for diabetes because it worked by having patients urinate or pee sugar, right? And so that gives it a bit of a diuretic effect, which in turn may have the potential to replace something like one of the medications that you are already on.

And then we are going to take a little bit more time to explore cost and what options we have with these medications.

[01:19:54]

          Example Sentence Starters for Discussing SGLT2 Inhibitors With Patients

So there is lots of ways that you can start the conversation with shared decision making. But I think the most important part is to meet your patient, whomever they are, wherever they are, where they are. So if it is a patient who is coming to you, who is a professor at a university, let us give them the pitch that Javed gave us. Let us give them the data. Let us show them the Kaplan-Meier curves. That might be the best way to meet them.

Whereas there are many other patients with heart failure whose health literacy is different that we need to approach with some of these ideas and speaking very simply, in layman's terms for them to understand.

So I think it is always important that we are very honest with our patients. I find that the more honest I am with my patients, the more that they trust me, especially when initiating medications that we know have side effects.

So I am very honest about the potential for genital urinary infections and what that might look like. I find that the more you have people look out for them, the more trust you build with your patients, because then they know that you have anticipated this concern on their behalf, right?

[01:21:12]

          General Patient Counselling Points for SGLT2i Possible Adverse Effects

I talk with them a little bit about the symptoms you see, or the adverse effects you see on the screen of orthostatic hypotension, avoiding alcohol use specifically as 2 things that are risk for any patients with heart failure, right? So orthostatic hypotension can happen in dehydration with loop diuretics. So would not it be better for us to try this other medication, right, that has been shown to help you live longer, feel better, stay out of the hospital with heart failure and watch your fluid intake and adjust that loop diuretic as needed to tolerate that. So talking about the potential for dehydration with the diuretic effect of this medication.

And really we want all patients with heart failure to avoid excess use of alcohol. And so this is one of those things that is an all comer for patients with heart failure as well.

And as Ty talked about, we do need to hold these before surgery. And we do need to educate our patients on those symptoms of DKA that can be euglycemic or hypoglycemic.

[01:22:14]

          Posttest 3

So let us take a third posttest question here. When discussing an SGLT2 inhibitor in a patient with heart failure, which of the following counseling points should you provide?

1. SGLT2 inhibitors greatly decrease blood sugar values, and you need routine monitoring for low blood sugar;
2. Can cause kidney damage and should be held with any decrease in the health of your kidneys;
3. Have negligible effects on blood pressure and are safe to use in combination with other blood pressure lowering medications; or
4. May cause fungal infection and should be stopped, if one occurs.

All right. Let us see how we did. So it looks like a lot of us have chosen here may cause fungal infection of the genitals and should be stopped, if one occurs.

So let us kind of revisit that option. So actually it may, you are right. It may cause fungal infections but it does not necessarily need to be stopped if one occurs. And so I think that that is the key to making choice D incorrect is that it should not necessarily be stopped if one occurs. We see that if this is a recurrent issue and we are not able to control it with improvements in hygiene, or simple over the counter treatment. If we are able to do that and it never happens again, we should move forward and move on.

I have also found, anecdotally in my clinical practice that patients who develop these fungal infections or who have GU mycotic infections, oftentimes have very poorly controlled blood sugar. And if we are able to get their blood sugar better control, they are better able to tolerate the SGLT2 inhibitor without that side effect.

But I think what we really want to focus on is that the SGLT2 inhibitor really has negligible, impact on blood pressure, and we can safely use it with medications like ARNI, MRAs and beta blocking.

[01:24:28]

Posttest 3: Rationale

So when we look here, right. So SGLT2 inhibitors do not increase the risk of hypoglycemia, okay? We just need to be careful and utilize multidisciplinary collaboration in patients who are very well controlled diabetics who are either on a sulfonylurea or insulin. They do not cause renal damage. In fact, they are renal protective. And while they can potentially cause mycotic infections, this should not preclude the use of the drug. And in fact, we should try additional things to see if we can compensate for that side effect and continue the use of the medication, and only consider discontinuation if this is recurrent and significantly interfering with our patients quality of life.

[01:25:17]

          Financial Toxicity in the Management of Heart Failure

So now let us talk a little bit about financial toxicity, right. So we have got a condition now heart failure with reduced ejection fraction where we have given you and shown you today compelling data for 4 drugs and 4 weeks, right? Two of those drugs at least, which can be cost prohibitive. And at least 2 drugs, if not more, in heart failure with preserved ejection fraction.

But we know that these SGLT2 inhibitors can be quite cost prohibitive. And so I think things that we need to think about is, is beyond the multiple medications that we need to manage this condition. And reverse the damage done in patients with heart failure across the F spectrum. And think about scale out a little bit, take a 30,000 foot view and say, this is not just their medications. This is what their insurance premium are. What about their hospital co-pays?

They will easily meet their out-of-pocket max with a heart failure hospitalization. What about their specialist copay to come see cardiology or people like that in the outpatient world? And so we really need to do our best to try to synergize care for these patients, to limit the cost as much as possible.

So are there opportunities for telehealth? Are there opportunities to reduce transportation costs or consolidate laboratory testing? And then we are going to talk a little bit more about some great strategies on how do we reduce the cost of these lifesaving medications.

[01:26:59]

          Insurance Coverage of SGLT2 Inhibitors

So when we look at insurance coverage for SGLT2 inhibitors, you will notice here that regardless of insurers for dapagliflozin and empagliflozin, it appears that the coverage is very good, greater than 80% for most insurer options, right?

And what I think is an important distinguishing factor here is coverage does not translate into affordability. So coverage may come with a significantly high unaffordable copay. so I think that that is really important to consider that, yes, Medicare covers it. But yes, Medicare has a donut hole. And that coverage may be at the cost of $500 or more per month for your patients on a fixed income.

So the reality is we still have to get prior authorization as the graph to your right will show for most comers who are needing an SGLT2 inhibitor. But we really need to focus on that while we have coverage, what does it mean in terms of affordability for our patients who need these SGLT2 inhibitors.

[01:28:12]

          Average Costs for SGLT2 Inhibitors and Strategies to Decrease Costs

So the average cost you will see here for SGLT2 inhibitors are most popular at this point in time would be dapagliflozin and empagliflozin, are in the about $750 to $800 for a 30-day out of pocket, no insurance cost. If you look under the GoodRx column here, largely unaffordable to the majority of our patients that are living with heart failure.

Empagliflozin with Medicare Part D comes down a little bit to $45. But if you really think about what does that look like practically for your patients who are on multiple medications, it is easily unaffordable very quickly. So what can we do?

So what can we do to help get these from the bench to the bedside? Well, I think there is a lot of things that we can do. We can do things like patient assistance programs. So we can fill out paperwork for patients who meet the qualifications for patient assistance directly with the pharmaceutical companies that provide these drugs, that can really help bridge the gap, especially for our patients with Medicare.

And I think we can continue to advocate for our patients. And I think all of us in the heart failure, advanced heart failure space have a lot of hope for some of these medications which are in place with the Medicare, the Biden-Harris administration Medicare, cost reduction medications that will be implemented in 2026. So there is a negotiated lower cost for these drugs.

So if we can kind of get our patients through the next year's Medicare beneficiaries, which are the most challenging, then we may have some opportunities to make these medications more affordable for them at that time.

[01:30:05]

          How to Approach the Patient Who Declines SGLT2i Use

So how do we approach our patients who say no, right? I think the first and most important thing to do is to listen why are they declining the drug? And if we can understand why, then we can help bridge the gap and help get them to a place where they may be amenable to consider it.

We can look at other options. We really do want to look at these, especially for patients who are having frequent heart failure hospitalizations and compare the cost of the drug to the cost of going to the hospital for heart failure, and how that may actually be a more cost benefit analysis in favor of the patient.

We should continue to treat our patient with everything we have got, even if they do decline use. And then we need to revisit this. We need to not always just say this is a one and done thing. I like to take the kind of look of saying, okay, well, I am going to give them a visit off for my hard sell for 4-drug therapy. And then at their next visit, we are going to go for it again.

So just trying to remind yourself, even in your documentation, we will discuss again with patient at their next visit.

[01:31:21]

          SGLT2i: The Ideal Heart Failure Therapy

So all of that to say. So SGLT2 inhibitors, it is a great drug for all comers with heart failure. across the spectrum of ejection fraction. It is a one pill a day. My patients tend to love this because they feel like it works more consistently over the course of the day versus kind of that take it and have frequent urination that the loop diuretics do. It helps you live longer, feel better, stay out of the hospital with heart failure. All good things.

It is safe, well tolerated and renal protective, as well as minimal to no effects on blood pressure. And it really is affordable. And we are able to get this to our patients if we use a little bit of creativity, and I think each and every one of us takes great joy in giving our patients what they need when it seems like all bets are against them and being able to afford it.

So I will hand it back to Ty for our question and answer session.

Q&A

Dr Gluckman: Lauren, that was fantastic. That was really great. We have got about ten minutes and I am going to encourage the audience, if you have not put in questions and you have them, you can put them in the Q&A section. You can put them in the chat. Javed, I am going to start with you with a little bit of a provocative question. In my section, I highlighted the fact that the Europeans, they specifically name the drugs that have evidence based on clinical trials. You nicely showed it with dapagliflozin, empagliflozin and sotagliflozin.

Should we think of these as a class effect? As the US guidelines have listed it as SGLT2 inhibitor. Should we prioritize those specific drugs that have randomized controlled trial evidence. How do you approach this in your practice?

Dr Butler: I do not know an acceptable answer, Ty. So this is really complicated, right. And the reason why it is complicated is that, as clinicians, we would love for everything to be a class effect because it just makes it easy. You do not worry about insurance and coverage and whichever drug within a class is available, you just give it.

The problem is that there are molecular differences. That is why there are different drugs, even if they have their majority of mechanism of action the same. And when we have assumed that all the drugs are the same in the past, we have been proven wrong multiple times. I will just give you 2 very quick examples within the heart failure space.

One is beta blockers, as we know that with carvedilol, long acting metoprolol and bisoprolol, we had positive trials, but we did not achieve significant improvements with bucindolol and nebivolol. And that then raises the question, what do you do with like the tenolols of the world for which there is no data? Do you assume they are like carvedilol, or do you assume they are like bucindolol? So we do not know that.

Another example is in the diabetes space is with DPP-4 inhibitors. So with saxagliptin you worsened heart failure risk. With alogliptin you also worsened, although it was not statistically significant but clearly going in the wrong direction. Whereas with linagliptin and sitagliptin, it was completely safe. So there are enough differences.

So I would say that the best option is to stick with SGLT2 inhibitors, for which we have clinical evidence. But if you are in a practicing setting that there is just no SGLT2 inhibitor available which has been tested, then giving something is a better idea than not giving it just because there was no trial.

Dr Gluckman: It is a great answer. And Lauren, I am going to turn to you building off of that. Do you go through if someone says, I cannot afford, are you naming off 2 SGLT2 inhibitors to check the out-of-pocket cost. And to Javed’s point, something is better than nothing. So you will go through, for example, if they cannot afford dapagliflozin and empagliflozin, sotagliflozin, you are then going to bexagliflozin, canagliflozin, ertugliflozin and exploring perhaps because of the vagaries of what is covered by a plan, what you can get them on?

Dr Eyadiel: Actually, I think one of my favorite parts of being an advanced heart failure is the opportunity for creativity. So a lot of times I will see is dapa or empa cheaper? And then I will prescribe the high dose and have my patient take half a tablet, so I can double the duration of their medication while helping with the affordability.

I find that I have a lot of success with patient assistance programs if my patients can bring in their paperwork. I always say it is easy if you have commercial insurance, there is a $0 co-pay card. It is easy if you have Medicaid. And you can just do your prior auth there, 4 bucks. It is easy if you have no insurance because they are totally going to qualify for patient assistance.

But if they have that Medicare, that is when we have to get really creative and implement some of those activities. But I find it difficult to convince myself to give them a non-data driven drug in that space when that one is still probably going to be cost prohibitive.

Dr Gluckman: And I am glad you brought up those other issues, because it is not necessarily intuitive to folks that somebody without insurance or insured under Medicaid may actually have better coverage and be better equipped to be able to get on it. So it is a great call out.

A question that I can answer. Someone had asked about recurrent genital urinary infections or even a first one. Does it make sense to switch between SGLT2 inhibitors? Most of this is informed by the diabetes literature, and we see a consistency of the risk across the different drugs. So the party line is switching to a different SGLT2 inhibitor is less likely to mitigate the risk of a recurrent infection.

More importantly is to be able to institute hygiene education, be able to try and prevent those infections from occurring. And when needed, phoning a friend if it involves an infectious disease specialist for people with recurrent or complicated infections.

Javed, somebody had asked a question about whether or not hyponatremia has any influence on your decision to use an SGLT2 inhibitor, the magnitude of the treatment effect, and whether that severity of hyponatremia has any potentiating effect?

Dr Butler: Yes. So hyponatremia is a bad prognostic sign. So the person is at a higher risk. So obviously they need the therapy maybe even more urgently. But a quick physiology one on one. Remember that the SGLT2 receptors in the kidneys are coupled with sodium hydrogen exchange receptors. So there are dual mechanisms of diuresis. When we give a SGLT2 inhibitor there is natriuresis. But there is also osmotic diuresis related to glucose and glucose-related fluid loss.

In other words, the urine is not iso-osmolar. There is more free water loss than sodium loss itself. So if anything, if you are hyponatremic, your hyponatremia may get better because of more free water loss with SGLT2 inhibitor. So there is no reason for concern. And I would give it.

Dr Gluckman: Really helpful. Lauren, this is a practical question that probably involves all medications for people under Medicare Part D. But you started medication, patients able to get on an SGLT2 inhibitor hits the donut hole. People will hit at different times throughout the year. How are you preparing people for that? And I know you called out the Inflation Reduction Act and some mechanisms by which hopefully this will become less problematic, or the magnitude of the problem will be less. But how do you prepare people for that concept, especially if this is the first of perhaps some higher cost medications that may put them in that situation?

Dr Eyadiel: Yes. So usually day I start the drug, we give them the patient assistance paperwork. We say bring it back to your next visit, or send it on in to us through your portal in the interim. And what we do is we hold on to the paper and tell them to let us know when they go to the pharmacy, and they tell them that it is the last set of drugs that they are getting before the donut hole. So we have them ask their pharmacist every time, like, where are they, and to follow that really closely.

And then we immediately submit the patient assistance paperwork. So we come ready to go, have it all teed up and then send it out as soon as we hit that donut hole. We have also used strategies of going ahead while they are out of the donut hole, of prescribing the higher, strength and having them go ahead and start with half a tablet of empa 25 or dapa 10, to just kind of give them a longer duration of medication and really reduce that cost burden for them. But I think creativity is everything.

Dr Gluckman: I really like everything that you suggested. These are really practical things for all of us and affect many medication classes as well. Javed, I am going to come back to you with a provocative question. We have seen recent data with GLP-1 receptor agonists, at least in heart failure with preserved ejection fraction. Do you see that as another tool being added to our toolbox to support patients with heart failure? Do you worry about that having any influence on future SGLT2 inhibitor use?

Dr Butler: Yes. Like in the early 1990s, we had digoxin and diuretics. And when ACE inhibitor came that was in the end of treatment for HFrEF, right? I mean, huge breakthrough with ACE inhibitors, but substantial residual risk. And I think that is where we are in 2020 with SGLT2 inhibitors, because we have proven now that HFpEF is not an invincible disease. But there is a lot of different phenotypes within HFpEF and post SGLT2 inhibitor, there is a substantial residual risk.

The data with quality of life and functional capacity with GLP-1 receptor agonist in obese HFpEF patients is very encouraging. But the clinical events were relatively very few. So we really need long-term outcomes data and hopefully those will come in due time.

But I am just going to be very bullish and optimistic that those outcomes trial with GLP-1 receptor agonists will be positive. And I see that as an add-on to not a replacement to SGLT2 inhibitor, because there is substantial residual risk with either of the 2 and the combination therapy would be the way to go.

Stop: [01:41:59]