Circulation July 26, 2022 Issue

This week, please join authors Mikhail Kosiborod and
Christian Schulze and Editorialist Stefan Anker as they discuss
the original articles "Effects of Empagliflozin on Symptoms,
Physical Limitations and Quality of Life in Patients Hospitalized
for Acute Heart Failure: Results From the EMPULSE Trial" and
"Effects of Early Empagliflozin Initiation on Diuresis and Kidney
Function in Patients With Acute Decompensated Heart Failure
(EMPAG-HF)" and the editorial "SGLT2 Inhibitors: From
Antihyperglycemic Agents to All-Around Heart Failure
Therapy."


Dr. Carolyn
Lam:            


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg
Hundley:          


And I'm Dr. Greg Hundley, associate editor, director of the
Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn
Lam:            


I'm so excited about the feature discussion this week. It is a
paired feature along with their editorial and it's all focused on
SGLT2 inhibitors. The first, results from the EMPULSE trial,
Effects of Empagliflozin on Symptoms, Physical Limitations and
Quality of Life in Patients Hospitalized for Acute Heart Failure;
and the second, the EMPAG-heart failure trial, The Effects of
Early Empagliflozin Initiation on Diuresis and Kidney Function in
Patients with Acute Heart Failure. Incredibly important topics,
incredibly important discussion. Wait up for it. We're just going
to tell you a little bit more about two other original papers in
today's issue, and I'm going to go first, Greg. Is that okay?


Dr. Greg
Hundley:          


You bet.


Dr. Carolyn
Lam:            


Now, really interesting topic here. We have strong evidence
supporting the effective blood pressure and cardiovascular
disease risk lowering properties of healthy diet such as the DASH
diet, Mediterranean diet, and so on and so on. But what about the
diet consumed by a fifth of the entire world's population? The
Chinese cuisine. Interestingly, today's paper addresses just
that. This is from authors, Dr. Wu, from Peking University
Clinical Research Institute and colleagues who performed a
multicenter patient and outcome assessor blind randomized feeding
trial among 265 participants with baseline systolic blood
pressure of 130 to 159 in four major Chinese cuisines.


And these are the Shandong, Huaiyang, Cantonese, and Szechuan
cuisines, and here's how they did it. After a seven day run in
period on a control diet matching the usual local diets,
participants were randomized to continue with the control diet or
the cuisine based Chinese heart healthy diet for another 28 days.
The primary outcome was systolic blood pressure. The study
developed the first heart healthy Chinese diet that fits Chinese
food culture and emphasizes its palatability by involving master
shifts in developing the recipes.


Dr. Greg
Hundley:          


Oh wow. Carolyn, this is really interesting, especially one fifth
of the world's population in studying a heart healthy diet. So
did it work? I can't wait to hear the results.


Dr. Carolyn
Lam:            


Well, the change in systolic and diastolic blood pressure from
baseline to the end of the study in the control group was five
millimeters mercury and 2.8 millimeters mercury reduction,
respectively. The net difference of change between the two groups
in systolic and diastolic blood pressure were a reduction of 10
and almost four millimeters mercury, respectively. The effect
size did not differ among cuisines, and so in summary, with a
patient and assessor blind randomized feeding trial, this study
really demonstrated that the blood pressure lowering effect of
the Chinese heart health diet could indeed be substantial, and
importantly, be compatible with medications while palatable and
affordable in Chinese adults with high blood pressure, and so
these results support the idea that food is medicine and will
give many patients with high blood pressure the confidence to
adopt heart healthy diets in their lifestyle treatment.


Dr. Greg
Hundley:          


Wow, Carolyn, that is really an interesting article. So many of
these articles today could all be features in and of themselves.
That was just outstanding. Well, my next paper comes to us from
the world of preclinical science, and it's from Dr. Sean Wu from
Stanford University School of Medicine. So Carolyn, immune
checkpoint inhibitors are monoclonal antibodies that are used to
activate the immune system against tumor cells. Now, despite
their therapeutic benefits, immune checkpoint inhibitors have the
potential to cause immune mediated adverse events such as
myocarditis, a rare but serious side effect with up to 50%
mortality in affected patients. Now histologically, patients with
immune checkpoint inhibitor of myocarditis have lymphocytic
infiltrates in the heart implicating T-cell mediated mechanisms.
However, the precise pathologic immune subsets and molecular
changes in immune checkpoint inhibitor myocarditis are unknown.


Dr. Carolyn
Lam:            


Wow. So insights into the etiology of these immune checkpoint
associated myocarditis cases must be very important. So what did
they find?


Dr. Greg
Hundley:          


Right, Carolyn? So clonal cytotoxic, TEMRA CD8+ cells were found
to be significantly increased in the blood of patients with
immune checkpoint inhibitor myocarditis corresponding with an
analogous increase in effector cytotoxic CD8+ cells in the blood
and hearts of PD-1 deficient mice with myocarditis. These
expanded effector CD8+ cells had unique transcriptional changes,
including upregulation of the chemokines CCL5, CCL4, and CCL4L2,
and they may serve as attractive diagnostic therapeutic targets
for reducing life threatening cardiac immune related adverse
events in immune checkpoint inhibitor treated cancer patients,
and Carolyn, just like so many of our articles, there's a very
nice accompanying editorial by Professor Gianluigi Condorelli
that also offers an update on current research pertaining to
non-systemic steroid therapy to treat immune mediated
myocarditis. Well, Carolyn, how about we jump to some of the
other articles in the issue?


Dr. Carolyn
Lam:            


Oh, you bet, Greg. There's an exchange of letters between Drs.
Madias and Knops regarding the article “Efficacy and Safety of
Appropriate Shocks and Antitachycardia Pacing in Transvenous and
Subcutaneous Implantable Defibrillators: The Analysis of All
Appropriate Therapy in the PRAETORIAN Trial.”


Dr. Greg
Hundley:          


And also in the mail bag, Professor Mark has a Research Letter
entitled “Effect of Empagliflozin on Kidney Biochemical and
Imaging Outcomes in Patients with Type 2 Diabetes, or
Prediabetes, and Heart Failure with Reduced Ejection Fraction,
The SUGAR-DM-HF Study,” and our own Tracy Hampton has several
synopses from articles published elsewhere in our piece on
cardiovascular news. Well, how about we get onto that feature
forum discussion, two papers, two editorialists. I can't wait.


Dr. Carolyn
Lam:            


Me too. Let's go, Greg.


Dr. Greg
Hundley:          


Welcome, listeners to this July 26th feature forum discussion. So
remember, listeners, for forum discussions, we have several
manuscripts that focus on a singular topic and we bring together
the authors, our associate editors, and also an editorialist, and
today, I want to introduce, we have with us Dr. Mikhail Kosiborod
from Mid America Heart Institute in Kansas City, Missouri, Dr.
Christian Shults from University Hospital Jena in Germany, Stefan
Anker from Charité in Berlin, Germany, and our Associate Editors,
Brendan Everett from Brigham and Women's Hospital in Boston,
Massachusetts, and Justin Grodin from University of Texas
Southwestern Medical Center in Dallas, Texas. Welcome, gentleman,
and we'll start with you, Mikhail. Could you describe for us the
background information that went into the preparation of your
study and what was the hypothesis that you wanted to address?


Dr. Mikhail Kosiborod:  


Well, thanks very much, Greg. The background for the study, which
was the secondary analysis of the EMPULSE trial was patients that
are hospitalized with acute decompensated heart failure represent
a very high risk group. We know that they have high risk of death
and hospitalizations, and we also know that they have very poor
health status that's very high burden of symptoms, physical
limitations, and poor quality of life, and so addressing those
treatment goals, trying to reduce the risk of clinical events
like death and hospitalizations and improve the symptoms and
physical limitations in this patient population are very
important treatment goals.


Now we previously demonstrated in the main results of the EMPULSE
trials that using empagliflozin initiating empagliflozin SGLT2
inhibitor in this patient population as compared with placebo
provided a significant total clinical benefit, which was a
composite of total death, repeat hospitalizations for heart
failure, or a change in a Kansas City cardiomyopathy
questionnaire, which is a kind of a gold standard measure of
patient's health status. What we tried to do in a much more
granular fashion in this study is to understand the effects of
empagliflozin as compared with placebo on this very important
outcome, the Kansas City cardiomyopathy questionnaire, and we
actually evaluate all of the key domains and composite symptoms,
physical limitations, as well as quality of life.


Dr. Greg
Hundley:          


Very nice, and Mikhail, can you describe for us what study
population specifically, and then what was your study design?


Dr. Mikhail Kosiborod:  


Well, this was a population of patients that were hospitalized
with heart failure and that EMPULSE was unique in its design
because first of all, previous SGLT2 inhibitor trials mostly
focused on patients with chronic heart failures that were in an
outpatient setting, including prior trials of empagliflozin, and
EMPULSE really focused on acutely hospitalized patient
population, but it included patients regardless of ejection
fraction. So as they were hospitalized with decompensated heart
failure and reduced or preserved ejection fraction. They were
enrolled regardless of if they had type 2 diabetes, they were
enrolled essentially, regardless of kidney function, only
patients with EGFR of less than 20 were excluded, and also
importantly, was this study and a unique feature of the study in
particular was that we enrolled patients whether they had acute
de novo heart failure.


That means that was a new diagnosis of heart failure that was bad
enough for them to be hospitalized or worsening chronic heart
failure requiring hospitalization. So it was really an all-comer
trial for patients acutely hospitalized for heart failure. So we
had just over 500 patients and they were randomized in the
hospital. After a brief period of stabilization, we use
empagliflozin, 10 milligrams daily or placebo and treated for 90
days, and the primary outcome at 90 days was a total clinical
benefit that I described that was a composite, hierarchical
composite of total death hospitalizations, repeat
hospitalizations for heart failure and changing KCCQ. In this
study, again, we focused predominantly on KCCQ, trying to
understand the effects on health status, again, symptoms,
physical limitations, and quality of life.


Dr. Greg
Hundley:          


Excellent. And Mikhail, what were your study results?


Dr. Mikhail Kosiborod:  


Well, what we observed, a couple of things. One is we first
examined the effects of empagliflozin on the primary endpoint
across the range of KCCQ and baseline, and what we found was that
regardless of the degree of symptomatic impairment and baseline,
empagliflozin was consistent in providing them total clinical
benefits that I described previously, and then kind of shifting
to what I think is the most interesting findings, the effects of
empagliflozin versus placebo on KCCQ, what we found was that as
you would imagine in this population of patients that were
acutely hospitalized with heart failures, that had very poor
health status, very low KCCQ at baseline, and within the first 90
days, which was observation period, both groups of patients had
substantial improvements in KCCQs. As one would expect after
acutely decompensated episode of heart failure and treatment in a
hospital, everyone got better.


But patients treated with empagliflozin had significantly greater
improvement in KCCQs than those that were treated with placebo,
and that was first of all, a very substantial difference between
the two groups. It was more than five points in favor of
empagliflozin already at 15 days and was highly statistically
significant, and it was maintained throughout the 90 day
treatment period. So the fact that we saw both a clinical
meaningful and statistically significant improvement in just 15
days, I think is a very important clinical message, and then
finally, I guess what I will mention is these benefits of
empagliflozin while main outcome we looked at was KCCQ total
symptoms, we're focusing on the symptoms, but it was consistent
when we looked at physical limitations as well as quality of
life. So really, all key domains of KCCQ were impacted in a
similar way.


Dr. Greg
Hundley:          


Very nice. So in acute heart failure, marked symptomatic
improvement after the administration of the SGLT2 inhibitor
empagliflozin at 10 milligrams per day. Well, now listeners,
we're going to turn to our associate editor, Dr. Brendan Everett,
and Brendan, again, you have many papers come across your desk.
What attracted you to this particular manuscript?


Dr. Brendan Everett:     


Well, thanks, Greg, and I think this manuscript caught my eye
because of the importance of the clinical question, and Mikhail
outlined why I think that was really relevant. So we understand
that this class of medications or SGLT2 inhibitors have important
effects on outcomes like re-hospitalization in patients with
heart failure, and what was particularly striking about this
paper is that it took patients rather than those with chronic
heart failure, but as Mikhail mentioned, enrolled a patient
population that was actually in the hospital, and I think this
was an important frontier for this particular question about when
to start the SGLT2 inhibitor and what kind of benefits there
might be. Furthermore, I think the fact that they did not select
the population based on ejection fraction was particularly
striking, and of course, I think is remarkable, but now old news,
they did not select on the presence or absence of diabetes as
well.


And so those three components really attracted me to the paper. I
also think the outcome is one that really is valuable and worth
exploring, and specifically, I'm talking about how patients feel
on the medication after a hospitalization for heart failure.
Appropriately, we focused on re-hospitalization for heart failure
and cardiovascular death in prior trials in this space, and I
think we need to embellish those findings or further deepen those
findings with a perspective on how patients actually feel when
they get the medication, and of course, it goes without saying
that what's particularly important here also is that it was a
randomized placebo controlled trial, and so the results have some
element of internal validity that I think is really important. So
those were the things, Greg, that really attracted my attention
as I read the paper for the first time.


Dr. Greg
Hundley:          


Thank you so much, Brendan. Well, listeners, we've got a second
paper today and we're next going to hear from Dr. Christian
Shults, and he also is focusing on really another aspect of the
administration of empagliflozin in patients with acute heart
failure and that pertains to the renal function of the patients.
So Christian, could you describe for us the background pertaining
to your study and what was the hypothesis that you were intending
to address?


Dr. Christian Schulze:    


Thanks, Greg. Well, it's great to introduce all study here in
this running. So our study impacted those in acute decompensated
heart failure. The impact HF trial was a study based on the
hypothesis that we wanted to test, whether empagliflozin has
effects in acute decompensated heart failure, and we focused on
the patient population that was not addressed in EMPULSE,
patients that came to the ER and needed to be treated right away,
and we wanted to know and this was our main hypothesis, but are
the diuretic and [inaudible 00:17:11] effects of the SGLT2
inhibitor on this case, empagliflozin, actually had an impact on
diuretic regimens and kidney functions since this is one of the
main end points that limits treatment, and also is one of the
outcomes of patients with acute decompensated heart failure in
the hospital.


Dr. Greg
Hundley:          


Very nice. And so Christian, what study design did you implement
and who was included in your study population?


Dr. Christian Schulze:    


So we also used the randomized two arm study design. We included
patients with acute decompensated heart failure independent of
left ventricular ejection fraction. Patients needed to have an
NT-proBNP of more than 500. The average NT-proBNP in fact was
4,300 in our entire patient population, and we included patients
within 12 hours of presentation. So many of these patients have
been recruited in the ER, they presented two hour cardiology
heart failure service, and then were immediately randomized to
the trial in the two arms, and we tested not 10 milligrams of
empagliflozin. We actually tested 25 milligrams of empagliflozin
based on in-house data that 25 milligrams potentially had a
stronger diuretic effect compared to 10 milligrams.


Dr. Greg
Hundley:          


And what did you find?


Dr. Christian Schulze:    


So we followed patients for five days. It was a relatively short
period of time. It was designed to address the in-house phase of
patients with acute decompensated heart failure. The mean
duration of stay was 6.3 days in the hospital so this was exactly
the time that we wanted to test. We had a 30 day endpoint for
safety issues, and what we could see is that patients on 25
milligrams on empagliflozin on top of standard diuretic regimens
and medical care had 25% higher diuretic outputs compared to
patients in the placebo group. We also found no differences in
markers of renal injury dysfunction, and could in fact confirm
that after 30 days, patients in the empagliflozin group had a
better EGFR compared to patients in the placebo group. On top, we
saw a more rapid decrease in body weight and also a more profound
decrease in NT-proBNT values.


Dr. Greg
Hundley:          


And Christian, just for our listeners to put a little bit of this
in perspective, what was the range of serum creatinine for the
patients that were enrolled in your study?


Dr. Christian Schulze:    


So the main EGFR in the entire population was around 60 and the
creatinine values were around 107 on average in the entire
cohort. So this is a very typical population. We had around 30%
of the population with de Novo heart failure, around 20 to 30% of
the population was pre-treated for preexisting heart failure. So
very typical population of patients with heart failure presenting
to the emergency room.


Dr. Greg
Hundley:          


And did you have any kind of lower level EGFR cutoff, I mean, for
enrollment into this study?


Dr. Christian Schulze:    


So when we designed the trial, we actually still had the sub
classification of diabetes or impaired glucose or homeostasis as
an inclusion criteria. We dropped it before we started the trial
because the data came out that this is actually, in fact, not a
critical issue for patients with heart failure. So diabetes was
not a subgroup in our trial and the lower limit of EGFR was
actually a thoroughly defined protocol.


Dr. Greg
Hundley:          


Very nice. Well, listeners, now we're going to turn to our second
associate editor, Dr. Justin Grodin from University of Texas
Southwestern Medical Center in Dallas, Texas, and Justin, similar
to Brendan, and you see many papers come across your desk and so
what attracted you to this particular paper by Christian and his
colleagues?


Dr. Justin
Grodin:           


Well, Greg, I think first and foremost, and I think very similar
to Brendan, but I think what's always striking is if I may just
take a step back, decompensated heart failure in the United
States is the number one cause for hospitalization among Medicare
beneficiaries. So I think really, the brunt and really the truly
public health message of the disease is very important in the
applicability, and even though that decompensated heart failures
is one of the most common things that we ever encounter when we
practice, internists, cardiologists, et cetera, we have very,
very little clinical trial guidance that tells us how to
decongest individuals when they're hospitalized with swelling and
heart failure and a lot of these individuals can be quite ill,
and we have some clinical trial data, but largely, we have a lot
of negative studies or inconclusive studies in this space.


So certainly, what drew me to this trial was definitely that
context, and obviously, based on the mechanistic data with SGLT2
inhibitors, I think one of the natural questions, which Christian
addresses, is that we know that up front, they do augment
natriuresis. So I think it's very compelling to marry those two
together because this is what many of us that use these
medications regularly have been asking is whether or not they
would have some efficacy in that regard, and then another thing
that caught my eye and me as a cardiorenal investigator was, just
as Christian highlighted, was we have a clinical trial that
randomly assigned individuals, really that were ill and many of
whom were not stabilized within 12 hours of presentation, and
we're talking about patients that are coming into the hospital at
all times during the day in and I think that's very remarkable
that we have something with standard...


We have a study with standardized assessments where we're really
trying to ask a very practical, pragmatic question, which is do
these therapies lower the sodium balance in individuals with
decompensated heart failure, and I think what's important is
largely, we've got a lot of medications that supplement loop
diuretics, which are the class of drugs that the majority of us
use, and we have a lot of other therapies that we use that really
have very little data or poor data that guide us such as thiazide
diuretics, carbonic and hydrase inhibitors, mineralocorticoid
receptor antagonists, and so here, we have a clinical trial that
asks a question that's on many people's minds.


And then we do have very compelling, at least short term
pragmatic and mechanistic data that does tell us that these
individuals do have a greater natriuretic effect when
empagliflozin is used as an adjunct to standardized loop diuretic
therapy. So it's a very practical clinical question, and I think
what's very important, and we could debate probably all day about
the implications of GFR change and kidney function change while
we're decongesting somebody with diuretics, but I think what's
reassuring to all the clinicians is we really didn't see an
effect on kidney function despite a greater natriuretic effect or
enhanced diuretic effect, if you will, with the use of
empagliflozin.


Dr. Greg
Hundley:          


Very nice. Well, thank you, Justin. Listeners, now we have an
editorialist and as you know, editorialists really help us put
the scientific presentation of an original manuscript into the
perspective of really the global theme of a topic, and we have
Stefan Anker from Berlin, and Stefan, can you describe for us how
do we put these two manuscripts and results that we've heard
about really in the context now of moving forward with the use of
SGLT2 inhibitors in the management of patients with acute
decompensated heart failure?


Dr. Stefan
Anker:           


Thank you so much. Really, I think these two papers, on the one
hand, enhance our certainty about early use, and on the other
hand, possibly show us that there might be even more to achieve
by, on the one hand, moving even earlier with the application of
SGLT2 inhibitors or possibly consider the higher dose. Now let's
take one step back. These drugs were developed in type two
diabetes and the first successful trial was the [inaudible
00:25:42] outcome trial. Many people have forgotten that this
trial tested two doses and not only one, the 10 and the 25
milligram dose, and of course, with the success for improving
kidney outcomes and heart failure hospitalization outcomes, we
move forward into these two specialist areas, on the one hand,
broadening it to the non-diabetic communities, but on the other
end, narrowing it by focusing on the 10 milligram dose regardless
of whether there is [inaudible 00:26:12].


And we basically now learn A, to use these drugs even earlier
than we did in the big trials and we can now be sure to start
their use in the hospital, and if you take the average change in
quality of life results seen, you actually get a better result
for the patient on quality of life when you start earlier than
when you start late in the ambulatory studies where basically, in
the chronic setting, maybe you have one and a half to two points
difference. Here, you now have four and a half points in the
study shown by Mikhail, and of course, it's also good to know
that you can start this in any type of patient, regardless of
their quality of life. The impact study from Christian, they
basically moved it now even earlier, moving into the hospital
space is possible based on EMPULSE. Moving it into the acute
admission space is at least a consideration now based on what
Christian here has shown.


And he is actually addressing the one question I hear very often
in my presentations about SGLT2 inhibitors, what about this 25
milligram dose? Is there a place for this in cardiology as well,
and a possible place is shown here, not only that this is a safe
thing to do, but also you get urinary output. Of course, we may
in the future, want to see this compared, directly compared to
the 10 milligram dose, but of course, the world is not created in
one day, but needs more than one and so really, I think these two
studies, on the one hand, address an important issue, when to
start using them. On the other hand, show us a little bit of a
glimpse to the future.


Dr. Greg
Hundley:          


Very nice, Stefan, and listeners, we get to take advantage of
having these authors, editors, and editorialists together and ask
them what they see as the next study to be performed in this sort
of sphere of research. So Mikhail, we'll start with you. In 30
seconds or less, what do you see as the next study to be
performed in this arena of research?


Dr. Mikhail Kosiborod:  


I think, Greg, what we've learned recently, including from the
EMPULSE trial, we have this population of patients in a hospital
with heart failure's a huge issue as Justin mentioned, and until
recently, we had very little [inaudible 00:28:31] for them beyond
the usual kind of decongestion with loop diuretics and trying to
make them feel better, but you look at outcome data. It really
was a dearth of effective therapies that have meaningful impact
on important outcomes. Now that's changing, SGLT2 inhibitors is
one example. There are some other recent examples in this patient
population, like a firm HF and iron deficient patients with heart
failure.


But the bottom line is it's no longer kind of a desert, if you
will, of positive trials. We now have something we can do and I
think what this proves is that we need to actually invest more,
both in terms of resources and time to really do what we we're
being able to do in other areas of heart failure and those
patients with chronic, half and half where we can start
developing pillars of therapy that can actually truly improve
outcomes with this patient population and there is a lot going on
that makes me optimistic that's going to be the case in the
coming years.


Dr. Greg
Hundley:          


Very nice. And Brendan?


Dr. Brendan Everett:     


Well, I think both trials mentioned today really pushed our
understanding of this population forward. I think the biggest
clinical question that I face when I'm caring for these patients
is that we have four, at least, guideline directed therapies,
right? We have beta blockers, we have ARBs, ACE inhibitors and
ARNIs. We have mineral receptor antagonists and we have SGLT2
inhibitors. So which do we use in what order and how do we start
them, and what kind of parameters do we use to guide us if we're
limited either by renal function or by blood pressure or by some
other factor.


And we often, if not always, have one of those constraints that
we're dealing with and so I would say the next step for me is
trying to sort out which of these therapies and what order ought
to be our highest priority for patients with acute decompensated
heart failure as we move quickly from the acute decongestion
stage towards discharge and a chronic therapy that will then be
followed as an outpatient over the ensuing days and months.


Dr. Greg
Hundley:          


Very nice. And Christian.


Dr. Christian Schulze:    


Thank you again, and Brandon pointed out very nicely. I mean, we
have good evidence now for chronic heart failure treatment. We
have the four columns of heart failure medical therapy. Questions
that remain open is what do we do with all these patients that
are now guideline medicated, come to the hospital with an acute
decompensation? Should we carry on with the medication? Should we
terminate and in particular, should be carry on with full dose,
50% dose of SGLT2 inhibitors, and the next question is, what dose
should we use, in fact, for SGLT2 inhibitors? Is it in group
effects or is sotagliflozin comparable to empagliflozin, and then
is there a role for a step by scheme that we initially have in
high dose therapy that we then downgrade to 10 milligrams on the
chronic heart failure treatments, and then of course, quality of
life is very important. We should ask this question also in this
patient population that is early on treated, do we see benefits
that carry on in the outpatient setting and do we see an effect
of early treatment on long term benefits?


Dr. Greg
Hundley:          


Justin?


Dr. Justin
Grodin:           


Well, I would have to agree with all of my colleagues here on
this call. I think all have raised really good points, but I
think one very simple, and I'll echo some of Brendan's
statements, but one very simple question is we know that when we
decongest people and initiate a negative salt balance in the
hospital for decompensated heart failure, we cause neurohormonal
activation and there are a lot of downstream untoward effects
from chronic decongestive therapies, and I think one of the more
compelling things is we still yet have defined what is the best
way to decongest individuals with swelling or volume overload in
the hospital. Here, we have compelling studies with SGLT2
inhibitors for quality of life and really, the way patients feel.


And this is really what's important to them, and then something
very pragmatic to clinicians and let's make people pee more, but
I think one of the compelling questions, and I don't know if it
will be answered, is we have a lot of choices for supplemental
therapies and different diuretic strategies when patients come in
the hospital for decompensated heart failure, and I do think that
these studies do move the needle with SGLT2 inhibitors. I think
that's abundantly clear, but we still don't know what is the best
way to dry out my patient or make my patient pee so that they
feel better, but I do think that these studies do at least set
the stage that there's some compelling advantages to SGLT2
inhibitors.


Dr. Greg
Hundley:          


And then lastly, Stefan.


Dr. Stefan
Anker:           


Thank you. Besides the detailed points mentioned by many, and
Christian, totally support 25 versus 10 milligram, how long 25
milligram, if at all in the future. Besides this, I'm interested
in the big picture question. So what about the post myocardial
infarct congestion/heart failure situation, and there will be two
trials in the next 18 to 24 months that report on this, and my
pet kind of area is actually to treat heart failure where nobody
thinks it is heart failure, and what I mean is for instance,
advanced cancer patients, cardiac wasting cardiomyopathy. So the
heart failure in sick cancer patients, and indeed, we are
planning to do exactly that now in a study focusing on hospice
care patients to really improve the quality of life, the very
thing focus here on the EMPULSE trial.


Dr. Greg
Hundley:          


Well, listeners, we want to thank our authors, Dr. Mikhail
Kosiborod from Mid America Heart Institute in University of
Missouri, and Christian Shults from the University Hospital in
Jena, Germany. Also, our associate editors, Dr. Brendan Everett
from Brigham and Women's Hospital in Boston, and Dr. Justin
Grodin from University of Texas Southwestern in Dallas, Texas,
and also, our editorialist, Dr. Stefan Anker from Charité in
Berlin, Germany for bringing us these two manuscripts pertaining
to two randomized clinical trials regarding the administration of
the SGLT2 inhibitor, empagliflozin in acute heart failure,
demonstrating first, marked improvement in heart failure symptoms
and health related quality of life.


And second, in those with estimated GFRs greater than 30 mls per
minute, an augmentation of natriuresis in the setting of the
co-administration of diuretics without deterioration in renal
function. Well, on behalf of Carolyn and myself, we want to wish
you a great week and we will catch you next week on the run. This
program is copyright of the American Heart Association, 2022. The
opinions expressed by speakers in this podcast are their own and
not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.