Circulation January 24, 2023 Issue

Please join author Subodh Verma and Guest Editor
Christopher Granger as they discuss the article "Empagliflozin
and Left Ventricular Remodeling in People Without Diabetes:
Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized
Clinical Trial."


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-host. I'm Dr. Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr. Peder Myhre:


And I'm Dr. Peder Myhre, social media editor and doctor at
Akershus University Hospital at University of Oslo in Norway.


Dr. Carolyn Lam:


Peder, I am so excited to be discussing this issue. So many great
articles and a feature discussion coming up on the SGLT2
inhibitor, empagliflozin. And do you think it's got effects on
left ventricular remodeling in people without diabetes? Very
interesting question.


Dr. Peder Myhre:


That is so interesting, Carolyn. I can't wait to hear this
discussion.


Dr. Carolyn Lam:


Yep, I agree, but we got to wait till we discuss the other papers
in today's issue. I want to go first. So we know that non-vitamin
K oral anticoagulants, or NOACs, they've become the standard
therapy for preventing stroke and ischemic thromboembolism in
most patients with atrial fibrillation. But, what is the
effectiveness and safety of NOACs in patients on dialysis? That
is hemodialysis. The AXADIA-AFNET 8 study sought to test the
hypothesis that apixaban would be non-inferior to vitamin K
antagonists in these very patients undergoing hemodialysis.


Dr. Peder Myhre:


Oh wow. This is really a gap of knowledge that we've been waiting
to hear more about. NOACs in patients with hemodialysis. Tell us
about this trial, Carolyn.


Dr. Carolyn Lam:


Sure. So this is from corresponding author, Dr. Reinecke, and
colleagues, from University of Munster in Germany. And it's an
investigator initiated prospective randomized open-blinded
outcome assessment of 97 patients with atrial fibrillation on
chronic hemodialysis randomized to either apixaban 2.5 mg BID, or
a vitamin K antagonist, aiming for an INR between 2 and 3. Over a
median follow-up time of 429 days for apixaban, and 506 days for
the vitamin K antagonist, the composite primary safety outcome of
first, major bleeding, clinically relevant, non-major bleeding,
or all cause death, occurred in 46% of patients on apixaban, and
51% of patients on the vitamin K antagonist. That would be a
hazard ratio of 0.91, with a p for non-inferiority being 0.157.


How about the primary efficacy outcome? While this was a
composite of ischemic stroke, all cause death, myocardial
infarction, or deep vein thrombosis, and/or pulmonary embolism,
and that occurred in 21% of patients on apixaban and 31% of
patients on the vitamin K antagonists. Again, no difference when
there was testing. So, in summary, Peder, there were no
differences in the safety or efficacy observed between apixaban
and vitamin K antagonists in patients with atrial fibrillation on
chronic hemodialysis.


Of note, however, even receiving oral anticoagulations, these
patients remain at very high risk of cardiovascular events. So
these data really support the consideration of apixaban for
prevention of cardiovascular complications in patients with
atrial fibrillation on chronic hemodialysis, but larger studies
are definitely needed.


Dr. Peder Myhre:


Oh wow, Carolyn, that is so clinically relevant. And the next
paper is also a clinically relevant paper. And it comes to us
from the SPRINT authors. And to remind you, the SPRINT study was
a study of intensive systolic blood pressure lowering compared to
standard blood pressure lowering. And the results demonstrated
that there was a robust reduction in both heart failure endpoints
and all cause mortality. And in this sub-study that comes to us
from corresponding author Jarett Berry from University of Texas
Tyler School of Medicine, these authors look at the mechanisms
through which intensive blood pressure lowering reduces the risk
of these endpoints. And given the important role of cardiac
injury and neurohormonal activation in the pathways leading from
hypertension to heart failure, and strong association that has
been observed between hypertension and levels of cardiac troponin
and NT-proBNP, the authors hypothesized that intensive systolic
blood pressure lowering would decrease levels of high sensitivity
cardiac troponin T and NT-proBNP.


Dr. Carolyn Lam:


Cool. That's interesting. So how did they do this, and what did
they find?


Dr. Peder Myhre:


So, as expected, Carolyn, the authors found that increases in
troponin and NT-proBNP from baseline to 1 year were associated
with a higher risk of heart failure and death. And there were
really no significant interaction by treatment assignment. But
let's look at the changes in troponin. And these results showed
that randomization to intensive blood pressure lowering versus
standard blood pressure lowering resulted in a significant 3%
increase in cardiac troponin T level over 1 year follow up, and a
higher proportion of participants with more than 50% increase,
and that's with an odds ratio of 1.47. And Carolyn, in contrast,
NT-proBNP decreased by 10% in intensive blood pressure arm. And
these patients had substantially lower probability of increasing
more than 50% in NT-proBNP, with an odds ratio of 0.57 compared
to the standard arm.


And now, to the most interesting part of this analysis, Carolyn,
the association of randomized treatment assignment on changes in
troponin was completely attenuated after accounting for changes
in eGFR during the follow up, whereas the association of
treatment with NT-proBNP changes were completely attenuated after
adjusting for changes in systolic blood pressure. So Carolyn, the
authors highlight in their discussion the importance of
non-cardiac factors influencing variation in cardiac biomarkers,
and raise questions about the potential role of cardiac troponin
T as a surrogate marker for heart failure or death in blood
pressure lowering studies.


Dr. Carolyn Lam:


Wow, very interesting. Thanks, Peder. Can I tell you now about a
preclinical study? Very interesting, because it shows that
cardiac inflammation and hypertrophy are regulated by a
heart-brain interaction.


Dr. Peder Myhre:


Wow, Carolyn, a heart-brain interaction. I'm excited to hear more
about this. Please explain.


Dr. Carolyn Lam:


I'd love to, but first some background. Interleukin-1 beta, now
that is a pro-inflammatory cytokine that causes cardiac
hypertrophy and heart failure. I need to familiarize you with
this, the nucleotide-binding domain leucine-rich containing
family, pyrin domain-containing-3, NLRP3 for short, which is an
inflammasome, which is a cytosolic multiprotein complex that
mediates active interleukin-1 beta production. Okay? So you know
these terms, and now I want to tell you about the study.


This is an elegant series of experiments performed by
co-corresponding authors, Dr. Higashikuni, from University of
Tokyo, and Dr. Sata, from Tokushima University Graduate School of
Medicine, and their colleagues. They first showed that genetic
disruption of the NLRP3 inflammasome resulted in significant loss
of interleukin-1 beta production, cardiac hypertrophy, and
contractile function during pressure overload. Next, a bone
marrow transplantation experiment revealed an essential role of
NLRP3 inflammasome in cardiac non-immune cells in myocardial
interleukin-1 beta production and the cardiac phenotype. It was
extracellular ATP released from sympathetic nerve terminals that
induced the hypertrophic changes of cardiac cells in an NLRP3 and
interleukin-1 beta dependent manner in vitro. And finally,
depletion of ATP release from sympathetic efferent nerves, or
ablation of cardiac afferent nerves, or a lipophilic
beta-blocker, all reduced cardiac extracellular ATP, and
inhibited the NLRP3 inflammasome activation, the interleukin-1
beta production, and the adaptive cardiac hypertrophy during
pressure overload.


So all of this suggests that controlling the neuronal brain
signals might have therapeutic potential for the treatment of
hypertensive heart disease. Neat, huh?


Dr. Peder Myhre:


Oh, that is so interesting. The heart and brain interaction. And,
Carolyn, we're going to stay in the field of preclinical science.
And now we're going to talk about another field that is really
interesting, and that is regeneration of cardiomyocytes. Because,
Carolyn, developmental cardiac tissue holds remarkable capacity
to regenerate after injury, and consists of regenerative
mononuclear and deployed cardiomyocytes. Whether reprogramming
metabolism promotes persistence of these regenerative mononuclear
and deployed cardiomyocytes that enhance cardiac function in
repair after injury is unknown. Therefore, these researcher, led
by corresponding author, Mohsin Khan, from Temple University
School of Medicine, investigated whether the RNA binding protein,
LIN28a, which is a master regulator of cellular metabolism, plays
a role in cardiac repair following injury.


Dr. Carolyn Lam:


Wow. That is always, always interesting, regeneration and repair
following injury. So what did the authors find?


Dr. Peder Myhre:


Well, Carolyn, through a number of elegant experiments, the
authors made the following key findings. For the first time, they
documented a role for RNA binding protein LIN28A in regulating
cardiomyocyte turnover in the postnatal and adult heart. And
LIN28a overexpression promotes cardiomyocyte cell cycle activity
during postnatal development and extends cardiac regenerative
ability of the mammalian heart to postnatal day 7. And in the
adult heart, the authors could demonstrate that LIN28a drives new
myocyte formation, augmenting cardiac structure and function
after myocardial injury. And Carolyn, I'm sure you're going to
ask the clinical implications of this study.


Dr. Carolyn Lam:


Indeed.


Dr. Peder Myhre:


And that is that these results may suggest a novel translational
role for LIN28a based strategy to replenish cardiomyocytes in the
adult heart after injury.


Dr. Carolyn Lam:


Very nice, Peder. Thank you. Also in the issue is a Research
Letter by Dr. Bick on interleukin-6 receptor polymorphism
attenuates clonal hematopoiesis mediated coronary artery disease
risk among many individuals in the UK Biobank. There's also
Cardiology News by Tracy Hampton, where she highlights few really
interesting things, like aging cardiomyocytes accumulate new
genetic mutations that was published in Nature Aging, cytokines
promote tissue repair after a heart attack in mice, and that was
published in Science, and scientists identifying molecular
alterations in a failing heart at a single cell resolution, which
was published in Nature.


Dr. Peder Myhre:


And there are a couple of other papers also in this issue,
Carolyn. And there's first, an exchange of letters by Drs.
Halushka, Lu, and Mayr, regarding the article "Circulating
MicroRNA-122-5p is Associated with a Lack of Improvement in Left
Ventricular Function after TAVR and Regulates Viability of
Cardiomyocytes Through Extracellular Vesicles."


And finally, we have an "On My Mind" piece by doctors Monda and
Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction
Model for Patients with Hypertrophic Cardiomyopathy."


Dr. Carolyn Lam:


Oh, nice. Nice full issue. Thank you, Peder. Let's go to our
feature discussion now. Shall we?


Dr. Peder Myhre:


Let's go.


Dr. Greg Hundley:


Welcome listeners to this feature discussion on January 24th. And
we have with us Dr. Subodh Verma, from St. Michael's University
in Toronto, Canada. And a guest editor, Dr. Christopher Granger,
from Duke University in Durham, North Carolina. Welcome
gentlemen. Well, Subodh, we will start with you. Can you describe
for us some of the background information that went into the
preparation of your study, and what was the hypothesis that you
wanted to address?


Dr. Subodh Verma:


First, my great pleasure to be here, and thank you very much for
the opportunity to discuss this paper with your viewers. As you
know, SGLT2 inhibitors have been truly transformative therapies.
From a heart failure perspective, we know that they prevent
incident heart failure in people with diabetes who have vascular
disease or risk factors. They also have been shown to treat
prevalent heart failure in people with heart failure and either a
reduced, mildly reduced, or preserved ejection fraction
independent of glycemic status. And really, these have been the
basis of very strong recommendations to use these agents in the
prevention of heart failure in people with diabetes, and also in
the treatment of prevalent heart failure in people with and
without diabetes.


Now, the fact that these drugs have such broad effects in people
with heart failure has led to a theory that maybe these drugs
could be introduced earlier on in the natural history of heart
failure in people who neither have diabetes nor have significant
heart failure, the so-called sort of stage A or stage B patient.
But there really have been no clinical trials evaluating this
question. There've been a lot of translational randomized trials
that have provided some mechanistic insights about LV remodeling
in people with diabetes or in people with prevalent heart
failure. And we hypothesized that maybe the first step to
evaluate whether SGLT2 inhibitors may have favorable effects on
cardiac remodeling in people without diabetes or without heart
failure would be to conduct a randomized double-blind control
trial looking at indices of left ventricular remodeling in a
population that I've just described.


Dr. Greg Hundley:


Very nice, Subodh. So you've started us into your study design.
Maybe describe that a little more fully, and then who was
included in your study population?


Dr. Subodh Verma:


So EMPA-HEART 2 CardioLink was a multi-center double-blind
placebo control randomized trial in which we studied the effects
of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day
versus placebo in people who did not have type 2 diabetes or
significant heart failure. We included people who were adults
between the age of 40 and 80 who met 1 of 2 entry criteria.
Either they had to have one major criteria, which was an increase
in left ventricular mass index by specific echo criteria or MRI
criteria, or they could have increased LVH as identified by ECG
or by intraventricular septal or posterior wall thickness. They
could also get in if they had resistant hypertension,
hypertension despite being on 3 antihypertensive agents, or the
second strata was entry through 2 minor criteria, which included
a history of myocardial infarction, a GFR between 30 or 60, or
evidence of overweight or obesity.


Dr. Greg Hundley:


And how many subjects did you randomize?


Dr. Subodh Verma:


So we randomized, of the 318 that we screened, 169 were
randomized to receive empagliflozin 10 mg or a placebo. Patients
had a baseline cardiac MRI done, and then the exposure was 6
months. They had a follow-up MRI at the end of 6 months. And the
primary outcome measure was a 6-month change in left ventricular
mass index from baseline to 6 months between the two groups.


Dr. Greg Hundley:


Very nice. And so , Subodh, can you describe for us now, what did
you find? What were your study results?


Dr. Subodh Verma:


So, first and foremost, what we found in terms of baseline
characteristics was that we enrolled a population of people with
a mean age of around 60 with a BMI of around 30 kg/m2,
predominantly men, about 80% or so were men. These were patients
who did not have significant heart failure. The NT-proBNP at
baseline was around 50 pg/mL. The eGFR was around 80 mL/minute,
and the vast majority of these patients actually had a history of
hypertension. Of course, none of them had diabetes by definition.
The hemoglobin A1C was around 5.8%.


Now what we found was, despite the fact that we went after
patients who we thought would be enriched for a baseline increase
in LV mass indices, the baseline LV mass index was mildly
elevated, was around 63 g/m2. And over the course of 6 months, we
did not find any significant difference in terms of LV mass
regression between the placebo and empagliflozin groups. In fact,
the adjusted treatment effect was minus 0.30 g/m2, which was not
statistically significant. No other differences were found in
terms of other indices of a remodeling, including left
ventricular and diastolic or end systolic volume indices or in
terms of left ventricular ejection fraction. There was a 2%
increase in ejection fraction, and the p-value for that was 0.07,
but really was not statistically significant.


Dr. Greg Hundley:


And very nice. And realizing that women may have smaller LV
masses, any stratified analysis that evaluated effects on men
versus women? And then what about, perhaps in the higher quartile
versus lower quartile, of age?


Dr. Subodh Verma:


Right. So, Greg, we actually did look at various subgroups and
covariates, including gender, including age. And age or gender
did not really influence the overall result that we obtained.
There was really a neutral result in empagliflozin, irrespective
of these 2 covariates. We also looked at baseline blood pressure,
baseline NT-proBNP, LV mass indices, the presence or absence of
heart failure, chronic kidney disease. So for the covariates that
we have evaluated over a short term of 6 months in this
relatively low risk population, we did not find any heterogeneity
the result, per se.


Dr. Greg Hundley:


Very good. Well, Subodh, thank you so much for that beautiful
presentation. And listeners, now we're going to turn to our guest
editor, Dr. Chris Granger. And Chris is an expert in the field of
heart failure. Also, a lot of familiarity with HFpEF, which
sounds a little bit, we're looking at precursors. We don't have
HFpEF yet, but maybe trying to inhibit this from happening using
empagliflozin. How do you put these results in the context with
other studies that have emphasized utilizing SGLT2 inhibitors in
patients with sort of a preserved ejection fraction and absence
of diabetes?


Dr. Christopher Granger:


Yeah. Well thanks, Greg. And again, congratulations, Subodh, to
your study. And I think you framed some of the context here as
these drugs, the SGLT2 inhibitors, as being transformative, which
I think is exactly right. And it's such a fascinating story.
Right? These drugs, which we thought originally, with their cause
of glucose spilling in the urine, and a modest decrease in blood
glucose, might have a role for modestly improving glucose control
in diabetes. And low and behold, they've turned out to be one of
the great stories I think in recent, across all of medicine, in
terms of their consistent and substantial improving clinical
outcomes for patients with heart failure, with diabetes and
cardiovascular disease, and now even kidney protection, and much
broader implications. And their well tolerated, and they don't
have dose titration. So there's some practical appeal to this
class of drugs in terms of their benefits, in terms of clinical
outcomes.


But we're left with having this amazing evidence-based generated
without really understanding why are these drugs so effective?
And what are they doing? And you've provided, I think, an
important piece to the puzzle. We did have the data from patients
with diabetes and heart failure, with diabetes and left
ventricular hypertrophy, that there is a modest reduce in LV mass
with SGLT2 inhibitors. And what you've shown is that for patients
that with mild LVH, with risk for LVH, that we simply don't see a
substantial reduction in LV mass with the use of these drugs. So
I think that provides this evidence that that's not a major cause
of benefit, at least in this earlier phase of development of
heart failure.


And I think it really underscores the fact that there's a lot of
work to do still to understand. We know that the renal effects
are obvious place that these drugs have such an important
benefit. And then the linkage of renal disease and cardiac
performance is one of the areas, I think, that's a very exciting
aspect of a probable contribution of the mechanism of these
drugs. But I think in the end, we're left with still not really
understanding why these drugs are so beneficial. But
understanding that, I think, will be important, both for opening
new avenues of targeting pathways, as well as being able to tell
the clinical community, okay, you have these important benefits,
but people do want to also know why are we seeing these benefits.


Dr. Greg Hundley:


Very nice. Well, listeners, we're going to turn back to Dr. Verma
here. Subodh, what do you see is the next study to be performed
in this sphere of research?


Dr. Subodh Verma:


Well, first, my thanks to Professor Granger, Chris, for handling
this paper and for his very thoughtful comments. And he's
absolutely right. We have such wonderful clinical data, and these
results, of course, should not in any way take away from the
importance of using empagliflozin or other SGLT2 inhibitors in
the prevention of heart failure in people with diabetes, or in
the treatment of HFpEF or HFrEF. But we're struggling with trying
to understand what is the dominant mechanism of action here. And,
in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in
people with diabetes, and we saw a modest effect that was
statistically significant of reduction in LV mass index. And we
did not see this, of course, in a lower risk population without
diabetes. And that tells me that remodeling may be occurring to a
modest effect, it may require a longer time to actually show its
benefits, but that this is unlikely a dominant sort of mechanism
through which these drugs are working.


And I do share Chris's thoughts that one of the key mechanisms of
benefit that needs to be further explored is looking at the renal
cardiac axes. We know that these drugs are profoundly renal
protective, and that the benefits may actually be secondary to
improvements in renal hemodynamics, improvements in renal
function. And I think that is a population that needs to be,
that's a mechanism that needs to be studied further.


So I think the next generation of translational mechanistic
studies need to really tease out the renal cardiac axes, maybe
tease out populations that are at risk but have more significant
left ventricular hypertrophy, maybe evaluate patients for a
longer duration of treatment, or select people who truly have
significant hypertension at baseline. I think those are groups
and questions that need further exploration. And, of course, the
translational science needs to be also studied in the context of
larger completed clinical trials, where biomarkers are currently
available and they can be linked, of course, to the outcomes in
those trials. So those are some of my thoughts as to where the
field could move towards.


Dr. Greg Hundley:


Very nice. And Chris, do you have anything to add?


Dr. Christopher Granger:


Subodh, I think that was a great summary. And I might just make a
comment on the other end of the spectrum. That is, we have these
drugs and the evidence of their benefit, and yet they're grossly
underused in the populations that have proven to have benefit.
Now it takes some time to educate, to get people familiar with,
and get them to integrate these treatments into practice, but
there's an enormous opportunity, and I think there is a linkage
here. I think when people understand the mechanism, and when
they're thoughtful about how these drugs may be working, that
that really helps to make the case that the drug should be used,
and that people are on board with using them. So I think there's
this linkage here, there's the need to both better understand
mechanism, and there's the need to have systems of care where
these treatments are integrated to provide the benefit that's
been so clearly shown in the randomized trials.


Dr. Greg Hundley:


Very nice. Well, listeners, we want to thank Dr. Subodh Verma,
from St. Michael's University in Toronto, and our guest editor,
Dr. Chris Granger, from Duke University in Durham, North
Carolina, for bringing this paper highlighting that among people
with neither diabetes nor significant heart failure but with risk
factors for adverse cardiac remodeling, that SGLT2 inhibition
with empagliflozin did not, did not, result in a meaningful
reduction in LV mass index after 6 months.


Well, on behalf of Carolyn, Peder, 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 2023.
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.