Circulation August 9, 2022 Issue

This week, please join authors John McMurray and David
Cherney, editorialist Kausik Umanath, as well as Associate
Editors Ian Neeland and Brendan Everett as they discuss the
original research articles "Initial Decline (Dip) in Estimated
Glomerular Filtration Rate After Initiation of Dapagliflozin in
Patients With Heart Failure and Reduced Ejection Fraction:
Insights from DAPA-HF" and "Renal and Vascular Effects of
Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition" and
editorial ""Dip" in eGFR: Stay the Course With SGLT-2
Inhibition."


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 Centre and Duke National University of Singapore.


Dr. Greg Hundley:


I'm Dr. Greg Hundley, Associate Editor and director of the Pauley
Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Greg, it's the season of double features. Except this time, we're
having a forum discussion of two related articles and an
editorial that discusses both. What is it on? SGLT2 inhibitors.
In the first paper, an analysis from the DAPA-HF trial, looking
specifically at that initial dip in GFR that follows initiation
of dapagliflozin in patients with HFrEF. Then we will discuss
further, in a mechanistic way, the renal and vascular effects of
combining SGLT2 inhibition on top of ACE inhibition. Lots and
lots of good learning and insights, but let's go on first to the
other papers in today's issue. Shall we?


Dr. Greg Hundley:


You bet, Carolyn, and I'm going to grab a cup of coffee. Carolyn,
in this issue, wow, so many exciting original articles. In fact,
there are two more articles that were going to pair together,
both clinical and pertaining to TAVR procedures. In the first
one, it was a group of authors led by Dr. Duk-Woo Park from the
Asan Medical Center at the University of Ulsan College of
Medicine. They conducted a multicenter, open-label randomized
trial comparing edoxaban with dual antiplatelet therapy or DAPT,
aspirin plus clopidogrel, in patients who had undergone
successful TAVR and did not have an indication for
anticoagulation. Now in this study, Carolyn, the primary endpoint
was an incidence of leaflet thrombosis on four-dimensional
computed tomography, CT, performed at six months after the TAVR
procedure. Key secondary endpoints were the number and volume of
new cerebral lesions on brain magnetic resonance imaging or MRI
and the serial changes of neurological and neurocognitive
function between six months and that time immediately post the
TAVR procedure.


Dr. Carolyn Lam:


Oh, interesting. What did they find?


Dr. Greg Hundley:


Right, Carolyn. In patients without an indication for long-term
anticoagulation after successful TAVR, the incidence of leaflet
thrombosis was numerically lower with edoxaban than with dual
antiplatelet therapy, but this was not statistically significant.
The effect on new cerebral thromboembolism and neurological or
neurocognitive function were also not different between the two
groups. Now because the study was underpowered, the results
should be considered really as hypothesis generating, but do
highlight the need for further research.


Dr. Greg Hundley:


Carolyn, there's a second paper pertaining to transcatheter
aortic valve prosthesis. It's led by a group directed by Dr. Paul
Sorajja from the Minneapolis Heart Institute Foundation and
Abbott Northwestern Hospital. Carolyn, these authors
prospectively examined 565 patients with cardiac CT screening for
HALT, or what we would define as hypoattenuating leaflet
thickening, at 30 days following balloon-expandable and
self-expanding TAVR. Now, deformation of the TAVR prosthesis,
asymmetric prosthesis leaflet expansion, prosthesis sinus
volumes, and commissural alignment were analyzed on the
post-procedural CT. For descriptive purposes, an index of
prosthesis deformation was calculated, with values greater than 1
representing relative midsegment underexpansion. A time-to-event
model was also performed to evaluate the association of HALT with
the clinical outcomes.


Dr. Carolyn Lam:


Oh, interesting. What did they find?


Dr. Greg Hundley:


Right, Carolyn. Nonuniform expansion of TAVR prosthesis resulting
in frame deformation, asymmetric leaflet, and smaller neosinus
volume was related to the occurrence of HALT in patients who
underwent TAVR. What's the take home here, Carolyn? These data
may have implications for both prosthesis valve design and
deployment techniques to improve clinical outcomes in these
patients. Now, Carolyn, both of these articles are accompanied by
an editorial from Dr. Raj Makkar from the Smidt Heart Institute
at Cedars-Sinai's Medical Center. It's a very lovely piece
entitled Missing Pieces of the TAVR Subclinical Leaflet
Thrombosis Puzzle.


Well, how about we check what else is in this issue? My goodness,
this was a packed issue. First, Carolyn, there are three letters
to the editor from Professors Ennezat, Dweck, and then a response
from Dr. Banovic pertaining to a follow-up from a previously
published study, the AVATAR study, in evaluating valve
replacement in asymptomatic aortic stenosis. There's also a
Perspective piece from Dr. Wells entitled “Treatment of Chronic
Hypertension in Pregnancy: Is It Time For A Change?” There's a
Global Rounds piece from Professor Berwanger entitled
“Cardiovascular Care in Brazil: Current Status, Challenges, and
Opportunities.” Then there's also a Research Letter from
Professor Eikelboom entitled “Rivaroxaban 2.5 mg Twice Daily Plus
Aspirin Reduces Venous Thromboembolism in Patients With Chronic
Atherosclerosis.”


Dr. Carolyn Lam:


There's another Research letter by Dr. Borlaug on longitudinal
evolution of cardiac dysfunction in heart failure with normal
natriuretic peptide levels. There's also a beautiful Cardiology
News piece by Bridget Kuehn on the post-COVID return to play
guidelines and how they're evolving. Well, that was a great
summary of today's issue. Let's hop on to our feature forum.
Shall we?


Dr. Greg Hundley:


You bet, Carolyn. Can't wait.


Dr. Carolyn Lam:


Today's feature discussion is actually a forum because we have
two feature papers in today's issue. They all surround the
cardiorenal interaction, should I say, of the SGLT2 inhibitors.
For the first paper, discussing that initial decline or that dip
in the GFR following initiation of dapagliflozin would be Dr.
John McMurray, who's the corresponding author of this paper from
DAPA-HF. Dr. John McMurray's from the University of Glasgow. Now
next, we have also the corresponding author of another paper,
really going into the mechanistic insights of the renal and
vascular effects of combined SGLT2 and ACE inhibition. Dr. David
Cherney is from Toronto General Hospital, University of Toronto.


Dr. Carolyn Lam:


We have the editorial list of these two wonderful papers, Dr.
Kausik Umanath from Henry Ford Health in Michigan. Finally, our
beloved associate editors, Dr. Ian Neeland from Case Western
Reserve and Dr. Brendan Everett from Brigham and Women's
Hospital, Harvard Medical School. Thank you, gentlemen. Now with
all of that, what an exciting forum we have in front of us. Could
I start by asking, of course, the respective authors to talk a
little bit about your papers? I think a good place to start would
be with Dr. McMurray. John, please.


Dr. John McMurray:


Thanks, Carolyn. I think our paper had three key messages. The
early dip in eGFR that we saw was, on average, very small in
patients with heart failure, about 3 mLs/min or about 5%. Very
few patients had a large reduction in the eGFR. It was around 3%.
Dapagliflozin-treated patients had a 30% or greater decline
compared to about 1% of placebo patients. Finally, very few of
those patients had a decline in the eGFR below a critical
threshold, which for cardiologists might be around 20 mLs/min. We
saw that in only five patients; that's 0.2% of the
dapagliflozin-treated patients. Second message was that that
early decline partially reverses. The nadir in our study was
about 14 days. But by 60 days, on average, eGFR had increased
again. Hold your nerve if you see an early decline in eGFR.


 


Dr. John McMurray:


Maybe the most important message was that that decline in the
eGFR is not associated with worse cardiovascular or renal
outcomes. In fact, if anything, the opposite. If you look at the
patients in the dapagliflozin group with a 10% or greater decline
in eGFR, then compare it to patients who didn't have that
decline, these individuals were about 27% less likely to
experience the primary composite outcome of worsening heart
failure and cardiovascular death. If you look at the placebo
group, we saw exactly the opposite. Amongst those who had a
greater than 10% decline in eGFR compared to those who didn't,
those people with the early decline in eGFR were 45% more likely
to experience the primary composite endpoint. The same is true
for other cardiovascular outcomes for worsening kidney function.
In the dapagliflozin group, decline in eGFR was not associated
with more adverse events, not associated with more treatment
discontinuation. That small decline in the eGFR is not a bad
prognostic sign. If anything, it might be the opposite.


Dr. Carolyn Lam:


Thank you so much. That was really clear. David, are you going to
tell us why this decline occurs?


Dr. David Cherney:


Yeah. Perhaps the paper that we published gives some insights
into the mechanisms that are responsible for some of those
changes in GFR that are thought to be acute hemodynamic effects.
In the between trial, which is the trial that we published
examining the effect of ACE inhibition followed by SGLT2
inhibition in patients with type 1 diabetes, we also saw that
there was an expected effect of adding SGLT2 inhibition on top of
an ACE inhibitor in people with uncomplicated type 1 diabetes.
This acute dip in GFR was seen in this cohort of patients. We
included only 30 patients in this small mechanistic study. At the
same time, along with that dip in GFR, we also saw an increase in
measures of proximal natriuresis. That proximal sodium loss is
linked with changes in sodium handling in the kidney, which then
causes changes in both probably afferent and efferent tone, which
causes this dip in GFR primarily through natriuresis in this
phenomenon called tubuloglomerular feedback. That was one major
observation that gives insight into what we see in larger trials
around the dip in GFR.


Dr. David Cherney:


In our mechanistic study, we also saw an additive effect on blood
pressure. Blood pressure went down further with the addition of
empagliflozin on top of an ACE inhibitor. In terms of the
mechanisms that are responsible for the reduction in blood
pressure, natriuresis certainly may be in part responsible, but
we also saw a novel observation whereby there was a reduction in
peripheral vascular resistance using noninvasive measures. There
are likely several mechanisms that are responsible for the
reduction in blood pressure. Then finally, we also saw reductions
in markers of oxidative stress, which may also account for some
of the effects that we see in blood pressure, as well as
potentially some of the anti-inflammatory and anti-fibrotic
effects that we see at least in experimental models that may have
some clinical translatability to humans as well around the
clinical benefits. I think the blood pressure, the renal
hemodynamic effects, and some of the neurohormonal mechanisms are
the major observations that we saw that may in part explain some
of the really nice changes that were seen in Dr. McMurray's
study.


Dr. Carolyn Lam:


Right. Thanks, David. But these were patients with type 1
diabetes and no heart failure. John, do you have any reflections
or questions about how that may apply? By the way, what a
beautiful study. Thank you, David.


Dr. David Cherney:


Pleasure. Thank you.


Dr. John McMurray:


Yes, David. I really enjoyed your study. In fact, I think,
Carolyn, it does shed some insights perhaps to what's going on.
As David pointed out, the reduction in peripheral arterial
resistance, reduction in blood pressure, that may play some role
in that early dip in eGFR as well as autoregulation in the
kidney. Then the other interesting thing is that the distal
nephron seems to adapt to that effect in the proximal tubule.
Again, that may account for some of that recovery in eGFR, that
reversal in the early dip that I spoke about, and which I think
is very clinically important because, of course, physicians
should make sure that they recheck eGFR if they see that early
dip. Because they may find that few weeks later that that dip is
much smaller and of much less concern.


Dr. Carolyn Lam:


Thank you, John. In fact, you're saying, stay the course, right-


Dr. John McMurray:


I have.


Dr. Carolyn Lam:


... with the SGLT2 inhibitors. I'm actually stealing the words of
the title of the editorial, a beautiful editorial by Kausik. I
love that. Stay the course. Kausik, please, could you frame both
papers and then with an important clinical take home message for
our audience?


Dr. Kausik Umanath:


Sure. I think the analysis by John and his group was really
relevant with the large sample size. What's impressive? Similar
to a lot of these other SGLT2 studies that have come out, both in
heart failure and in kidney disease progression and so on, it's
remarkable how the other analysis, like the analysis of EMPA-REG
and CREDENCE and so on, of similar dips. All show more or less
the same magnitude, the same relative proportions of this GFR
trajectory. I think the mechanistic study only highlights that
though it's working with a slightly different population of type
1 patients and much earlier in their course in terms of where
their GFRs are.


Dr. Kausik Umanath:


The other piece is that ultimately we need to understand this dip
and know to monitor for it and so on. But I think the general
clinician should really understand that a dip of greater than 10%
really occurs in less than half the population that takes these
agents. That dip, if it occurs, certainly doesn't do any harm.
That said, if they see a bigger dip in the 30% range, monitor
more closely and consider making sure that there aren't any other
renal issues out there for that patient because they are a much
smaller proportion of patients in these large trials that
generate that level of dip. They should be monitored.


Dr. Kausik Umanath:


The other thought that we had, and thinking through this in a
practical sense, is because you expect this dip, many of our
cardiologists or even the nephrologists when we titrate these
drugs, they're on a suite of other drugs. It's probably best to
not adjust their Lasix or their loop diuretic, or their RAAS
inhibitor at the same time as you're adjusting the SGLT2
inhibitor or starting it because then you may just introduce more
noise into the GFR changes that you see over the next several
weeks. It may be a sequential piece or at least holding those
other agents constant while this gets titrated and introduced is
a prudent course of action, so you don't misattribute changes.


Dr. Carolyn Lam:


Thanks so much. What clinically relevant points. In fact, that
point about the diuretic especially applies in our heart failure
world. You see the dip. Well, first, make sure the patient's not
overdiuresed. Remember, there's more that the patient's taking.
Thank you. That was a really great point. Brendan and Ian, I have
to get you guys to share your views and questions right now. But
before that, can I take a pause with you and just say, aren't you
just so proud to be AEs of Circulation when we see papers like
these and we just realize how incredible the data are and the
clinical implications are? I just really had to say that. All
right. But with that, please, what are your thoughts, Brendan?


Dr. Brendan Everett:


Yeah, sure. Thank you, Carolyn. Hats off to all three of our
authors today for doing some amazing science. Thank you for
sending it to Circulation. I think, in particular, I handled
David's paper. I'm not a nephrologist and I'm probably the
furthest thing from a nephrologist. Had to do my best to try and
understand these concepts that I'm not sure I ever even was
exposed to in medical school many years ago. I think it shows the
breadth of the interest in our readership. The fact that these
changes in eGFR have become a primary focus for our
cardiovascular patients and that the clinical implications are
really important. I guess my question, David, is... In your
paper, you talked a little bit about this hypothesis of
hyperfiltration and the role that hyperfiltration plays in
setting patients with diabetes up for kidney disease. Is that
playing a role in John's observation or not? Again, as a
non-nephrologist, I have trouble connecting the dots in terms of
that hypothesis and John's observation of the clinical benefit
for patients that have a reduction in eGFR as opposed to no
change.


Dr. David Cherney:


Yeah. It's a great question. It's very difficult to know with
certainty in a human cohort because we can't measure the critical
parameter, which is intraglomerular pressure, which we think
these changes in GFR are a surrogate for. But if we go along with
that train of thought, along reductions in glomerular
hypertension, it very much makes sense that the patients who dip
are those who have the... They're taking their medication, number
one. Number two, they respond physiologically in the way that you
expect them to, which is that their GFR dips at least transiently
and then goes back up again through some of the compensatory
mechanisms that John mentioned earlier. As was mentioned not only
in this paper, but also in previous analyses from CREDENCE and
previous analyses from VERTIS CV and others have shown that
indeed that dip in GFR is linked with longer term renal benefits,
at least. That is reflected in a reduction in the loss of kidney
function over time.


Dr. David Cherney:


The patients who are on an SGLT2 inhibitor and those who dip by
around 10% or less, those patients tend to do the best over time
in terms of preserving GFR, not losing kidney function compared
to patients who are on an SGLT2 inhibitor but do not dip, or
those patients who actually have an increase in GFR. That is
consistent with this idea that there may be a reduction in
glomerular pressure, which is protective over the long term. That
ties back into your question around hyperfiltration that this may
indeed be due to a reduction in glomerular pressure, which is
linked with risk over the long term.


Dr. Carolyn Lam:


Ian?


Dr. Ian Neeland:


I wanted to echo Brendan's comments about the excellent science.
When I read these papers, it really speaks to the existential
struggle that cardiologists have between kidney function and
these medications that we know have cardiovascular benefits. How
do we manage that practically? It's so clinically relevant, both
the observation that John's paper made about the dip in the
DAPA-HF trial as well as, David, your mechanistic insights.


Dr. Ian Neeland:


I wanted to ask John potentially about the most fascinating
aspect to me of this paper was that patients with a dip of 10% or
more actually ended up doing better in terms of cardiovascular
outcomes, specifically hospital heart failure and
hospitalizations than people on placebo with a greater than 10%
dip. It speaks to the fact that... Is the physiology going on
here different between those individuals whose GFR went down on
placebo versus those who are on SGLT2 inhibitors? All the
mechanistic insight that David's paper had in terms of blood
pressure and intraglomerular pressure, how does that feedback and
speak to why heart failure is strongly linked to this mechanism?
We see this not just with SGLT2 inhibitors, but there are other
medications now coming out showing that there's a relationship
between this dip in GFR and heart failure. Can you speak to why
this heart failure-kidney connection is so important and becoming
greater and greater in terms of our understanding?


Dr. John McMurray:


Well, thank you for asking me the hardest question and one that I
truly don't think I have a good answer to. I think it's obvious
to all of us that the kidney is central in heart failure and
perhaps cardiologists have neglected that fact, focusing more on
the other organ. But by definition, almost the fluid retention
that characterizes heart failure in terms of signs, and probably
is the primary cause of symptoms, that clearly is a
renally-mediated phenomenon. The kidney must be central to all of
this. I think David right. I think the decline in eGFR that you
see with this drug is simply a marker that the drug is having its
physiological effect or effects. Whatever those are, they're
beneficial. Clearly, patients who have an eGFR decline on placebo
are different and they reflect, again, the patients that we see
all the time. As our patients with heart failure deteriorate, one
of the things that we commonly see, in fact becomes one of the
biggest problems that we have to deal with, is that their kidney
function declines. As their symptoms get worse, as their cardiac
function gets worse, their kidney function also declines.


Dr. John McMurray:


I think you're seeing two contrasting effects here. One is the
background change in eGFR, which is the placebo patients, and
we've always known that that's a bad thing. Then we're seeing
that early within 14 days marker of the pharmacological or
physiological action of the drug. I hope you don't ask me how
SGLT2 inhibitors work in heart failure. That's the other most
difficult question I can think of, but I think this is just a
marker of the fact that they are working.


Dr. David Cherney:


Yeah. Just to add to that briefly, there is this difficulty in
sorting out the mechanisms that are relevant around the acute
effects in the kidney that the dip in GFR reflects natriuresis
that could keep patients out of heart failure; that the reduction
in glomerular pressure reduces albuminuria. Albuminuria reduction
is linked with kidney protection. It's linked with heart failure
and ASCVD protection. Then there's also this concept of if you
dip and then you stay stable afterwards, your GFR stays stable
afterwards, those patients with stable kidney function that's not
declining, the dippers in other words, those patients are
probably able to maintain salt and water homeostasis better than
someone who's declining more rapidly. All these things probably
tie together in order to reflect, of course, there's a renal
protective effect, but that some of those mechanisms may also tie
into the heart failure mechanisms that John was mentioning.


Dr. John McMurray:


But, David, it's hard to imagine if we don't protect the kidney,
we won't protect patients with heart failure given how
fundamental, as I said, the kidney is, and how fundamentally
important worsening kidney function is. Not only because it is a
marker of things going badly, but also because it often results
in discontinuation or reduction in dose of other life-saving
treatments. To Kausik's point, it was very important about the
risk of changing background life-saving disease modifying
therapy. Actually, we didn't see that in DAPA-HF, which was very
intriguing. There was no reduction in use of renin-angiotensin
system blockers or mineralocorticoid receptor antagonists.


Dr. Carolyn Lam:


Thank you so much, gentlemen. Unfortunately, we are running out
of time, but I would really like to ask one last question to the
guests, if possible. Where do you think the field is heading?
What next? What's the next most important thing we need to know?
David, do you want to start? Then John, then Kausik.


Dr. David Cherney:


I think one of the aspects that we need to know in the future is
where else can we extend these therapies into novel indications
and extend the boundaries of where we currently work with these
therapies. People with type 1 diabetes, for example, with either
heart failure or with significant kidney disease, patients with
kidney transplantation, is there a renal or cardiovascular
protective effect? Then another high risk cohorts who have not
been included in trials, those on immunosuppressants, for
example, who were excluded from the trials. I think those are
some of the areas that we need to extend into now that we
understand how these therapies work in even very sick patients
and that we also know that they likely have at least some benefit
through suppressing inflammation, and possibly reducing
infectious risks. That would provide a rationale for extending
into some of these new areas. I think that's certainly, hopefully
on the horizon for us.


Dr. Carolyn Lam:


John?


Dr. John McMurray:


Carolyn, obviously I think looking at post myocardial infarction
population, that's an obvious place to go. There are a couple of
trials there. I suppose the trial that I would love to see, and
which I think would address the core question that we've been
discussing today, which is: Is this all about the effect in the
kidney and how important is the diuretic and natriuretic action
of these drugs in heart failure? I think the key study that would
address this would be doing a study in patients on dialysis.
Because in those patients we could, I think, separate the issue
of natriuresis, diuresis, and maybe even the dip in EGR that
we've been talking about. If these drugs prove to be effective in
end-stage kidney disease, patients on dialysis, that would be
really fascinating.


Dr. Carolyn Lam:


Kausik?


Dr. Kausik Umanath:


That is a very interesting point. I don't know that we know
necessarily outcomes, but I think from working with the DAPA-CKD,
we do have a little bit of the safety data because we did
continue it. I was the US MLI for that study and we did continue
the SGLT2 passed into renal failure. There is a little bit of
safety data there. But I don't think once you've declared an
outcome, you're not collecting outcomes data after that point.
That's a very interesting area to look into.


Dr. Kausik Umanath:


I also think the other place where this field's heading is trying
to better tier and layer the multitude of agents. I think we've
been waiting for about 20 to 30 years, at least in the kidney
field, for something new to affect the progression of kidney
disease after the ACE/ARB trials and so on. This one we've got
SGLT2 inhibitors. We've got the new MRA, finerenone, and so on,
which also have very beneficial cardiovascular effects. The
question becomes: How do we layer these therapies? Which sequence
to go in? Some of the others that are in pipeline as well that
are out there that have very beneficial cardiovascular effects
that may indeed also help kidney function and diabetes control,
which do you go with first and so on?


Dr. Carolyn Lam:


Wow! Thank you so much. We really could go on forever on this
topic, but it has been tremendous. Thank you once again. On
behalf of Brendan, Ian, Greg, thank you so much for joining us
today in the audience. You've been listening to Circulation On
the Run. Don't forget to tune in again next week.


Dr. Greg Hundley:


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.