Circulation February 22, 2022 Issue

This week, our very own Carolyn Lam is in the author role
along with author Vlado Perkovic, Associate Editor Naveed Sattar,
and Guest Editor John McMurray as they discuss the articles
"Efpeglenatide and Clinical Outcomes With and Without Concomitant
Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes:
Exploratory Analysis of the AMPLITUDE-O Trial" and "Effect of the
Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and
Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes:
A Pooled Analysis of SUSTAIN 6 and LEADER Trials."


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:          


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


Dr. Carolyn
Lam:            


I have a confession. I am nervous because right after this, Dr.
Greg Hundley is going to interview me and, thank goodness, not
just me, but really, really interesting other authors and editors
with feature papers, all about GLP-1 receptor agonists and the
SGLT-2 inhibitors. Very, very, very hot topic. Do listen up! But
for now, Greg, you're going to be nice, right? How would you
start?


Dr. Greg
Hundley:          


Well, thank you, Carolyn. I am really looking forward to that.
Maybe we'll have a few quiz questions in there. Before we get
started, how about we grab a cup of coffee? I am going to bring
to our listeners a paper from the world of preclinical science.
It's from Professor Vincent Christoffels from Amsterdam. Carolyn,
there's a pathogenic variant in the fifth exon of TBX-5 entitled
PG125R. It's found in a Dutch atypical Holt-Oram syndrome family
with early onset atrial fibrillation. These investigators modeled
this in a mouse. Carolyn, this is the first human pathogenic
variant based on a patient family in this key cardiac
transcription factor that's been explored in an in-vivo animal
model.


Dr. Carolyn
Lam:            


Wow, that's interesting. So, what did they find, Greg?


Dr. Greg
Hundley:          


Right, Carolyn. The investigative team identified widespread
electrophysiological transcriptional and epigenetic changes
including coding and non-coding RNA, chromatin accessibility, and
H3K27ac associations in the atria of TBX5-PG125R heterozygous
mice distinct from the changes in the atria of TBX5 insufficient
animals.


Dr. Carolyn
Lam:            


Okay. Could you give us the clinical take home message, Greg?


Dr. Greg
Hundley:          


Right, Carolyn. What these authors really have found is that the
characterization of the TBX5-BG125R mouse model... it indicates
that a patient-specific pathogenic variant in TBX5 induces
changes in regulatory element activity, an altered balance in the
regulatory network of atrial cardiomyocytes, and clinically
relevant changes in cardiomyocyte function. So therefore,
Carolyn, this work may provide insight into the epigenetic
changes and transcriptional underpinning of arrhythmias in the
general population caused by small increases in TBX5 expression
also caused by common variants predisposing ones to atrial
fibrillation.


Dr. Carolyn
Lam:            


Wow. Thanks Greg. Well, guess what? I've got an interesting mouse
model to share about as well. This next paper comes from
co-corresponding authors, Drs. Chen, Fu, and Wu from UCSD. What
they do is provide insights into possible underlying factors in a
molecular mechanism responsible for left ventricular
noncompaction cardiomyopathy. Now, we know this condition, but...
It was discovered half a century ago, yet owing in part to the
lack of a suitable mouse model that faithfully mirrors that
selective left ventricular vulnerability in patients, the actual
mechanisms underlying susceptibility of the left ventricle to
dilatation dysfunction in this condition actually remain unknown.
Well, until now.


Dr. Greg
Hundley:          


Wow, Carolyn. So, what actually did this investigative team do,
and what did they find?


Dr. Carolyn
Lam:            


At the basis of their study is a transcription factor. This is
PRDM16. This transcription factor has previously been implicated
in this condition through characterization of defects associated
with the 1P36 syndrome. What the authors did this time, though,
is they generated two new conditional knockout mouse models of
PRDM16. Their subsequent characterization of the phenotype is a
tour de force of gene expression analysis that uses a myriad of
functional genomic approaches, including RNA-seq, ChIP-seq,
single cell RNA-seq spatial transcriptomics.


What they found is cardiomyocyte specific ablation of PRDM16 in
mice indeed caused left ventricle specific dilation and
dysfunction, as well as biventricular non-compaction. In other
words, fully recapitulating the left ventricular noncompaction
syndrome in patients. Mechanistically, PRDM16 functions as a
compact myocardium enriched transcription factor which activated
compact myocardial genes while repressing trabecular myocardial
genes in the left ventricular compact myocardium. Consequently,
PRDM16 knockout cardiomyocytes shifted from their normal
transcriptomic identity to a transcriptional signature resembling
trabecular myocardial cardiomyocytes and/or neurons and chamber
specific transcriptional regulation by PRDM16 was in part due to
its cooperation with left ventricular and rich transcription
factors.


Dr. Greg
Hundley:          


Carolyn, wow. Mechanistic understanding now for cardiovascular
noncompaction. This is really exciting research. Clinically, how
can we interpret this work from this animal model?


Dr. Carolyn
Lam:            


Thought you may ask. This study provides a unique left
ventricular noncompaction mouse model for developing therapeutic
interventions for any person with a left ventricular dilation and
dysfunction, which emerge as the most important disease features
in this condition. Improper specification of compact or
trabecular cardiomyocytes is likely the common mechanism in the
pathogenesis. Spatial single cell gene expression profiles in
normal or disease conditions can be shown in this example to
facilitate future studies for identifying new targets. This paper
is accompanied by an editorial by Drs. Mably, Joe Wu, and Dr.
Wang.


Dr. Greg
Hundley:          


Very nice Carolyn. Well, there are some other articles in this
issue, and before we get to that feature forum let's go through
those with our listeners. First, Carolyn, I've got a Research
Letter from Professor Cornel entitled "Long Term Efficacy of
Colchicine In Patients With Chronic Coronary Disease With
Insights From LoDoCo2."


Dr. Carolyn
Lam:            


Wow. There's an exchange of letters between Drs. Wang and Ji
regarding the article "Histidine Triad Nucleotide Binding
Protein-1 Attenuates Cardiac Hypertrophy Via Suppressing Homeobox
A5 Expression," Global Rounds paper by Dr. Indolfi on the
universal healthcare system and cardiovascular disease burden in
Italy. There's a cardiovascular case series by Dr. Raber on a
pacemaker red herring and a hypertrophic cardiomyopathy copycat.
Finally, there's a Perspective piece by Dr. Drakos on a
mechanical bridge to recovery as bridge to discovery learning
from few and applying to many.


Dr. Greg
Hundley:          


Well, Carolyn, I can't wait to get to this feature forum
discussion, and I get a chance to interview you.


Dr. Carolyn
Lam:            


Ah! All right, let's go.


Dr. Greg
Hundley:          


Welcome listeners. We have on this February 22nd a forum feature
discussion where we have two papers that we are going to present,
and oh, what an honor it is. Guess who I get to interview first?
Dr. Carolyn Lam from the National Heart Center of Singapore,
along with a guest editor, Dr. John McMurray from Glasgow
University in Scotland, followed by another paper from Dr. Vlado
Perkovic from the Georgia Institute for Global Health in Sydney,
Australia. Then lastly, Dr. Naveed Sattar, one of our associate
editors who also comes to us from Glasgow, Scotland. Welcome to
all of you.


Well, Carolyn, we're going to start with you today. I know you've
got a paper combining the use of GLP-1 receptor agonists with
SGLT-2 receptor antagonists. Can you tell us, Carolyn, a little
bit about the background that went into this study? What was the
hypothesis that you wanted to test?


Dr. Carolyn
Lam:            


Happily, Greg. First of all, what a pleasure to be sitting on the
opposite side of the mic, if I might say so, and a real privilege
to be speaking on behalf of the AMPLITUDE Executive and Steering
Committee about this paper. The whole idea is that we know that
SGLT-2 inhibitors and GLP-1 receptor agonists are the rage being
recommended for their reduction in cardiovascular events in
patients with Type 2 diabetes. However, they appear to do this by
complimentary mechanisms. That really raises the tantalizing
question of, "Can we combine them?"


Now, What do I mean by that? Well, GLP-1 receptor agonists are
known for their reduction in the risk of atherosclerotic ischemic
events, particularly like stroke, that benefit being greater,
whereas a relatively modest effect on kidney function, perhaps
heart failure. Whereas SGLT-2 inhibitors more impressively reduce
the risk of heart failure, kidney function decline, kidney
outcomes, and so on with a modest effect on myocardial infarction
and perhaps no effect on stroke. So, you see, very complimentary.
The whole question was, "What would it be like to combine these
treatments?" And, in the absence of a trial that actually does a
two by two randomization perspective or anything, we decided to
look back at the AMPLITUDE-O trial, which was a large
multinational trial of patients with Type 2 diabetes randomized
to the GLP-1 receptor agonist efpeglenatide versus placebo, but
was unique in including the largest proportion thus far of
concurrent SGLT-2 inhibitor use in these prospective GLP-1
receptor agonist trials to date.


Dr. Greg
Hundley:          


Very nice. And so, you've told us a little bit about your study
design. How about specifically your study population? And then,
Carolyn, what did you find?


Dr. Carolyn
Lam:            


All right. So, of the 4,076 participants in the AMPLITUDE-O
trial, 618 reported SGLT-2 inhibitor use at baseline. They were
fairly similar to those not receiving SGLT-2 inhibitors. They had
similar age and body mass index, but were less likely to be
women, they had a longer duration of diabetes, similar history of
cardiovascular disease, but lower prevalence of prior heart
failure and lower blood pressure, HB A1C, LDL cholesterol, and
albuminuria, but similar GFR.


When we looked at the effect of efpeglenatide in the presence or
absence of baseline SGLT-2 inhibitor use, we basically found no
difference. The P for interaction for each of these outcomes was
basically not significant, whether we were looking at MACE and
expanded MACE, which included revascularization and angina on top
of standard MACE, whether we were looking at a renal composite or
a composite of MACE and death, or whether we were looking at
heart failure hospitalization. Which, by the way, all of these
were significantly reduced by efpeglenatide, and so, similarly,
whether or not there was a baseline SGLT-2 inhibitor. Very
importantly, side effects were also similar whether or not
patients were on an SGLT-2 inhibitor concurrently. This bodes
really well for the combination.


Dr. Greg
Hundley:          


Very nice Carolyn. Well, John, as a guest editor to Circulation,
several papers often come your way each year. What in intrigued
you about this particular manuscript?


Dr. John McMurray:      


Well, exactly as Carolyn said, Greg, this asks a question and
gives some of an answer to a question that all of us are asking
which is, "Should we be using these two drugs together? Do they
have complimentary additive benefits, or are those benefits
independent of each other?" I think, as Carolyn said, her data
from the AMPLITUDE-O trial, which was a fantastic trial, go some
way towards addressing that.


And, Carolyn, I wondered... Maybe to give some more context to
these really interesting data... I think this question was asked
the other way around. I think our colleagues in the DECLARE–TIMI
58 trial looked at it in reverse. They were able to look at
adding of an SGLT-2 inhibitor to the subset of patients who were
in a GLP-1 receptor agonist. What... Can you remind us what they
found, because I think that's an interesting alternative approach
to this?


Dr. Carolyn
Lam:            


Excellent point, John, thank you. Because DECLARE was so big a
trial that even though the percentage of patients on a concurrent
GLP-1 receptor agonist was a bit smaller if you look at percent,
it was still a very large subgroup. Thankfully, those results
were extremely consistent with what we are seeing, too.


In a trial of an SGLT-2 versus placebo, the SGLT-2 inhibitors
benefits were regardless of concurrent GLP-1 receptor agonist,
and we showed the mirror image of that. Again, I think with the
totality of evidence, it's very reassuring and also very
important because to truly answer this, we would need a huge
prospective randomized two by two trial, or... Which, I think
will not be feasibly accomplished except in a pragmatic trial.


Dr. John McMurray:      


Carolyn, maybe one very last point to make again about context,
which Greg asked about. Here, we're talking about the primary,
secondary prevention of cardiovascular events. You mentioned
heart failure, which we're both very interested in. That's
intriguing, because it looks to me like the heart failure was
largely the prevention... perhaps the incident heart failure. I
think there is still a question mark about the role of GLP-1
receptor agonists as a treatment for prevalent heart failure. Do
you agree? Do you think that's still an unanswered question? Or,
do these results in some way make you more comfortable about
using GLP-1 receptor agonists in patients with established heart
failure?


Dr. Carolyn
Lam:            


Wow. Again, an excellent question. These data reassure me that if
I had a patient with Type 2 diabetes who developed heart failure
and still required glucose control I would be very comfortable
continuing a GLP-1 receptor agonist, because many of these
patients in this trial who got heart failure obviously didn't
drop out of the trial. They continued on the GLP-1 receptor
agonist and the safety profile looks okay. However, I do not
agree that the GLP-1 receptor agonists have become a treatment
for heart failure the same way the SGLT-2 inhibitors have. That
would require, in my mind, evidence in a prospectively defined
validated population of heart failure, with known ejection
fraction or not. And, to be even more provocative, I suppose,
even perhaps without diabetes. Now, that would really put the
nail in the coffin, if I may. Basically exactly what you did,
John, in DAPA HF.


Dr. John McMurray:      


All right, to finish on a provocative comment for the audience
just before we leave this segment, it may of course depend on the
heart failure phenotype type as well. In all of these trials,
we're never really sure whether the patients have HFpEF, HFrEF,
or a combination. So, lots of questions still.


Dr. Greg
Hundley:          


Very nice. Well, thank you so much, Carolyn and John.


Listeners, next we want to turn to our second feature article.
This one is from Dr. Vlado Perkovic. Vlado, welcome. You have a
paper involving GLP-1 receptor agonists and focusing on renal
disease. Can you describe for us a little bit about the
background pertaining to your paper, and what was the hypothesis
that you wanted to address?


Dr. Vlado
Perkovic:        


Thanks so much, Craig, and thanks for having me here. It's such a
joy to be part of this conversation. Our paper was a post hoc
analysis of two completed clinical trials, the LEADER and SUSTAIN
trials that looked at liraglutide and semaglutide, respectively,
compared to placebo in people at high cardiovascular risk. We
wanted to ask the question of... in more detail, the effects of
these agents collectively and individually on important kidney
outcomes to try and understand whether the GLP-1 receptor
agonist, which, as Carolyn says, have clearly had significant
benefits for MACE in particular, might also have the sorts of
benefits that we've seen, for example, with SGLT-2 inhibitors on
renal outcomes recognizing the massive burden of ill health,
premature mortality, morbidity, economic, and social costs that
go along with kidney disease as a complication of diabetes. What
we've done here is we've pulled the data from the two trials and
looked at them collectively and individually to try and unpack
the effects of GLP-1 receptor agonists on a range of kidney
outcomes.


We've looked at different thresholds of loss of kidney function.
Traditionally we've used doubling of creatine, which equates to a
57% loss of kidney function. More recently, we've moved to a 40%
loss of kidney function as being a good outcome in kidney trials.
There's been a push for 30 and 50% outcomes to be used. Here we
wanted to look really comprehensively at all of those outcomes,
as well as the outcomes of change in albuminuria and change in
EGFR slope, where we had more power, perhaps, to detect
differences between the agents. Our hypothesis was that GLP-1
receptor agonists would have evidence of kidney protection. We
thought up front that the likelihood was the kidney protection
would be consistent at different levels of kidney function and
might be similar between different agents. But, that wasn't what
we ended up finding.


Dr. Greg
Hundley:          


Very nice. So, you mentioned the SUSTAIN and the LEADER trials.
Can you describe for us a little bit more, and some of the
specifics, perhaps, to your study population? And then, walk us
through your study results.


Dr. Vlado
Perkovic:        


Yeah, so very happy to do that. Thank you. As I say, these trials
were primarily cardiovascular outcome trials that were designed
to assess the cardiovascular effects of the GLP-1 receptor
agonists and therefore the populations reflect that intent with
people who had preexisting cardiovascular disease primarily. What
we found when we looked at the results was evidence of perhaps
modest reduction in some of the renal outcomes based on different
thresholds of loss of kidney function of the order of 10 to 20%
overall when we looked at the pooled study population. Of course,
that compares to a much more significant 30 to 40% reduction in
the risk of these same outcomes when we look at drugs like SGLT-2
inhibitors.


Overall, they didn't appear to be quite as effective. But, we
were somewhat surprised when we started to dig into the data in
more detail in that we found that people who had reduced kidney
function based on a lower EGFR, particularly an EGFR below 60, or
those who had either micro or macro albuminuria, the benefits of
treatment appeared to be greater in absolute and proportional
terms. It also was much clearer, such that in people who had both
had reduced EGFR and an increased level of albuminuria, there
were reductions in the risk of the constant renal outcomes of
approximately 40%, suggesting that these drugs may be
particularly effective in people with established kidney disease,
which... there's a novel finding today.


We were able to dig into that in more detail, looking at
albuminuria and EGFR slope and effectively found consistent
results for those outcomes as well, giving us some confidence
that the findings perhaps were more likely to be real. We, in
addition, looked at the different drugs and found some evidence
that high dose semaglutide... in particular, one milligram weekly
dose, and appeared to be more effective than the lower dose of
semaglutide or liraglutide for some of those intermediate
markers, if you like.


Dr. Greg
Hundley:          


Very nice. Naveed, now, as the associate editor, what intrigued
you about this particular study? What drew your attention to it
and caused you to bring it through that review process to our
readers?


Dr. Naveed
Sattar:         


Yeah. Thanks Greg, and thanks Vlado. Now, I think this is a
lovely study. I think we've been familiar with the effect of
GLP-1 and albuminuria for a long time. I think that's fine, but
not... that doesn't really float everyone's button. You know,
albuminuria is not necessarily a hard endpoint. But, EGFR and
EGFR slopes are becoming something that people are starting to
become interested in as a marker of future diabetic kidney
disease in end stage kidney disease. Vlad could probably comment
on that. I think there was a suggestion if you meta-analyze all
the GLP-1 trials, which we did recently on the back of
efpeglenatide, both Carolyn and John were co-authors.... that
there's a suggestion that GLP-1 may actually improve hard kidney
outcomes. This paper, on the back of that, with a detailed look
at EGFR slopes and different thresholds, does further support the
fact that liraglutide and semaglutide do slow kidney outcome
progression, particularly in those who've already got a degree of
kidney damage.


Now, the context of that is actually really important in the
sense that Vlado and colleagues and nephrologists around the
world are very excited about the SGLT-2 inhibitors. But, also
having another drug on top of that would might further slow
kidney damage is excellent, particularly in a population which
also has more atherosclerotic cardiovascular disease. These drugs
could therefore have a double benefit, not only slowing kidney
damage, but also preventing atherosclerotic cardiovascular
disease and the population at high risk of both conditions. Of
course, the future then also, as John mentioned, will be, "what
about the benefit on top, and going forward in heart failure as
well?" I think this study looks... well, adds to the support that
GLP-1 receptor agonists actually improve hard kidney outcomes. I
think that's the realization. But, going back to Vlado, I'd be
interested to get his comment of, "Well, does this study and
associated evidence now lead you to think when should we be using
these drugs in our patients with chronic kidney disease?" That
probably is the question, Vlado.


Dr. Vlado
Perkovic:        


Yeah. That's an important question. I think, Naveed, for us as a
community. I think one of the nice things is that we can use
these drugs in people with kidney disease already. They're
approved, and we don't have the same sort of EGFR restrictions as
we've had with SGLT-2 inhibitors. But, what we really want to
know is, "What are the benefits that we're offering to our
patients, and at what price might that come? Is there an
increased risk of adverse events in this very sensitive
population?"


Of course, the only way to answer those questions is to test it
prospectively, which we're now doing in the FLOW trial, where
we're randomized three and a half thousand people on semaglutide
and placebo. So, over the next couple of years we will answer
that question more definitively I hope. We're particularly
focused on people with kidney disease in that trial. But of
course it also... These data, if they're confirmed in that trial,
raise important questions, I think, about the mechanism of the
renal effect that needs teasing out. If they're truly more
effective in relative terms, as well as absolute terms, in people
who've got established kidney disease what does that tell us
about the way that they might be providing that renal benefit?
And its relative interaction, not only with SGLT-2 inhibitors,
but also with mineralocorticoid receptor antagonists, which have
recently additionally been shown to be beneficial on the kidney
in the FIDELITY and the FIGARO trials.


Dr. Greg
Hundley:          


Very nice. Well, Naveed, you have led us and Vlado into our next
very quick rapid fire question for our listeners, in working
through each of you, both as authors and editors, what do you see
is the next study to be performed in this sphere of research?
Carolyn, we'll start with you, then John, then Vlado, and then
Naveed.


Dr. Carolyn
Lam:            


Well, I think I alluded to it a little bit earlier that what
we'd, of course, really love is a prospective randomized trial
looking at the combination of the treatments versus placebo and
versus one of each only. That sounds like pie in the sky, though.
Maybe a pragmatic trial. Maybe an... Oh, John, shut your ears,
but maybe looking back at real world data to look at this a
little bit better. We're going to need a little bit more, at
least I think, also to reassure ourselves that the combination is
really safe in these patients.


Dr. Greg
Hundley:          


John?


Dr. John McMurray:      


I think we need to know about GLP-1 receptor agonists in patients
who don't have Type 2 diabetes because I think it's going to be
critically important going forward to know whether this is just
about dysglycemia and glucose lowering, which it seems probably
isn't. Because my interest is in heart failure, of course, I
would like to see these drugs tested in patients with symptomatic
heart failure and both the major heart failure phenotypes with
and without Type 2 diabetes.


Dr. Greg
Hundley:          


Vlado?


Dr. Vlado
Perkovic:        


Yeah, I'd support what John says and add people with and without
diabetes in kidney disease as well to that group, as we've seen
with DAPA-CKD study. I think the other really big opportunity for
us here that's been highlighted by work done by John and others
is the possibility that we might dramatically reduce the
prevalence of these terrible complications of diabetes by using
combination therapy and multi-drug combination therapy.
Potentially, we've got not just the GLP-1 receptor agonist and
the SGLT-2 inhibitors, but we've got MRAs and other drugs,
depending on which outcome we're talking about. If these drugs
are truly independent, as Carolyn's important work suggests, we
could have a major impact at a population level on the prevalence
of these terrible disorders in our patients.


Dr. Greg
Hundley:          


And finally, Naveed.


Dr. Naveed
Sattar:         


Yeah, thanks. I'm glad I'm not the only one who upsets John
McMurray now and again, but it's probably good for him. What I
would say is I agree with all the comments thus far. I would love
the fact that with the newer stronger GLP-1s giving us additional
weight loss, and, perhaps, with the combined GLP-1 GIP drugs, I
would love if we could test them early in diabetes, actually, to
actually reverse diabetes, as it were. And, can we delay these
complications for 5-10 years, and perhaps with combination
SGLT-2? Of course, we can't really do that now because of the
costs, but going forward... And, John and I have had lots of
conversations about multi-morbidity and obesity is being a big
driver to all of that. Now we've got class of drugs coming that
actually could cause significant weight loss and improve multiple
outcomes that we've discussed: kidney, heart failure,
atherosclerotic cardiovascular disease, and also possibly improve
patients quality of life, particularly if the weight loss is
quite substantial. I would love if we target that, but I think
that's partly linked to some of the answers that've already been
heard.


Dr. Greg
Hundley:          


Well, listeners, we want to thank our investigators, Dr. Carolyn
Lam and Dr. Vlado Perkovic, and also our editors, Dr. John
McMurray and Dr. Naveed Sattar for bringing us these two papers.
The first highlighting that the efficacy and safety of GLP-1
agonists appear independent of concurrent SGLT-2 inhibitor use.
And the second paper, emphasizing that GLP-1 receptor agonists
offer renal protection, particularly in those with advanced renal
disease.


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.


Speaker 7:         


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.