Circulation February 23, 2021 Issue

This week, join author Chintan Dave and Associate Editor Naveed
Sattar as they discuss the risk of cardiovascular outcomes in
Type 2 Diabetes patients following the addition of SGLT2
inhibitors versus sulfonylureas to baseline GLP-IRA therapy.


TRANSCRIPT BELOW:


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:


Greg, I love today's featured paper. It's a question everybody's
asking. It's about cardiovascular outcomes, potential benefits,
following the addition of SGLT2T2 inhibitors versus sulfonylureas
to baseline GLP-1 receptor agonist therapy. Now, okay, I'm going
to keep you waiting because that was just a hook. We got to get
to us summaries first. And I'm going to start. The first original
paper I want to describe is an analysis of myocardial infarction
from the ischemia trial. And it looks at the impact of different
definitions on the incidents, prognosis and treatment
comparisons.


Dr. Carolyn Lam:


Because I know you're going to ask, I'm going to tell us a little
bit about ischemia. So in an ischemia and initial invasive
strategy did not significantly reduce rates of cardiovascular
events or all-cause mortality compared with a conservative
strategy in patients with stable ischemic, heart disease, and
moderate to severe myocardial ischemia. The most frequent
component of the composite cardiovascular end points was
myocardial infarction. So in the current report from Dr. Chaitman
and colleagues from St. Louis University school of medicine, the
aim was to compare treatment effects on the primary and major
secondary competent end points in the ischemia trial using the
pre-specified primary and secondary MI definitions.


Dr. Greg Hundley:


So Carolyn, what were those two EBI definitions, the primary and
secondary?


Dr. Carolyn Lam:


Right. Now, I'm going to try to simplify this. So, for procedural
MI, the primary MI definition use CK-MB as the preferred
biomarker, whereas the secondary definition used cardiac
troponin.


Dr. Greg Hundley:


Great, Carolyn. So what did they find?


Dr. Carolyn Lam:


So procedural MI definition had an important impact on event
frequency and subsequent prognosis. When the pre-specified
secondary MI definition was applied, the conservative strategy
had a significantly lower composite event rate for the primary
and major secondary trial end points, due to an increased number
of procedural MIs in the invasive strategy. Furthermore,
spontaneous Type One MI events associated with increased risk of
cardiovascular death were reduced with an invasive strategy,
which is either PCI or CABG.


Dr. Greg Hundley:


Nice, Carolyn. Well, my first paper actually is a favorite topic
of yours, HFpEF. And it really involves the central command and
the regulation of exercise rate response. It comes to us from Dr.
Ben Levine and colleagues at the University of Texas Southwestern
Medical Center in Dallas.


Dr. Carolyn Lam:


Yay.


Dr. Greg Hundley:


All right, Carolyn. So chronotropic incompetence is common in
HFpEF. And it's linked to impaired aerobic capacity. Whether
upstream, autonomic signaling pathways are responsible for
raising exercise heart rate are impaired in patients with HFpEF,
That's really unknown.


Dr. Carolyn Lam:


Yep. It is something that we wonder. And so what did Dr. Levine
find?


Dr. Greg Hundley:


Thanks Carolyn. So the central command, so vaguely mediated and
the metabo-barrow receptor function, which is sympathetically
mediated in patients with HFpEF, We're not different from healthy
senior controls, despite significantly lower peak whole body
exercise, heart rates. So these results, Carolyn, demonstrate key
reflex autonomic pathways, regulating exercise, heart rate
responsiveness are actually intact in patients with HFpEF. Great
new work from Dr. Ben Levine.


Dr. Carolyn Lam:


And I love the way you summarized that. Thank you, Greg. Well, my
next paper is the first report implicating the cross priming
function of dendritic cells in immunopathology after Type Two MI.
And that includes inflammation, fibrosis and functional decline.


Dr. Greg Hundley:


So tell us a little bit more Carolyn about these dendritic cells?


Dr. Carolyn Lam:


Ah-ha so I was ready for that question. So after ischemic injury
to the myocardium, dendritic cells respond to cardiomyocyte
necrosis present the cardiac antigen to T-cells and potentially
initiate a persistent auto-immune response against the heart. So
cross priming dendritic cells may have the ability to activate
both CD4-positive helper and CD8-positive cytotoxic T-cells in
response to necrotic cells. And may thus be crucial players in
exacerbating auto-immunity targeting the heart.


Dr. Carolyn Lam:


So, in this study, authors led by Dr. Sattler from Imperial
College, London, performed some elegant mouse experiments and
showed that cross-priming dendritic cells were present in the
heart and activate it after ischemic injury. Depletion of these
dendritic cell cross priming function, inhibited accumulation,
and activation of cytotoxic T-cells and stopped myocardial
immunopathology and functional decline. So with cross-priming,
these authors provided a targetable pathway to prevent activation
of T-cells cyto-toxicity and persistent post Mia immunopathology
exacerbating heart failure risk.


Dr. Greg Hundley:


Oh, beautiful. Carolyn, what a great description there. So my
next paper comes to us from Dr. David Park from the New York
University school of medicine. So Carolyn elevated intracardiac
pressure due to heart failure, induces electrical and structural
remodeling of the left atrium that begets atrial myopathy and
arrhythmias. At present the underlying molecular pathways that
drive atrial remodeling during cardiac pressure overload are
poorly defined. So the purpose of this study for these
investigators was to characterize the response of the ETV1
signaling axis in the left atrium during cardiac pressure
overload in humans, as well as mouse models. And explore the role
of ETV1 in atrial electrical and structural remodeling.


Dr. Carolyn Lam:


Ah, another study involving both animal and human models. Very
important subject too. So what were the results?


Dr. Greg Hundley:


Well, Carolyn, evidence from both the Cleveland Clinic, Biobank
Human Subjects Repository and the animal science experiments
revealed that ETV1 is downregulated in the left atrium during
cardiac pressure overload. Thereby contributing to both the
electrical and the structural remodeling that we observe in the
left atrium during cardiac pressure overload.


Dr. Carolyn Lam:


Nice. Well, let's quickly finish up with what's in the mailbag.
We've got a research letter by Dr. Randi on the lack of evidence
of AEs to expression and replicative infection by SARS-CoV-2 in
human endothelial cells. There's another by Dr. Stokes on the
association of cigarette and electronic cigarette use patterns
with levels of inflammatory and oxidative stress biomarkers among
US adults. And another research letter by Dr. Hemelsoet on
screening for Fabry disease in male patients with arrhythmia
requiring pacemaker or ICD.


Dr. Greg Hundley:


Thanks Carolyn. So I've got a paper it's a cardiovascular case
series from Dr. Workman that involves a case of presyncope after
transcatheter aortic valve replacement. Dr. Özeke has an ECG
challenge reminding us that common things occur commonly. Dr.
Zaha has a Perspective entitled, "Mending Broken Hearts, a New
Treatment Paradigm for Immune Checkpoint Inhibitor Induced
Myocarditis." And then finally, Dr. David Goff, the director of
the NHLBI has a wonderful perspective piece (Special Report). And
it really addresses some results from the Bethesda conference at
the National Heart Lung and Blood Institute and the American
Heart Association. And it was co-sponsored the bending curve of
cardiovascular disease mortality, the Bethesda plus 40 years
Symposium.


Dr. Greg Hundley:


The report, Carolyn, summarizes the relevant research, policy,
and practice opportunities discussed at the symposium, including
participant led discussion that explored the challenges and
barriers in promoting cardiovascular health, across lifespan. And
established a potential framework for observational research
interventions that would begin in early childhood. Well, Carolyn,
how about now we jump forward to that feature discussion.


Dr. Carolyn Lam:


All right, now we can go.


Dr. Greg Hundley:


Well, listeners, we are to the feature discussion today. And we
have with us Dr. Chintan Dave from Rutgers University in New
Jersey, and our own associate editor, Dr. Naveed Sattar from
Glasgow, Scotland. Welcome gentlemen. Chintan, could you explain
to us some of the background information that went into the
construct of your study and then what hypothesis did you want to
test?


Dr. Chintan Dave:


So just for background, so we know that artheriscraotic
cardiovascular events in heart failure typically occur in higher
prevalence in patients with type two diabetes. What's been really
exciting in recent years is that certain second-line therapies,
namely SGLT2 inhibitors and GLP-1 receptor agonist in these large
cardiovascular outcome trials have shown to reduce the incidents
of cardiovascular events. So from these trials, we can infer that
SGLT2 inhibitors typically reduce heart failure hospitalizations,
and also have an impact on 3P-MACE, which is just the composite
of cardiovascular death, non-fatal MI and non-fatal stroke
hospitalizations. While GLP-1 receptor agonist tend to reduce,
also have an impact on 3P-MACE, but they also have some modest
benefits in heart failure hospitalizations as well.


Dr. Chintan Dave:


So now that we know that these agents reduce cardiovascular risk,
what's not known is, whether or not, if we can use these agents
together to further maximize a reduction in cardiovascular
events. So in the cardiovascular outcome trials the dual use of
SGLT2 two inhibitors and GLP-1 receptor agonists was rare and
ranged from between 0% to 5.3%. So as a starting point, we said,
"Okay, let's look at observational data to see what happens when
you add SGLT2 inhibitors to patients who are already using GLP-1
receptor agonist." And we hypothesized that, given the orthogonal
pharmacodynamic effects on cardiovascular risk, adding SGLT2
inhibitors to existing GLP-1 receptor therapy should further
reduce cardiovascular events.


Dr. Greg Hundley:


Very good. And can you describe for us your study population and
study design?


Dr. Chintan Dave:


Sure. So we used three databases in the US. Two of these
databases were commercial claims data, which is typically your
employer based insurance plans, which have patients between the
ages of 18 and 64. And we supplemented that data with Medicare
fee for service claims, which have patients over the age of 65.
So within these three databases, we identified patients who have
a diagnosis of type two diabetes and are already a GLP-1 receptor
therapy or GLP-1RAs and initiating either SGLT2 inhibitors or
sulfonylureas.


Dr. Chintan Dave:


And after we identified this patient population, we controlled
for several pertinent variables that could be considered
confounders, including socio-demographic variables, diabetes
complications, and cardiovascular conditions. And we had two
primary endpoints. The first primary end point of interest was a
composite cardiovascular endpoint, which is defined as the
composite of non-fatal MI or nonfatal stroke hospitalizations in
all cause mortality. The reason we used all cause mortality
instead of cost specific mortality is basically because we didn't
have information on cause of death. So we have to resort to a
more generic definition of mortality in the composite
cardiovascular endpoint. The second primary endpoint that we used
was heart failure hospitalizations. So we then in this
population, estimated hazard ratios using basically a time to
event framework.


Dr. Greg Hundley:


Okay. And what were your results?


Dr. Chintan Dave:


So after applying the eligibility criteria in all three databases
and after doing a one-to-one propensity score matching, we had
12,500 patients who initiated SGLT2 inhibitors and 12,500
patients in the sulfonylurea groups. For the true primary end
points the addition of SGLT2 inhibitors to baseline GLP-1RA
therapy was associated with a 22% decrease in the incidents of
composite cardiovascular end point or an adjusted hazard ratio of
0.78. And the caught 95% confidence intervals were statistically
significant. For the endpoint of heart failure hospitalizations,
we noted a 36% decrease in the risk of heart failure
hospitalizations with the adjusted hazard ratio being 0.64. And
again, that was statistically significant as well.


Dr. Chintan Dave:


The CCE or the Composite Cardiovascular Endpoints was driven
primarily by non-statistical decreases in the risk of MI by about
25%, in all cause mortality by about 32%. But we also found no
effect on stroke, which is also in line with what others have
reported. The other thing we looked at was also to look at any
evidence for heterogeneity in treatment effects by presence of
cardiovascular diseases. And we found no statistical significant
difference in that aspect. The last thing we looked at also was
to look at any evidence of heterogeneity by baseline
cardiovascular disease in the patient groups. And we found no
evidence to that effect.


Dr. Greg Hundley:


Very nice. Well, Naveed help us put this study in perspective
with some of the other research that I know you're familiar with
related to the use of SGLT2 inhibitors and GLP-1 receptor
agonists.


Dr. Naveed Sattar:


Yeah. Thanks Greg. So as we all know, the biggest gains in
diabetes in the last few years is these two costs of the trucks
SGLT2 inhibitors and GLP-1. We believe and the evidence suggests
that SGLT2s, are more cardiorenal in its benefits, and GLP-1 more
atherothrombotic. So the hope is that if you combine these drugs,
you get additional benefits, but there are no trials that have
actually tested this. So this particular paper being kind of
first observational, look at adding an SGLT2 versus another drug
on top of a GLP-1, tries to get at that particular question. And
it provides an early hint that yes, if you add an SGLT2 on top of
the GLP-1, you get additional benefits. Giving us some insight
that yes, you combine these two classes of drugs, you might get
additional benefit in one drug on its own.


Dr. Naveed Sattar:


Of course, this is not trial. Some of our readers are going to be
nihilist and will not believe the data because it's not a trial,
but that's fine. But it's done as well as it possibly can. This
observational propensity analysis is well matched. The data have
some kind of external validity in the sense that the greatest
benefits or risks reductions, but for heart failure
post-acquisition, which is what we would believe ratio to
inhibitors. So there is some sense of validity here, but clearly
colleagues, they want to know, and I actually had a patient in
the clinic on Tuesday who was on a GLP-1 and actually was an
SGLT2. And I wanted to add the GLP-1. And this kind of evidence
provides me some evidence of confidence that yes, by adding both
drugs, I might get additional benefits in that one drug on its
own.


Dr. Naveed Sattar:


So what you're going to ask next, Craig, and I'll give my answer
first. What we really need to do now is actually do the trials.
And I think the trials will predominantly work, adding GLP-1 on
people who are on SGLT2, because I think more people will be
initially an SGLT2 because it's a oral therapy. Then we'll add
GLP-1. Although we do have a new oral GLP-1 in play as well. So,
that's the kind of paradigm we're in. Some hints, the combination
gives you more than the single drug and I think that's really
quite promising for people.


Dr. Greg Hundley:


Very nice. So Naveed suggesting a clinical trial to confirm some
of these results. Chintan, do you have anything to add? What
study do you think or what area of investigation in this field do
you feel is next in line?


Dr. Chintan Dave:


Yeah, I mean, I would just start by saying that I agree with
everything that Naveed said in the sense that this is a starting
point. And that I think the key take home from this study that
sort of is going to be published is basically that not only do
SGLT2 inhibitors reduce the cardiovascular events in patients
using GLP-1 therapy, but the fact that the magnitude of this
reduction is very similar. What was noted in cardiovascular
outcome trials of SGLT2 inhibitors for GLP use was very minimal.
In other words, you can super impose the cardiovascular benefit
profile of the SGLT2 inhibitors, which were seen in trials two
patients using GLP-1 therapy.


Dr. Chintan Dave:


Now the converse is what needs to be done next, basically, where
we need to look at what happens when you add GLP-1 receptor
agonist, to SGLT2 inhibitors, as Naveed just said. And he raised
a really good point in that more patients are going to be on
SGLT2 inhibitors, because they want to avoid GLP-1 receptor
agonist because they don't want to use injectable therapies. Of
course we have oral semaglatites maybe that may mitigate these
issues. But the fact that that aspect is still unknown, could
potentially be really good idea for future studies. So that
potentially would be a nice, good step.


Dr. Greg Hundley:


Excellent.


Dr. Naveed Sattar:


Can I see one last thing, Greg? There is a trial coming this year
called AMPLITUDE‐O, which is a GLP-1 trial, which does have a
fair number of people on base than SGLT2s. We might be able to
get a curly hint at that ongoing trial in the next six months to
a year.


Dr. Greg Hundley:


Excellent. Well, we want to thank both Chintan Dave from Rutgers
and our own associate editor, Dr. Naveed Sattar from Glasgow,
Scotland. And really presenting information from US Claims
databases highlighting the addition of SGLT2 inhibitors to GLP-1
receptor agonists and finding there was an association with a
further reduction of cardiovascular risk relative to the use of
GLP-1 agonists alone. On behalf of both Carolyn and myself, we
want to wish you a great week. And catch you next week On the
Run. This program is copyright of the American Heart Association,
2021.