Circulation Jul 18, 2017 Issue

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


                                               
Now, the SGLT2 inhibitor, empagliflozin, has been shown to
improve outcomes in the EMPA-REG OUTCOMES trial. But do these
benefits also apply in the real world, and to other SGLT2
inhibitors as a class? Well, we may just have some answers this
week in the CVD-REAL study. More soon right after these
summaries.


                                               
The first original paper this week uncovers the mechanism of
beneficial action of T-cells for proper healing after myocardial
infarction. Now, the pro-inflammatory danger signal, adenosine
triphosphate or ATP, is released from damaged cells, and degraded
by the ectonucleotidase CD73 to the anti-inflammatory mediator,
adenosine.


                                               
Using newly-generated CD4-CD73 null mice, first author, Dr. Borg,
corresponding author, Dr. Schrader, and colleagues from Heinrich
Heine University of Düsseldorf in Germany, showed that a lack of
CD73 on T-cells enhanced tissue fibrosis and worsened myocardial
function in the remodeling phase after myocardial infarction.


                                               
T-cells migrated into the injured heart and upregulated their
enzymatic machinery to enhance the extracellular degradation of
ATP to adenosine. T-cells lacking CD73 showed accelerated
production of pro-inflammatory and profibrotic cytokines.
Finally, the adenosine 2B receptor was upregulated on cardiac
immune cells in the remodeling phase.


                                               
In summary, therefore, local adenosine formation by CD73 on
T-cells appears to be the body's own defense mechanism to control
inflammation induced by myocardial infarction. This is a
mechanism that might be exploited to promote healing or
remodeling by specifically targeting the adenosine 2B receptor in
the infarcted heart.


                                               
The next paper provides insights on genetic determinants of
susceptibility to peripheral artery disease, and specifically
puts the spotlight on Bcl-2-associated athanogene-3, or Bag3,
which is a cell chaperone protein previously identified in a
genetic screen for determinants of tissue loss with hindlimb
ischemia.


                                               
In the current study, Dr. McClung from East Carolina University,
Brody School of Medicine in Greenville, North Carolina, and
colleagues, used adeno-associated viruses to show that an
isoleucine to methionine variant at position 81 in Bag3 was
sufficient to confer susceptibility to ischemic tissue necrosis
in BALB/c mice.


                                               
In a series of elegant experiments, they demonstrated that Bag3
was a modulator of ischemic muscle necrosis and blood flow. In
summary, this study provides evidence that genetic variation in
Bag3 plays an important role in the prevention of ischemic tissue
necrosis, and highlights a pathway that preserves tissue survival
and muscle function in the setting of ischemia.


                                               
The next study provides insights into inflammatory atherogenesis
by studying psoriasis, a chronic inflammatory disease associated
with an accelerated risk of myocardial infarction. First author,
Dr. Lerman, corresponding author, Dr. Mehta from the NHLBI,
National Institutes of Health in Bethesda, United States, and
colleagues, hypothesized that the increased cardiovascular risk
observed in psoriasis would be partially attributable to an
elevated subclinical coronary artery disease burden composed of
non-calcified plaques with high-risk features.


                                               
To test this hypothesis, they compared total coronary plaque
burden, non-calcified coronary plaque burden, and high-risk
plaque prevalence between 105 psoriasis patients, 100 older
hypolipidemic patients eligible for statin therapy, and 25
non-psoriasis healthy volunteers. All patients underwent CT
coronary angiography, and a sample of the first 50 psoriasis
patients were scanned again at one year following therapy.


                                               
The authors found that patients with psoriasis had greater
non-coronary burden and increased high-risk plaque prevalence
compared to healthy volunteers. Furthermore, compared to older
hypolipidemic patients, patients with psoriasis had elevated
non-calcified burden, and equivalent high-risk plaque prevalence.
Finally, improvement in skin disease severity was associated with
an improvement in non-calcified coronary burden at one year.


                                               
The clinical implications are that patients with psoriasis have
similar coronary artery disease risk as hyperlipidemic patients
one decade older, and these patients with psoriasis should be
screened earlier for cardiovascular disease and educated about
their elevated risks. Further investigations focus on the
longitudinal impact of psoriasis treatment on high-risk plaque
morphology, as well as on the extent of cardiovascular risk
mitigation in randomized trials.


                                               
Well, those were your summaries. Now for our feature discussion.
Now, we've heard of the EMPA-REG OUTCOME trial, that prospective
randomized, controlled trial, showing a substantial reduction in
cardiovascular death and hospitalization for heart failure with
the sodium-glucose cotransporter 2, or SGLT2 inhibitor,
empagliflozin, and that's, remember, that was in patients with
type 2 diabetes and established atherosclerotic cardiovascular
disease.


                                               
Well, our paper today really extends our knowledge and tells us a
bit more about the role of SGLT2 inhibitors in real-world
clinical care. And I'm so please to have with us the first and
corresponding author, Dr. Mikhail Kosiborod from Saint Luke's,
Mid America Heart Institute, as well as Dr. Gabriel Steg,
associate editor from Paris, France, joining us today. Hello,
gentlemen.


Dr. Gabriel
Steg:              
Hello.


Dr. Mikhail Kosiborod:   Hi. Good morning, Carolyn.


Dr. Carolyn
Lam:              
Mikhail, I am going to say what I said to you at the ACC and at
the ESC Heart Failure: Congratulations on CVD-REAL. Please tell
us about CVD-REAL.


Dr. Mikhail Kosiborod:   Right, well, we know, as you
just mentioned, that the EMPA-REG OUTCOME trial showed
substantial reduction in cardiovascular death, and
hospitalizations for heart failure in patients with type 2
diabetes and established cardiovascular disease. We were all very
excited once that data got presented in September of 2015 in
Stockholm, but there were several very important questions that
weren't really addressed, and truly, could not be addressed, in
EMPA-REG's trial.


                                               
The first, actually, and probably the most important is, we all
know that clinical trials, while we regard them as the gold
standard of evidence, as we should, they do have their own set of
limitations, the most important of which is that they examine a
relatively small sliver of patients; and many patients we see in
the clinic, in the hospital, don't look like patients in clinical
trials. I think the most important questions we tried to address
was, "Will this translate to real-world clinical practice?"


                                               
The second was, as you recall, again, all patients on EMPA-REG
had established cardiovascular disease, so we wanted to know
whether the benefits associated with the use of SGLT2 inhibitors
could potentially extend to lower-risk patients with type 2
diabetes without established cardiovascular disease, a much
broader spectrum of patients.


                                               
And finally, and also very importantly, I think, the third
question was, "Is it an empagliflozin-specific effect or is it a
class effect?" These are all the critical questions we tried to
address in the CVD-REAL study.


Dr. Carolyn
Lam:              
Great. Could you give us the topline results, please?


Dr. Mikhail Kosiborod:   Right. So, just as a reminder,
we collected data from well-established registries in six
countries, so the United States and some five countries in
Europe, Sweden, Norway, and Denmark, and also, the United Kingdom
and Germany. And really, the inclusion/exclusion criteria for the
study were quite broad, you just had to have type 2 diabetes and
be newly started on either an SGLT2 inhibitor or any other
glucose-lowering medications, which was the comparative group.


                                               
And after we did the one-to-one propensity match to make sure,
comparable samples, we ended up with about 154,000 patients, and
each treatment group, over 300,000 patients overall. What we
actually observed was a marked and highly significant reduction
in the risk of hospitalization for heart failure that was
associated with use of SGLT2 inhibitors versus other
glucose-lowering drugs.


                                               
In fact, the magnitude of reduction in risk that was associated
with SGLT2 inhibitors, so that outcome was quite similar, about
39% relative risk reduction, quite similar to what we see in the
EMPA-REG OUTCOME trial. But this, of course, was for the entire
class of SGLT2 inhibitors, so patients in the study were treated
primarily with canagliflozin and dapagliflozin, with a small
proportion being treated with empagliflozin.


                                               
We also saw dramatic and highly significant associated reduction
in the risk of all-cause death with SGLT2 inhibitors versus other
glucose-lowering drugs, about a 51% relative risk reduction, and
the composite of those two outcomes, obviously, there was
significant associated reduction in risk as well.


                                               
So, again, the hazard ratio estimate that we saw for these
outcomes were quite similar, and in some cases, almost identical
to what we've seen in EMPA-REG, but for a patient population that
was much broader, in fact, about 90% of patients, close to 90% of
patients in our study did not have established, documented
cardiovascular disease. And, of course, as I mentioned before,
important implications to these findings, in my opinion.


Dr. Carolyn
Lam:              
Yeah, that is just remarkable. Gabriel, could you share some of
the discussions that happened among the editors about this paper?


Dr. Gabriel
Steg:              
We were really excited by this paper. I think this is truly a
landmark paper for a number of reasons. It's a very large,
multinational study, but even more than the size, I think what's
interesting here are a couple of key aspects. First of all is
data on all-cause mortality, which is a highly reliable outcome
when you look at many of the observational studies.


                                               
Non-fatal outcomes can easily be skewed or biased in
ascertainment or assessment, but this is relatively reliable. And
here, we have a very large multinational cohort that finds
benefits on death, heart failure, and their composite, which are
remarkably consistent internally, consistent across countries,
and consistent with the randomized trial data evidence from the
EMPA-REG OUTCOME trial.


                                               
So that is striking, and this is consistent across six countries
using a very large sample size. But again, the size of the sample
is not the most important thing, because in observational
studies, you often have very large sample sizes, but if you have
bias in your observational study, the bias is just replicated
times the size of the study.


                                               
The consistency here between the treatment effects across the
various countries, the consistency with the efficacy assessed in
randomized clinical trials is really a crux in the quality of the
data and how believable the results are. Another key aspect that
got us really excited is the fact that only a minute fraction of
the data is related to use of empagliflozin.


                                               
Most of the data was acquired using other SGLT2, and we still
only have results now with empagliflozin, we don't have outcome
trial data with the other agents. They are pending, but pending
the availability of these trials, the fact that this large study
sees a consistent benefit, in terms of heart failure and
mortality, of the other agents in the class suggests that this is
a class effect.


                                               
And likewise, the fact that we're seeing these benefits in a
population that is much, much broader than the population of
EMPA-REG OUTCOMES is also very, very intriguing, and exciting,
and makes us really want to see more data not only from the
randomized trials that are upcoming, but also from this study.


                                               
Because now, what we would like to see is, see the detailed
cardiovascular outcomes in these cohorts, and I know that Mikhail
and his colleagues are working very, very actively on preparing
these analyses. I think this is going to be exciting. This is the
first of a series of landmark papers from a model observational
study.


                                               
There are many issues with observational studies. This is almost
as good as it can ever get, and I want to compliment Mikhail and
the consortium that's with him, because this is a tremendous
effort, across several countries, on achieving this. I think it's
very exciting for our readership and for clinicians around the
world.


Dr. Carolyn
Lam:              
I couldn't agree more, and I share your compliments for Mikhail.
Perhaps, Mikhail, could you give us a sneak peek at the future
and the ongoing work?


Dr. Mikhail Kosiborod:   We frequently think of, and I
think perhaps mistakenly at times, think of clinical trials and
observational real-world data as competing with one another. In
many cases, they're really complementary, and I think if you
really, kind of, think of interventions that we consider as those
gold standards enshrined in clinical guidelines, or something we
absolutely should be doing for our patients.


                                               
Just to pick one example, statins for secondary prevention after
a cardiovascular event, for example, there is data from both
sources suggesting that these drugs are highly beneficial, right?
So it is very important to have data from both sides, and I
think, as Gabriel mentioned, I look at CVD-REAL as a model, in
many ways, of how compelling the data from non-randomized, large,
real-world observational studies can be when done well.


                                               
In terms of a sneak peek for the future, there are many, many
things going on. We are carefully examining the outcomes that we
are reporting in circulation, including heart failure and
all-cause mortality in various subgroups. We are, of course, as
Gabriel mentioned, intently looking at other outcomes, including
myocardial infarction, stroke, cardiovascular death, and a
composite of major adverse cardiac events.


                                               
We're also examining some of the diabetes, one could argue,
maybe, diabetes-specific outcomes, such as hypoglycemia rates.
We, of course, as cardiologists tend to concentrate on
cardiovascular outcomes, but it's also important to remember that
there are other important outcomes that could be associated
benefits.


                                               
So these medications may be associated with marked reduction of
cardiovascular events, such as death and heart failure, but they
may also reduce hypoglycemia rates and, of course, that's
important from a quality-of-life standpoint for patients with
diabetes, so some of that work is ongoing.


                                               
And I would say, importantly, one of the other things that we're
hoping to be able to do in the future is to go beyond
cardiovascular outcomes, and perhaps blood glucose-specific
outcomes, such as hypoglycemia, and start looking at events such
as renal disease events, which I think are very important, of
course. Interact quite a bit with, I suspect, in many ways, with
some of the cardiovascular benefits that we're observing with
those agents, both in the clinical trials and, now, in large
observational studies.


                                               
And that's just the beginning. I mean, I think it's fair to say
that, as Gabriel mentioned, a huge amount of work went into
putting this together, right? And we're actually not only
expanding things from a standpoint of outcomes. We're also
expanding things from a standpoint of countries that will be
participating in CVD-REAL consortium.


                                               
So we're actually planning to add at least two or three more
countries from Europe, Middle East, and Asia in the coming
months, and more so in the future. And of course, once you have a
resource like this, there are additional questions that can be
addressed, actually, both with SGLT2 inhibitors as a class, but
also with other classes of type 2 diabetes medication. So that's,
I think, as much of a sneak peek as I can give you right now.
Just definitely promise you that there is a lot more coming.


                                               
In addition to ADA, we're going to have abstracts being presented
at ESC in August, and also the European Association for the Study
of Diabetes meeting in Lisbon, in September, and there's going to
be a lot more afterwards as well. So just stay tuned, I would
say. This is definitely just the beginning. There's going to be a
lot more coming.


Dr. Carolyn
Lam:              
You took the words right out of my mouth. Listeners, stay tuned,
and don't forget to tune in next week as well.