Circulation August 27, 2019 Issue

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


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


Dr Carolyn
Lam:               
In just a moment, we will be discussing further results from the
CREDENCE trial. That's canagliflozin in patients with type 2
diabetes and chronic kidney disease, this time focusing on the
cardiovascular outcomes as well as both primary and secondary
prevention groups. Really exciting stuff, huh, Greg?


Dr Greg
Hundley:            
Absolutely, Carolyn. Got any papers you want to have a coffee
chat about?


Dr Carolyn
Lam:               
Absolutely. So my first pick really tells us that allele-specific
RNA silencing of human alleles may be effective in treating
inherited cardiomyopathies. Want to hear more?


Dr Greg
Hundley:            
You bet.


Dr Carolyn
Lam:               
So, this is a study from Dr Ashley and colleagues from Stanford
University School of Medicine who performed a selective
allele-specific silencing of the human restrictive
cardiomyopathy, a specific mutation of asparagine to lysine in
the regulatory light chain, which is encoded by MYL2. So they did
this in a humanized transgenic mouse model using an
adeno-associated virus RNA interference approach. Using this
approach, they showed that an interfering RNA treatment
ameliorated disease phenotypes by specifically reducing the
cardiac expression of the mutated allele, hypertrophic carb
biomarkers and intramyocardial fibrosis. In fact, isolated
cardiomyocytes from the treated animals showed normalization of
contraction and relaxation dynamics with partial restoration of
calcium re-uptake dynamics.


Dr Greg
Hundley:            
Boy, Carolyn, sounds like improvement in cardiovascular function,
but were there any adverse effects?


Dr Carolyn
Lam:               
Great question. Well, they also performed cardiac genome-wide
transcriptome profiling, which showed a reduction in the
hypertrophic program without significant off-target effects, so
that's important. So in summary, these results show the
feasibility, efficacy, and safety of RNA interference
therapeutics directed at human restrictive cardiomyopathy. A
really promising step towards targeted therapy for a prevalent
disease.


Dr Greg
Hundley:            
Very nice. Carolyn. So I'm going to start my discussion also with
a basic science paper that's going to focus on ischemia
reperfusion injury and looking at the mechanism by which
mitochondrial dysfunction can be avoided. So, the paper emanates
from Dr Yu-Lin Li from Beijing Anzhen Hospital at the Capital
Medical University in Beijing. The study from Dr Li identifies an
important mechanism of this myocardial ischemia-reperfusion
injury in a mouse model and found, in human subjects, a biomarker
that was predictive of adverse cardiovascular events after those
individuals had sustained an MI.


Dr Carolyn
Lam:               
Oh, interesting. So tell us more, Greg.


Dr Greg
Hundley:            
Yeah, so the authors utilized a dynamic transcriptome analysis of
mouse hearts exposed to various myocardial ischemia-reperfusion
periods to identify a new inflammatory molecule that they termed
S100A8/A9, and it was an early mediator. And then they measured
this new inflammatory molecule level in patients, human subjects,
after myocardial infarction, before and after they had undergone
percutaneous intervention. So this S100A8/A9 was identified as
the most significantly up-regulated gene during the early
reperfusion stage and knockout of that molecule markedly
decreased cardiomyocyte death and improved heart function,
whereas hematopoietic overexpression of the molecule exacerbated
myocardial ischemia-reperfusion injury.


                                               
The authors then demonstrated that the levels in patients
significantly increased day one post-PCI in anterior MI patients
and elevated molecule levels were associated with the incidents
of future MACE. So perhaps, in the future, targeting this
molecule-initiated signaling may represent a novel therapeutic
intervention for myocardial ischemia-reperfusion injury.


Dr Carolyn
Lam:               
Interesting and very nicely explained. Now my next paper, the
title says it all. Three Public Health Interventions Could Save
94 Million Lives in 25 Years. So we know that preventable
noncommunicable diseases, which are mostly cardiovascular
diseases, are responsible for 38 million deaths annually. So,
these authors who are Dr Danaei and colleagues from Harvard T.H.
Chan School of Public Health in Boston, Massachusetts, quantified
the global mortality impact of three high-impact and feasible
interventions. One, scaling up treatment of high blood pressure
to 70%, two, reducing sodium intake by 30% and, three,
eliminating the intake of artificial trans fatty acids.


                                               
So, they used global data on mean blood pressure levels and
sodium and trans-fat intake by country, age and sex from a pooled
analysis of population health surveys and regional estimates of
current coverage of antihypertensive medications as well as
cause-specific mortality rates in each country, along with
projections from 2015 to 2040. They used the most recent
meta-analysis of epidemiologic studies to derive the relative
risk reductions for each intervention.


                                               
And, in summary, they found that the combined effect of the three
interventions delayed 94.3 million deaths during 25 years.
Increasing the coverage of antihypertensive medications to 70%
alone would delay 39.4 million deaths, whereas reducing sodium
intake by 30% would delay another 40 million deaths and
eliminating trans-fat would delay an additional 14.8 million
deaths.


Dr Greg
Hundley:            
Aha. So controlling blood pressure, cutting salt, eliminating
trans fats, but are there any regional differences around the
world, Carolyn, your part of the world versus United States?


Dr Carolyn
Lam:               
Good question as always. So the authors also estimated the impact
in different parts of the world and found that the estimated
impact of trans fat elimination was largest in South Asia.
Sub-Saharan Africa had the largest proportion of premature
delayed deaths out of all delayed deaths. National and
international efforts therefore need to scale up these
interventions and this should be a focus of cardiovascular
disease prevention programs.


Dr Greg
Hundley:            
Oh, my. Really interesting. Well, I'll tell you what, Carolyn, my
next article is going to take us to space, the unified efforts of
all these countries in the world trying to examine the effects of
prolonged space flight. So this article, it's headed up by Dr Ben
Levine at University of Texas Southwestern Medical Center, but it
has a very large group of coauthors and examines the impact of
prolonged space flight on orthostatic tolerance as those
astronauts return to earth.


                                               
So, as we know, astronauts returning to earth usually demonstrate
reduced orthostatic tolerance, especially when you assess them on
a tilt table. But no studies to date have evaluated sort of the
post-flight return to earth effects of orthostatic on activities
of daily living, and those are most clinically relevant. So in
this study, ambulatory blood pressure variability, that's already
been known to be associated with orthostatic intolerance in other
patient populations and can capture clinically significant
orthostatic hypertension during activities of daily living. So,
in the study, ambulatory beat-to-beat blood pressure was recorded
using a portable device for multiple 24-hour time periods before,
during, and after six months of space flight in 12 astronauts,
four women, age averaged 48 plus or minus five years.


Dr Carolyn
Lam:               
Fascinating. What a clever study. So what did happen to the
astronauts when they returned to earth?


Dr Greg
Hundley:            
So, in contrast to previous studies which employed the tilt
tables or the stand test, no astronaut experienced orthostatic
intolerance or hypertension during activities of daily living
before or after space flight. 24-hour systolic blood pressure
decreased in space as we might expect, but it returned to normal
upon landing and diastolic blood pressure was unchanged during
and following space flight. Systolic and diastolic blood pressure
variability remained the same before, during, and after space
flight. Given the current countermeasures that include exercise,
training in flight, volume resuscitation on return, no astronauts
experienced orthostatic hypertension or intolerance during
routine, for landing day, activities in the initial 24 hours
after landing, following six months in space. And prolonged
exposure to space fight, therefore, had little impact on systolic
blood pressure variability and its distribution. Though the
latter showed just a transient change in space and that might be
expected. It returned, however, to preflight values when we got
back to earth. Very nice work.


Dr Carolyn
Lam:               
Yes, indeed. Very clever. But let's carry on with our feature
discussion, shall we?


Dr Greg
Hundley:            
You bet. Welcome everyone to our featured article discussion, and
we're going to learn more about primary and secondary
cardiovascular-related events from the CREDENCE trial and we have
with us, Dr Ken Mahaffey from Stanford Medical Center in
California and our associate editor, Professor Naveed Sattar from
Glasgow in the United Kingdom. Welcome to you both and we feel
very honored to be able to discuss this paper today with you,
Ken.


                                               
Can you just refresh our memories a little bit about the CREDENCE
trial? What were its primary results? I understand they had
patients with diabetes and chronic kidney disease. Maybe tell us
a little bit about how that was defined and then transition to
what were the hypotheses in your study that you were going to
test?


Dr Kenneth Mahaffey:   So, the CREDENCE trial was a
trial of an SGLT2 inhibitor, canagliflozin, in patients with
diabetes who had chronic kidney disease with albuminuria. And it
was the first of any of the SGLT2 inhibitor trials that was done
in a dedicated renal population with a primary outcome that was a
composite of renal outcomes along with cardiovascular death, and
the trial was stopped early by the data safety monitoring board
on an interim analysis when they found overwhelming efficacy.
And, at the end of the day, the final results showed that
canagliflozin compared with placebo showed a 30% reduction in the
composite renal outcome as well as important reductions in
cardiovascular outcomes without any evidence of increase in
amputations.


                                               
Now, the study that we're talking about today is a pre-specified,
pre-planned subgroup analysis from CREDENCE where we wanted to
look at how canagliflozin worked in people or participants who
had known cardiovascular or cerebrovascular or peripheral
vascular disease and those who did not. And one of the reasons
this was an important analysis was that in previous studies of
SGLT2 inhibitors, there has not been a consistency in the message
about whether the drug worked in both primary and
secondary-prevention populations.


                                               
And what we found here in this analysis was that in the
primary-prevention participants, which actually was 50% of the
overall trial recruitment, had very similar reductions in renal
outcomes and cardiovascular outcomes compared with those who were
a secondary-prevention cohort. So a very different results and a
very important result in this patient population.


Dr Greg
Hundley:            
Really interesting. So in terms of the patients that you
evaluated in this sub study, were they any different than the
whole cohort and, in terms of participants and compliance with
the therapy, was there any difference with the placebo versus the
study drug that you noticed and can you infer from that any
particular groups of patients that may benefit more or be able to
take the therapy more? Just more about compliance.


Dr Kenneth Mahaffey:   First of all, you asked how the
primary and secondary-prevention groups in the study were
different and they were, as one would expect. Those participants
who did not have prior atherosclerotic cardiovascular disease
tended to be younger. They were more often women. They had
shorter durations of diabetes and they were less often treated
with cardiovascular preventive medications, in terms of staph and
antiplatelet therapies. All the patients were on an ACE or an
ARB.


                                               
In terms of overall compliance with canagliflozin, it was very
good. Now, the SGLT2 inhibitors, as a class, have a number of
important side effects including genital mycotic infections in
both men and women. They do cause some hypovolemia and volume
depletion, but we found overall in the CREDENCE trial that fewer
participants stopped the study drug prematurely in the
canagliflozin arm than in placebo arm. So we feel that we had a
very, very good comparison of the two therapies in the overall
trial and in the primary and secondary-prevention analyses.


Dr Greg
Hundley:            
And so just general thoughts of how do you think this might
impact the results of your study, or treatment, when we see
patients with diabetes and chronic kidney disease?


Dr Kenneth Mahaffey:   I think there's potentially a
big impact moving forward. Now, the SGLT2 inhibitor classes were
approved based on the early cardiovascular outcome trials, did
not enroll participants with lower EGFRs. So once these data are
reviewed by the FDA and if they accept these findings and change
the label, then the proportion of patients with diabetes who also
have EGFRs down to 30 would be potential candidates for this
therapeutic intervention. And it's important to point out that
the CREDENCE trial that showed this reduction in renal events in
patients with type 2 diabetes and chronic kidney disease, this is
the first positive trial in 20 years of an intervention and 20
years ago we had both ACEs and ARBs based on large outcome
trials, but we've had nothing since then that could be a
therapeutic intervention to improve outcomes in this very
important patient population.


Dr Greg
Hundley:            
Thank you so much, Ken. And, Naveed, I would like to just turn to
you and ask you a couple things. One, can you put this study on
the SGLT2 inhibitors with all the other information that's coming
out related to potential benefits, not only in controlling blood
sugar, but impacting cardiovascular disease-related events? How
does this fit in to all of the other studies that we're learning
about in such rapid fashion?


Dr Naveed
Sattar:           
This comes on the back of the three major trials and extends the
evidence based so that, yes, I think we now show clear evidence
that these drugs work in people with impaired renal function down
to a level of 30 which I think is very important, so that will
extend the guidelines. Yes, they seem to work in primary
prevention. Of course. I think Dr Mahaffey would accept that
these are probably high-risk primary prevention individuals
because you also have evidence for chronic kidney disease and I
suspect a lot would probably have subclinical cardiovascular
disease if we went to look for it.


                                               
Nevertheless, I think it will extend the guidelines in the sense
that physicians are not only going to be potentially using these
drugs in people with existing cardiovascular disease but also
patients like those in CREDENCE with chronic kidney disease or a
very high risk of cardiovascular disease without having had an
event. So I think that's also very reassuring as well and
exciting. And I think also the benefits of kidney outcomes is, as
we said beautifully, that this is a game changer. Over the last
few decades we've not really had any major trials to excite the
renal community. But now we have. This trial extends the promise
that we saw in the three previous trials and takes it a bit
further, that these drugs have substantial and meaningful
benefits in prevention of important kidney outcomes in our
patients with diabetes. It looks like those benefits appear
across the spectrum of diabetes. Whether they've existing
disease, chronic kidney disease, or even a primary prevention
when previous colleagues looked at it in a meta-analysis.


                                               
So, I think that's exceptionally exciting and I think, therefore,
given the profile of these drugs and as we're improving our
safety in the sense we're able to use these drugs better in
groups and also advise how to reduce side effects. I think really
they're changing the paradigm of how we care for many of our
patients with diabetes and I'd be interested to see what Dr
Mahaffey thinks about those comments. My sense is this is really
exciting.


Dr Greg
Hundley:            
Ken, any thoughts?


Dr Kenneth Mahaffey:   I think it was nicely
articulated, some of the important observations here. I do agree
that the patient population here that has chronic kidney disease
but no known atherosclerotic disease and therefore primary
prevention, it had higher risk. The event rates in CREDENCE were
much higher than event rates in the CANVAS trial where the mean
eGFR was much higher and so I agree that these patients may have
some subclinical atherosclerotic disease, but they are clearly at
higher risk of developing it.


Dr Naveed
Sattar:           
Again, this would be interesting to take Ken's take. But if
people have chronic kidney disease, they are, in a sense,
revealing themselves to have evidence of end organ damage or be
at the level of the kidney but not necessarily the heart. So my
sense is there's still people with evidence of disease and it's
just that we're seeing it in a different way. I don't know what
Ken thinks about that as a kind of interpretation.


Dr Kenneth Mahaffey:   Again, I think they're at high
risk and we know that people who have kidney disease often are at
higher risk of having cardiovascular disease during their
lifetime and where we are in the spectrum of those new disease
processes. We don't necessarily have the data in CREDENCE to
understand that at a very granular level, but I think it's an
important area that we need to evaluate sooner and it raises that
issue of treatment for primary prevention should occur earlier
and what we're seeing now is that when people develop type 2
diabetes and we notice that they have chronic kidney disease with
microalbuminuria, that is the time to intervene, intervene soon.
We now have a single therapy that's safe and effective and
reduces the metabolic derangements with improved glucose control,
improved blood pressure control, improved weight. It also has an
important impact on the renal outcomes and important impact on
cardiovascular outcome. So it's really a trifecta from a single
therapy that can be prescribed easily.


Dr Naveed
Sattar:           
I agree. And all those means of treatments were very, very
favorable as well across the board, which I think is also
important.


Dr Greg
Hundley:            
So, Ken, what are some key clinical aspects related to your study
that you feel we need to address?


Dr Kenneth Mahaffey:   What we need to think about
carefully is we now have a new therapy. These types of patients
are actually seen by a whole host of clinicians in our healthcare
systems, at least in the United States. They're seen by
diabetologists, cardiologists, nephrologists, and primary care.
And we need to think of ways that we can educate all four of
those groups of clinicians about these important data and provide
learning and other mechanisms to integrate these therapies into
clinical care. It's a message I've been trying to get out.


Dr Greg
Hundley:            
Well, listeners, what a great discussion between Ken and Naveed
on this very important topic, the emergence of SGLT2 inhibitors
and the results of these primary and secondary cardiovascular
prevention group analyses from CREDENCE.


                                               
We want to thank each of you for listening with us this week.
Carolyn and I look forward to talking with you next week. Take
care now.


Dr Carolyn
Lam:               
This program is copyright American Heart Association 2019.