Circulation December 18, 2018 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.


                                               
In today's feature discussion, we will be doing a deep dive into
the LEADER trial results, looking at new results of liraglutide
and its effects in patients with type two diabetes, with or
without a history of myocardial infarction or stroke. All of that
coming right up after these summaries.


                                               
In today's issue, five groups of investigators in two original
basic research articles and three research letters tackled the
same biological question, and all reached the same conclusion
that cells in the heart expressing the SCA-1 cell surface antigen
do not become cardiomyocytes to any meaningful degree, and
instead become endothelial cells. Among the original basic
papers, first author Dr Vagnozzi, corresponding author Dr
Molkentin from Howard Hughes Medical Institute and Cincinnati
Children's Hospital Medical Center, and their colleagues use the
inducible recombinase method and generated a constitutive
recombinase at the SCA-1 locus. They found that cardiac resident
SCA-1 positive cells were not significant contributors to
cardiomyocyte renewal in vivo. Instead, SCA-1 positive cells
generated cardiac vasculature throughout development, during
aging, and following injury with trivial contribution to the
cardiomyocyte population.


                                               
In the second paper from co-first authors, Drs Zhang and Sultana,
with corresponding author Dr Cai from Indiana University School
of Medicine and colleagues, these authors engineered a series of
genetically altered mice to identify and track SCA-1 positive
cells in the heart, and found that SCA-1 positive cells were
purely of the endothelial lineage. Together with three research
letters, these five papers add to the growing body of evidence
that in adult mammals, our new cardiomyocytes arise from
preexisting cardiomyocytes and rarely, if at all, from adult
cardiac stem cells.


                                               
Could metformin be cardioprotective in patients with type one
diabetes? Co-first authors Drs Bjornstad and Schafer,
corresponding author Dr Nadeau from University of Colorado School
of Medicine, and their colleagues hypothesized that adolescents
with type one diabetes have impaired vascular function, and that
metformin may improve insulin resistance and vascular
dysfunction.


                                               
To test this hypothesis, they studied 48 adolescents with type
one diabetes and 24 non-diabetic controls using MRI of the
ascending and descending aorta, as well as assessment of carotid
intima-medial thickness by ultrasound, brachial distance ability
by DynaPulse, fat and lean mass by DXA, fasting labs following
overnight glycemic control, and insulin sensitivity by
hyperinsulinemic euglycemic clamp. The adolescents with type one
diabetes were randomized one as to one to three months of 2000
milligrams metformin or placebo daily, after which the baseline
measures were repeated.


                                               
The authors detected early signs of cardiovascular disease with
MRI in these adolescents with type one diabetes compared to
controls. They further found that three months of metformin
therapy improved insulin sensitivity as assessed by gold standard
hyperinsulinemic euglycemic clamp, both in normal weight and
obese adolescents with type one diabetes. Moreover, metformin
improved carotid intima-medial thickness and aortic wall shear
stress and stiffness. Thus, metformin may hold promise as a
cardioprotective intervention in type one diabetes.


                                               
What are the clinical genetic and environmental determinants of
varicose vein formation? Co-first authors Drs Fukaya and Flores,
corresponding author Dr Leeper from Stanford University, and
colleagues applied machine learning to agnostically search for
risk factors of varicose veins in nearly half a million
individuals in the UK bio bank. They found that greater height
appeared as a novel predictor of varicose vein disease in machine
learning analyses, and was independently associated in
multi-variable adjusted Cox regression. Using Mendelian
randomization, they demonstrated that greater height had a causal
role in varicose vein development. A genome-wide association
study identified 30 new genome-wide significant loci, identifying
pathways involved in vascular development, and skeletal/limb
biology, and discovering a strong genetic correlation between
varicose veins and deep vein thrombosis. The knowledge greatly
expands our understanding of disease pathophysiology, and may
help future improvements in the management of varicose veins and
their associated complications.


                                               
The final original paper describes the effect of glucagon-like
peptide-1 receptor agonist liraglutide on cardiovascular events,
and all-cause mortality in patients with type two diabetes and
chronic kidney disease. First and corresponding author Dr Mann
from Friedrich Alexander University of Erlangen in Germany and
their colleagues performed a post hoc analysis of the LEADER
trial comparing the liraglutide's treatment effects in patients
with and without kidney disease.


                                               
As a reminder, LEADER was designed to recruit a subgroup of at
least 660 patients with an estimated glomerular filtration rate,
or eGFR, less than 60, approximately 220 patients with severe
renal impairment, eGFR less than 30, and at least 440 patients
with moderate renal impairment with an eGFR of 30 to 60. The
authors found that the liraglutide reduced the risk of major
adverse cardiovascular events, and all-cause mortality compared
with placebo in patients with chronic kidney disease defined as
an eGFR less than 60, and also in patients with albuminuria
defined as a urinary albumin to creatinine ratio above 30.


                                               
The overall risk of adverse events did not differ between the
liraglutide and placebo treated patients either with or without
chronic kidney disease in the LEADER trial. In summary, these
results show that liraglutide added to standard of care reduced
the risk of major cardiovascular events and all-cause mortality
in patients with type two diabetes and chronic kidney disease.
Furthermore, these results appear to apply across the chronic
kidney disease spectrum that was enrolled.


                                               
And that brings us to the end of our summaries. Now for this
week's feature discussion.


                                               
Cardiovascular outcome trials have transformed the world of
treating patients with diabetes. And for our feature discussion
today, we're going to be talking about a new analysis from a very
important trial, the LEADER trial of GLP-1 receptor agonists, and
that's the liraglutide. I'm very proud to have the corresponding
author of this paper with us, Dr Subodh Verma, and he's from St
Michael's Hospital and University of Toronto, and our senior
associate editor, Dr Gabriel Steg, from University of Paris.
Actually, Gabriel, I'm actually going to start with you for once
because I recall perhaps something you may have written about
cardiovascular outcome trials.


Dr Gabriel
Steg:               
Yeah, it's really funny. I'll try to take it graciously. You
know, I wrote a frame of reference in Circulation a few years
ago, wondering whether we were doing good by doing all these
large outcome trials for safety with new anti-diabetic drugs,
because there had been not one but two, three, four, five, six
trials that were essentially neutral, enrolling more than 107
patients and participants at the expense of millions of dollars,
and not much came out of it. And this was published in
circulation. I was very happy until the next trial comes up, and
this is EMPA-REG. And the next one is LEADER. And we have two
trials that literally transform our vision of anti-diabetic
agents as major agents for cardiovascular prevention. The trial
we're going to discuss today, which you wrote about, is one of
these trials. And I think I have to revisit my own writings and
probably eat my hat.


Dr Carolyn
Lam:               
So indeed, that's a great segue. Thank you, Gabriel. And Subodh,
tell us then, what did you look at this time in LEADER? And maybe
start by saying a little bit about LEADER, and the rationale for
doing this particular sub analysis.


Dr Subodh
Verma:          
Right. So, as Dr Steg mentioned, these were FDA-mandated studies
to look at safety and potential efficacy of newer
antihyperglycemic agents. The entire premise was that
cardiologists and cardiovascular specialists were not really
getting that excited about antihyperglycemic therapies in people
with diabetes, because there was no data that they did much. And
as Dr Steg mentioned, even the data leading up to some of these
trials were disappointing, suggesting that they're safe, but they
neither reduce nor increase events.


                                               
So, I think EMPA-REG and LEADER really changed the calculus in
many ways of how we look at cardiovascular risk reduction with
antihyperglycemic agents. LEADER was a trial that was 9,340
patients. These are patients that were at high cardiovascular
risk, but unlike EMPA-REG that only enrolled people with prior to
ischemic cardiovascular events ICAD, PAD, and CVD, LEADER took a
position of enriching the population with this spectrum of
patients with cardiovascular disease and risk factors.


                                               
So, some were in so-called high risk primary prevention who had
not had established ASCVD, but had multiple risk factors such as
uncontrolled hypertension or chronic kidney disease. Some had
evidence of ASCVD, but had not had a prior myocardial infarction.
And some, in fact, had had a prior MI stroke or PAD. So, it was a
broad population of patients that was enrolled. And the primary
result, again, for the primary outcome of MACE, demonstrated a
significant reduction in favor of liraglutide versus placebo. And
then for the individual components of that primary outcome, they
were all statistically significant, or at least went in the right
direction. Importantly, CV death was reduced by 22% with
liraglutide versus placebo.


                                               
I would like to emphasize that in this day and age, and Dr Steg
has nicely set the stage, we have started thinking about how do
we think about cardiovascular phenotypes of patients. You know,
is a drug more likely to reduce heart failure? More likely to
reduce ischemic events? And with LEADER, we found that in fact
the trial actually reduced mostly ischemic events, and was really
not that beneficial on heart failure related outcomes.


                                               
So, that was the broad positive outcome from LEADER. They've led
to guideline changes worldwide that patients with diabetes should
be prioritized to receive an agent that has shown benefit,
particularly if they have cardiovascular disease. And one of
those agents was empagliflozin. The other was liraglutide. But,
secondary prevention is a pretty crowded space, and not everybody
can get everything, and not everybody should get everything, and
not everybody can afford everything. So, I think leaders like the
two of you here are often thinking about, how do you
risk-stratify these populations, and how do we start thinking
about people who are at greater risk, people who can actually
derive benefit? And I think that's the smart and thoughtful way
of doing this. And is there a certain threshold at which point
the therapy loses its ability to reduce cardiovascular events, at
least in the short term?


                                               
So, in that theme, in that vein, what we looked at here was an
analysis of people in LEADER who truly had a prior ischemic
event. And the work that Dr Steg and others have done in REACH
registries, etc. clearly establish that that's a population of
patients, type two diabetes and a prior ischemic event. You don't
really need many more calculators beyond that. That's the highest
risk population. And then, the next level is really type two
diabetes with a ASCVD. And we know that from REACH as well, that
that's the next level of risk. And then, what about people who
have type two diabetes just by itself? Which certainly are much
higher risk than people who don't have diabetes, but we didn't
have a non-diabetic group to compare to.


                                               
And what we find is that the higher the baseline risk defined by
this, the greater is the absolute risk reduction. The P value is
consistent for ... You know, this is non-significant for
heterogeneity. but specifically, people with a prior ischemic
event derive benefit. People without a prior ischemic event
who've had ASCVD derive significant benefit. But, in fact, we
found that the curves were almost superimposable for people who
did not have prior ASCVD. And that's not to say the GLP-1
receptor agonists should not be used in diabetes in the absence
of cardiovascular disease, because they're great glucose lowering
agents. They cause hypoglycemia, they cause weight loss. And
potentially, within longer exposure times, cardiovascular benefit
may actually emerge. And we've heard data from Dr Gerstein's
study called Rewind that is positive, that will be presented next
year. Harmony Outcomes was a study that was presented recently
that also showed a benefit. So, whether in the primary prevention
group we see a benefit in the future remains to be seen.


Dr Carolyn
Lam:               
Oh, that's a great, great summary. But Subodh, you know, it's
become a bit of what do we define as a primary and secondary
prevention anymore, you know? And the patient that already got
type two diabetes. Now, in this paper, it's very nice. As you
said, has a history of myocardial infarction and stroke. And
maybe I could just clarify to the audience, you couldn't just
pick up the primary paper and see that because the way the
inclusion exclusion criteria were designed in LEADER, you can't
just pick up the sub-groups. So, this specific analysis, so
carefully and wonderfully done, was absolutely needed. But then
you know, what do you think? What's primary and what's secondary
prevention anymore?


Dr Gabriel
Steg:               
Well, I want to commend the authors for doing the careful
stratification of diabetic patients they've done in the paper,
and particularly for pointing out that it's one thing to have had
an event where you actually ruptured a plaque and had a traumatic
event. And it's very different from merely having plaque in one
of your carotids or your arteries, and which is, of course, in
turn very different from the majority of diabetic patients who
have neither an event, nor diagnosed plaque or established
plaque. And when we think about preventing cardiovascular and
diabetes, we have to remember that the outer circle, the broader
circle of diabetic patients who haven't had disease is the
largest component.


Dr Subodh
Verma:          
True.


Dr Gabriel
Steg:               
And these are the patients whom we treat every day with the hope
of eventually keeping them from harm, safe from harm, or with
therapies that are new and potentially beneficial. And I think
your research very clearly shows that there's a gradient of
benefit. The sicker the patient, the greater the benefit in
preventing MACE. And as long as you get to more healthier
phenotypes of diabetes, then there is less of a benefit. Which
doesn't mean that we shouldn't use these agents. As you point
out, they're very convenient and effective agents for glucose
control. But then, their cardiovascular benefits are more
uncertain. And I think this is the key message from this
analysis, and it's a great analysis.


Dr Subodh
Verma:          
Thank you. I appreciate that. I totally agree that for the doctor
in the trenches, particularly the cardiologist who's just trying
to get their feet wet with antihyperglycemic therapy, you know?
Cardiologists will embrace PCSK9 inhibitors and rivaroxaban at
low dose, and maybe a new way of doing surgery or putting an
LVAD. But it's very hard to get their attention when it comes to
antihyperglycemic therapy. So, defining for them the population
that matters the most, where the greatest risk and risk reduction
can be achieved, I think is quite important from a clinical
standpoint. And I think most cardiologists will agree that type
two diabetes and a prior ischemic event is a high-risk
population. Type two diabetes in a prior ASCVD is a high-risk
population, and the magnitude of CV death reduction here is
something meaningful for them to pay attention to.


Dr Carolyn
Lam:               
Yeah, indeed. That's what I love best about this paper. It's
actually asking the question the way a cardiologist would,
exactly like you had both put. So, what do you think is the next
step now? Do you think we need to look at this primary prevention
type two diabetics with no established cardiovascular disease? Do
we really need to? Is it that we need a method analysis, which
you can talk about? Or, is it that we need longer follow up? Or,
what next?


Dr Subodh
Verma:          
I think that first of all, we have to get rid of the terminology,
and maybe as a heart surgeon, I can be a little bit provocative
and just say it. I wrote an editorial to the Declare Study that
was just published yesterday in The Lancet called "Pumps, Pipes,
and Filter: Do SGLT2 inhibitors cover it all?" Then I made a
strong statement there that this nomenclature of primary and
secondary really is artificial because it only captures ischemic
risk, and does not capture risk of heart failure or renal
disease. So, in a patient, as you've asked, Carolyn, who has type
two diabetes, whose renal function is 54 or GFR is 55, who's not
had a prior MI ... Is that patient primary prevention? Maybe from
an ischemic standpoint, but he's clearly secondary prevention
from a renal standpoint.


Dr Subodh
Verma:          
So, I think we need to just think about all disease as a
spectrum, and not as an artificial cutoff that, if you've had an
ischemic event, suddenly the world changes for you there.
Because, that gradient I think is probably what we need to
somehow appreciate as to where that risk lies. The patient who's
40 who's had no risk factors, you know? The Rashami paper from
the New England Journal that looks at risk factor control and
diabetes make a very compelling story that if you control your
five risk factors, you actually don't have an excess risk of
cardiovascular events in diabetes, at least from MACE. The story
is whether anybody can have those five risk factors controlled.
But, early on in diabetes, with diabetes duration not being that
significant, with risk factors not being that significant, I
think maybe that's not the population to go after. But certainly,
waiting for ASCVD to develop and then start therapy is also not
the right way of doing it, so ...


Dr Carolyn
Lam:               
Interesting. I really wonder what new guidelines are gonna show.
Gabriel, any other perspective?


Dr Gabriel
Steg:               
Well, first of all, I love the editorial. I thought the title was
fantastic, and you summarize here what we need to think about
when we think about diabetes; not solely the pipes. As an
interventional cardiologist, I'm very interested in the pipes.


Dr Subodh
Verma:          
Me, too.


Dr Gabriel
Steg:               
Not solely the pump, but also the filter. And there's more than
the heart and vessels in the complications of diabetes. So I
thought it was a great, great title. My view is that we still
need to remember that if we take the lifetime perspective, a
healthy youngster with type one diabetes, a relatively healthy
patient in his fifties with type two diabetes, their probability
of dying from cardiovascular disease is enormous. Even though
risk calculators will give them a relatively low probability over
the 5 year or 10 year term, eventually that's what's gonna get
them. And therefore, we still have progress to make. We are
fortunate to have lived an incredible period in the past few
years where we've had emergence of new risk preventive therapies
in diabetes. That's incredible. It's an epiphany. But, it's not
over. We need more information, more trials in other populations.
We need to look at renal function and heart failure. So, it's a
great time to be doing clinical trials in diabetes.


Dr Subodh
Verma:          
Right.


Dr Carolyn
Lam:               
And indeed, a great time to be publishing in circulation. We've
been really doing a lot of publications in the cardiovascular
outcome trials in diabetes here.


Dr Subodh
Verma:          
And it's being noticed. There's no doubt about it.


Dr Carolyn
Lam:               
I hope so. And, maybe a time for a new frame of reference,
because what you just said was diametrically sort of in contrast.


Dr Subodh
Verma:          
I would emphasize one more point, and that is, you know in
atherosclerosis, the dominant mechanism has been LDL, right? And
Dr Steg here is changing the landscape of that with Odyssey
Outcomes and many other strategies. But again, in Circulation, Dr
Bhatt, and I, along with the LEADER investigators, recently
presented and published a paper showing that liraglutide's
benefit is seen independent of LDL cholesterol, and all the way
down to people with LDLs of below .5. So, the point is that this
mechanism of benefit of GLP-1 seems to be complimentary to LDL
lowering. And therefore, I think it offers great hope that you
can actually reduce the ischemic burden in diabetes, not just by
ultra-low LDL, but by potentially additional mechanisms as well.


Dr Carolyn
Lam:               
Absolutely. And then now, because I have to have the last word
here on this show, let's not forget heart failure outcomes in
diabetes. I think it's underestimated. I think it's really
important. Okay, and with that, thank you gentlemen for joining
me today.


                                               
You've been listening to Circulation on the Run. Don't forget to
tune in again next week.


                                               
This program is copyright American Heart Association, 2018.