Circulation April 23, 2019 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.


Dr Greg
Hundley:            
And I'm Greg Hundley, associate editor as well at Circulation,
and director of the Poly Heart Center in Richmond, Virginia, at
VCU Health. Well, I'm going to talk about anti-hyperglycemic
agents and look at a very important meta-analysis.


Dr Carolyn
Lam:               
Those are the rage: GLP-1 receptor agonists and SGLT-2
inhibitors. But first, let's talk about psychosocial stress and
cardiovascular health. So what is the joint impact of multiple
stressors on racial or ethnic disparities in cardiovascular
health?


                                               
Well, this question was tackled by Dr Albert, from University of
California San Francisco Center for the Study of Adversity and
Cardiovascular Disease and her colleagues. They basically studied
more than 25,000 women participating in the women's health study
follow-up cohort, and examined the relationship between
cumulative psychosocial stress and ideal cardiovascular health as
defined by the American Heart Association Strategic 2020 Goals.


                                               
As a reminder, this health metric includes smoking, BMI, physical
activity, diet, blood pressure, total cholesterol and glucose,
and higher levels indicate more ideal cardiovascular health and
less cardiovascular risk.


                                               
So, they found that both cumulative psychosocial stress and ideal
cardiovascular health varied by race or ethnicity. Mean
cumulative psychosocial stress scores were higher in Hispanic,
Black, and Asian women compared to white women, even after
adjusting for age, socioeconomic status and psychological status
such as depression and anxiety. The mean ideal cardiovascular
health scores remained worse in blacks and better in Asians
compared to whites, despite taking into account socioeconomic
factors and cumulative psychosocial stress.


Dr Greg
Hundley:            
So Carolyn, how should clinicians incorporate this information in
what we do every day?


Dr Carolyn
Lam:               
Although the cumulative psychological stress and socioeconomic
status did not fully explain the racial or ethnic differences in
ideal cardiovascular health that we saw, clinicians should be
informed by these data that psychosocial stressors are social
determinants of health that have different prevalence according
to race and ethnicity. I think that's what we need to learn. And
of course these data support the need for additional work that
addresses the joint impact of multiple social determinants of
health on cardiovascular disease and in diverse populations.


Dr Greg
Hundley:            
Very good, Carolyn. That was really an interesting article. Well,
I'm going to switch gears and talk about the role of red blood
cells in promoting vascular calcification. My article is from
Dimitrios Tziakas from the Department of Cardiology in Thrace,
Alexandropoulos, in Greece.


                                               
Now, the presence of extravasated erythrocytes in human
atherosclerotic lesions was described several years ago, but
little is known about a possible active role of red blood cells
during these cardiovascular disease processes. Clinical studies
suggest that intraplaque hemorrhage may be associated with the
progression of coronary, carotid, and atherosclerotic lesions and
degenerative calcific aortic valve stenosis. So, in the present
study, the authors examined the contribution of erythrocytes to
vascular and valvular lesion progression, focusing on the effects
of red blood cells on the osteoblastic transdifferentiation of
smooth muscle cells in calcification.


Dr Carolyn
Lam:               
Interesting. So, what did they find?


Dr Greg
Hundley:            
So, lysed erythrocytes, and in particular their membrane faction,
enhanced human and murine arterial smooth muscle cell
mineralization and vascular aortic ring calcification. Red blood
cell membranes injected in the vascular regions of
atherosclerotic-prone mice also promoted calcification and red
blood cells were found to co-localize with osteoblast like cells
in human atherosclerotic plaques, stenotic aortic valves, and
abdominal aortic aneurysms. And so, the study demonstrated that
intra plaque hemorrhage promotes atherosclerotic and valvular
lesion calcification and membranes of extravasated lysed red
blood cells appeared to play an important role in the process.
The investigators also showed a mechanism, that nitric oxide
derived from erythrocyte endothelial nitric oxides synthase is
involved, at least in part, in mediating the effects of red blood
cells on vascular calcification.


Dr Carolyn
Lam:               
Thanks, Greg. Now back to another, well, clinical paper with the
next one asking, do mid-life biomarkers of heart and kidney
damage associate with the level of and decline in physical
capability with aging? Dr Kuh and colleagues from MRC Unit of
Lifelong Health and Aging at University College London used data
on 1,736 men and women from the oldest British birth cohort
study. And, looked at their walking speed, chair rise speed,
balance time, and grip strength. Assessed at ages 60 to 64 and 69
years. They tested the associations between Cystatin C,
NT-proBNP, interleukin-6, and E-selectin all at ages 60 to 64
years with their performance at 69 years. And what they found was
the lower levels of NT-proBNP in interleukin-6 in middle aged
adults were independently associated with better physical
capability up to nine years later. And all these associations
were stronger than those observed for conventional risk factors:
including lipids, blood pressure, and glycemia, and were not
explained by the onset of cardio vascular and kidney disease or
diabetes.


Dr Greg
Hundley:            
Carolyn, is this saying we should now measure these biomarkers in
mid-life?


Dr Carolyn
Lam:               
Ah, before considering the use of NT-proBNP and IL-6 or
interleukin-6 for risk stratification, we really do need further
research to untangle whether these associations exist because the
biomarkers are an integrated measure of accumulated exposures to
stressors. Or, whether they are really capturing early an organ
damage. Or, whether they are marking additional risk pathways.
So, this and more is discussed in a great accompanying editorial
entitled "Putting the Measurement of Physical Capacity in Older
Adults in its Place". And that's by Dr Kritchevsky from Wake
Forest School of Medicine.


Dr Greg
Hundley:            
That's a favorite of my heart, Caroline. The old institution Wake
Forest. But, I'm going to switch now and tell you a little bit
about plasma ceramides and this is an article from Wei Zhao from
the Department of Epidemiology in Population Health at Albert
Einstein College of Medicine in Bronx, New York. The study
evaluates the role of ceramides and what are those? Well, they're
a class of bio-active lipids composed of sphingosines and fatty
acids. And are involved in the development of cardiovascular
disease. Elevated circulating levels of ceramides have been shown
to be associated with increased risk of cardiovascular events,
cardiovascular death, and even so, after adjusting for other
cardiovascular disease risk factors. Now, interestingly, ceramide
metabolism has long been noted to be closely related to HIV
infection. But, the relationship has not been fully understood.
HIV infected cells may cause enhancement of sphingomyelin volume
breakdown and accumulation of intercellular ceramides, whereas
intercellular accumulation is associated with enhanced
replication of HIV.


                                               
So, what did this study do? They evaluated circulating levels of
four ceramides species which have been investigated in previous
studies of non-HIV populations. And were measured in 737 women
and men, 520 HIV infected and 217 HIV uninfected from the Women's
Intra-Agency HIV Study and the Multi-Center Aids Cohort Study.
And they compared the relationships with the progression of
carotid artery disease assessed by B-mode ultrasound over a seven
year period.


Dr Carolyn
Lam:               
Interesting approach. So, what did they find?


Dr Greg
Hundley:            
Elevated ceramide levels were associated with anti-retroviral
therapy use. Particularly, protease inhibitor use HIV infected
individuals. All four ceramides were highly correlated with each
other and significantly correlated with total cholesterol and LDL
cholesterol. And of note, remember they were measuring four, but
C16:0 and C24:1 ceramides rather that C22:0 and C24:0 ceramides
were more closely correlated with specific modified activation
and inflammation markers and, surface markers of CD4 t-cell
activation. Elevated plasma levels of C16:0 and C24:1 ceramides
were also associated with progression of carotid artery
atherosclerosis. So, in summary, the results of this study
provide new information on biological mechanisms that may involve
the specific mono-site activation and inflammation beyond
cardiovascular disease traditional risk factors like cholesterol
levels. For the association between ceramides and CVD,
particularly among individuals living with HIV infection.


Dr Carolyn
Lam:               
Fascinating. Thanks, Greg. Now that sets us up for beautifully
for our featured discussion.


Dr Greg
Hundley:            
Welcome everyone, to our podcast. My name is Greg Hundley and
we've got a very exciting paper for the second part of our
program today. With us we have Dr Thomas Zelniker from Brigham
and Women's Hospital. And then, also, a guest editor, Dr John
McMurray from Glasgow, Scotland. We're going to be discussing a
meta-analysis in type 2 diabetic patients. Thomas, can you tell
us a little bit about the study population, your design, and what
where the outcomes that you saw in this study.


Dr Thomas Zelniker:        As
you know, the last half decade, members of two drug classes, GLP1
receptor agonists and SGLT2 inhibitors, so our goal was to
provide clear context by comparing or contrasting the benefit of
these two drug classes, and in particular to investigate the
potential heterogeneity in the treatment site between patients
with and without atherosclerotic cardiovascular disease. For that
reason, we performed meta-analysis of all randomized partially
controlled cardiovascular outcome trials of GLP-1 receptor
antagonists and SGLT-2 inhibitors. We included data from more
than 77,000 patients, nearly 43,000 patients coming from the five
GLP-1 receptor antagonist trials and approximately 34,000
patients coming from the three SGLT-2 inhibitor trials. We tried
to compare patients with those with known established
atherosclerotic cardiovascular disease with those that have
multiple risk factors for but no evident ASCVD. And as you can
see, our interests included MACE, or major atherosclerotic
cardiovascular events, and its individual components, MI, stroke
and cardiovascular death. And then we looked at hospitalization
for heart failure and progression of kidney disease. The
progression of kidney disease was defined as one of the broad
composites consisting of new onset of macroalbuminuria, worsening
of eGFR, end-stage kidney disease, or death due to renal cause.
And then we also had a more narrow kidney outcome which excluded
macroalbuminuria.


Dr Greg
Hundley:            
Thomas, did you observe differences in the types of events
between the two agents, as they would have impacted
hospitalization for heart failure or the progression of renal
disease?


Dr Thomas Zelniker:       
Right. So foremost both trial analyses reduced the risk of MACE,
major atherosclerotic events, but the reduction of MACE was
actually confined to those patients with atherosclerotic
cardiovascular disease. We saw a 40% reduction in patients with
known ASCVD, where neither of these groups reduced the risk of
MACE in patients with only multiple risk factors but without
ASCVD. Now, in terms of the individual components of MACE, both
trial analyses reduced the risk of myocardial infarction
cardiovascular death but only GLP-1 receptor agonist reduced the
risk of stroke. In contrast, as SGLT-2 inhibitors vastly reduced
the risk of hospitalization with heart failure by more than 30%,
where there was only a non-significant 7% relative risk reduction
with GLP-1 receptor antagonist.


                                               
GLP-1 receptor antagonists also reduced the broad kidney
composite outcome. However, this effect was mainly driven by
reduction macroalbuminuria. When excluding macroalbuminuria we
found a non-significant relative risk reduction by 8% and this
stands in contrast to a very robust relative risk reduction with
SGLT-2 inhibitors of more than 45%.


Dr Greg
Hundley:            
Thomas, you mentioned there was a difference in benefit for those
with existing cardiovascular disease versus no-known
cardiovascular disease upfront. What do you think the reason for
that might be, and then did you have the same number of patients
in the non-cardiovascular disease group? Did you have enough
events in that group? And finally, do you think we might need to
follow that patient population a little bit longer in time, to
see those events as they didn't have pre-existing cardiovascular
disease?


Dr Thomas Zelniker:       
These are fantastic points. I personally think it's biologically
plausible that both drugs and receptors have the same benefit in
both patient population to treatment effect may just require more
time to become evident in patients with lower risk. You also
mentioned a very good point, we had substantially more events in
the patient cohort with ASCVD.


Dr Greg
Hundley:            
Very good. So John, we want to turn to you now. Can you help us
put those results of this study in perspective? Can you put this
into context for us with other published reports using these
particular ages?


Dr John McMurray:        
Certainly Greg, and I'd like to congratulate Thomas on what very
important and very timely meta-analysis because, of course, what
Thomas and his colleagues have done Greg, is to put all these
studies together, to give us what meta-analysis does, which is
much more power to look, for example, at components of composite
outcomes, and we will in that way compare and contrast the
differences and similarities between these two treatments. And as
Thomas has mentioned, so interesting differences stand out but
there are also some similarities that perhaps were not clear from
the individual trials and I suppose the one that would perhaps
stand out to me and might not have been realized by many of our
readers, is myocardial infarction, that seems to be reduced to
pretty much a similar extent by both GLP1 receptor antagonists
and SGLT-2 inhibitors.


                                               
I think there had perhaps been a view out there from the
individual trials, that maybe GLP-1 receptor antagonists have
more effect on atherosclerotic events and SGLT-2 inhibitors more
effect on heart failure and renal events and to some extent
that's true, both agents seem to reduce myocardial infarction to
approximately the same extent. Which in itself is interesting,
perhaps raises some mechanistic questions. I mean, the
differences that stood out is stroke is reduced by GLP-1 receptor
antagonists but not by SGLT-2 inhibitors and conversely heart
failure which is the opposite, which is by SGLT-2 inhibitors, but
not by GLP-1 receptor antagonists in this meta-analysis.


                                               
So, I suppose, in summary what this tells us is that these drugs
have complementary, perhaps additive cardiovascular benefits.
Together, they potentially reduce the whole spectrum of the
adverse cardiovascular events that occur in our patients with
Type 2 diabetes, especially those who've got established
cardiovascular disease.


Dr Greg
Hundley:            
And so, just a last question here, for both Thomas and John, if
you're considering in your practice, you have a diabetic patient
that's not on these, one of these agents, and they have existing
cardiovascular disease, how do you go about considering the
addition or the switch to this type of medicine, and what
practices do you use to effect that change?


Dr Thomas Zelniker:        I
guess, looking at patients, so we know that both drug classes
have great benefits from MACE, right, but to people on
antagonists having also reductions in stroke. So probably the
associated risk is in the focus, I would probably rather go with
the GLP-1 receptor antagonist. While looking at it from the heart
failure perspective, or from the renal perspective, we see
obviously bigger advantages attributed to inhibitors.


Dr Greg
Hundley:            
And John, how about you?


Dr John McMurray:        
I would agree with Thomas' perspective, although I might add just
a little caveat which is, of course, that the prevention of heart
failure which is what, I think, the clear benefit of SGLT-2
inhibitors is, prevention of heart failure is different to the
treatment of heart failure. So, patients at risk of heart failure
sadly, an SGLT-2 inhibitor would make sense, but when it comes to
patients with established heart failure event, of course we will
get that answer because one of the great things about this recent
incredible development of new therapies for diabetes, is that now
there are now more studies underway including remarkable five
trials in patients with different heart failure phenotypes,
patients hospitalized, patients in the community, so we will
learn a lot more about the use of these drugs, in particular
cardiovascular populations.


Dr Greg
Hundley:            
Excellent. I want to thank both Thomas Zelniker from Brigham and
Women's Hospital and John McMurray, guest editor from Glasgow,
Scotland for helping us work through this just fantastic
meta-analysis study pointing us in a new direction for utilizing
medications to treat diabetes and those that we see every day,
with cardiovascular disease.


                                               
On behalf of Carolyn and myself, have a great week and we look
forward to seeing you, next week.


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