Circulation April 30, 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 Pauley Heart Center in Richmond, Virginia at
VCU Health. Carolyn, this issue, we've got a super-exciting
interaction to follow related to SGL2 inhibitors on 24-hour
ambulatory blood pressure in African-Americans, something used to
treat diabetes, and maybe a positive effect on blood pressure,
but more to come on that. Now, Carolyn, you're also planning to
discuss some results from another SGL2 study.


Dr Carolyn
Lam:                               
You bet. This time, I'm taking you to Japan for the results of
the SACRA study which stands for SGLT2 Inhibitor and Angiotensin
Receptor Blocker Combination Therapy in Patients with Diabetes
and Uncontrolled Nocturnal Hypertension and this is from Dr Kario
and colleagues from Tochigi in Japan. It's a multi-centered,
double-blind parallel study of 132 non-obese older adults with
type 2 diabetes and uncontrolled nocturnal hypertension,
receiving stable antihypertensive therapy, including angiotensin
receptor blockers, who were then randomized to 12 weeks'
treatment with empagliflozin 10 milligrams once daily or placebo.
Clinic blood pressure was performed at baseline in weeks four,
eight and 12. Twenty-four hour ambulatory blood pressure
monitoring was performed at baseline and week 12 and morning home
blood pressure was determined for five days before each visit.
The primary efficacy endpoint was changed from baseline in
nighttime blood pressure.


Dr Greg
Hundley:            
               
So, what did they find, Carolyn?


Dr Carolyn
Lam:                               
Well, empagliflozin significantly reduced nighttime systolic
blood pressure versus the baseline. The reductions in daytime
24-hour morning, home, and clinic systolic blood pressure at 12
weeks with empagliflozin was also greater than placebo. Between
group differences in body weight and glycosylated hemoglobin
reductions were significant, but small and the changes in
antihypertensive medication during the study also did not differ
significantly between the groups.


Dr Greg
Hundley:                            
Very good. Well, I'm going to switch gears and talk also on the
same theme of sugar and diabetes and evaluate the long-term
consumption of sugar-sweetened and artificially-sweetened
beverages and the risk of mortality in U.S. adults. This is a
study by Vasanti Malik from the Harvard School of Public Health.
Now, as you know, in epidemiologic studies, intake of
sugar-sweetened beverages has been associated with weight gain, a
higher risk of type 2 diabetes, coronary heart disease and
stroke, but to date, few studies have examined the association
between sugar-sweetened beverages and intake and mortality. All
right, Carolyn, I'm going to give you a quiz now. Here's the
first question.


Dr Carolyn
Lam:               
               
What?


Dr Greg
Hundley                              
That's right, sugar-sweetened beverages are the single largest
source of added sugar in the U.S. diet, true or false?


Dr Carolyn
Lam:               
               
I'm going to guess true.


Dr Greg
Hundley:                            
Okay, so all those consumption of sugar-sweetened beverages in
the United States has decreased in the past decade. National
survey data show a slight rebound in consumption in recent years
among adults in many age groups. With the average equivalent
being, multiple choice, 2%, 6.5% or 10% of our total energy
requirements?


Dr Carolyn
Lam:                               
Oh, my goodness. One of the higher ones. I'm just going to go in
the middle, 6.5.


Dr Greg
Hundley:                            
Excellent, good choice, you're a good multiple-choice taker,
6.5%. So, among younger adults, sugar-sweetened beverages
contributed. They're a little bit higher, 9.3% of the daily
calories in men and 8.2% in women in the United States. Now, how
about other parts of the world, particularly developing
countries? The intake of sugar-sweetened beverages, is it
dropping, is it flat or is it rising dramatically?


Dr Carolyn
Lam:               
               
Sorry, Greg, but that one's too easy. It's definitely rising.


Dr Greg
Hundley:            
               
Yup, you got that right.


Dr Carolyn
Lam:               
               
I live in those other developing countries, so I've seen so.


Dr Greg
Hundley:                            
And it's really thought due to widespread urbanization and
beverage marketing. So, now we've got an alternative,
artificially-sweetened beverages. And they're often suggested as
alternatives to sugar-sweetened beverages and intake levels have
increased of these alternative sweeteners in the United States.
So, next question. Are the artificially sweetened beverages a
better alternative to sugar--sweetened beverages in regard to
cardiovascular or all-cause mortality?


Dr Carolyn
Lam:                               
Yikes. Okay, so Greg I'm afraid to guess on this one because I
have to admit I sometimes, with a sweet tooth, like to take these
alternative beverages. I think you're going to be telling us.


Dr Greg
Hundley:                            
Well, we don't know. Most of the data in this area is from
research and comes from associative analyses utilizing
longitudinal cohorts and some studies suggest yes, some studies,
no. For example, one in the elderly suggested
artificially-sweetened beverages, but not sugar-sweetened
beverages were associated with adverse events, but critiques
indicated that finding may have related to reverse causation
because the elderly patients were switching from sugar-sweetened
to artificially-sweetened beverages. So, where are we now? Well
this study, in our Journal, examined the associations between the
consumption of sugar-sweetened beverages and
artificially-sweetened beverages with the risk of total and
cause-specific mortality among 37,716 men from the Health
Professionals Follow-up Study between 1986 and 2014 and 80,647
women from the Nurse's Health Study from 1980 to 2014, who were
free from chronic diseases.


Dr Carolyn
Lam:                               
Wow, that's a huge combined cohort. So, come on, what were the
results?


Dr Greg
Hundley:                            
So, the researchers found after adjusting for major diet and
lifestyle factors, consumption of sugar-sweetened beverages was
associated with a higher risk of total mortality and
cardiovascular mortality and cancer mortality and, thus, the
results provide further support for the recommendations and
policies to limit intake of sugar-sweetened beverages and to
consume artificially-sweetened beverages in moderation did
improve overall health. Now, what were the results from
artificially-sweetened beverages? Well, they were associated with
total and cardiovascular disease mortality in the highest intake
category only. So, those consuming large amounts of those daily,
but only in the cohort of women from the Nurse's Health Study,
not from the men in the Health Professionals Follow-up Study.
Artificially-sweetened beverages were not associated with cancer
mortality in either cohort.


So, moving forward, the positive association between high intake
of artificially-sweetened beverages and total and cardiovascular
disease mortality observed among women requires more study and
further confirmation and also, we might consider that even though
artificially-sweetened beverages could be used to replace
sugar-sweetened beverages among habitual sugar-sweetened beverage
consumers, higher consumption of the artificially-sweetened
beverages would probably be discouraged. Finally, policies and
recommendations should continue to call for reductions and limits
on sugar-sweetened beverages intake and also address alternative
beverage offerings with an emphasis on our favorite, water.


Dr Carolyn
Lam:                               
Sweet, Greg! Or maybe not so sweet. Oh, goodness. All right, well
my paper deals with related, but not related perhaps, but talking
about ketone body, 3-hydroxybutyrate and the cardiovascular
effects of treatment with this ketone body in chronic heart
failure and this is from corresponding author, Dr Nielsen from
Aarhus University Hospital in Denmark and his colleagues. Now,
they performed a series of studies. In the first 16 chronic HFrEF
patients were randomized in a crossover design to three hours'
infusion of 3-hydroxybutyrate or placebo and monitored invasively
with a Swan-Ganz catheter and studied with echocardiography and
they found that infusion of 3-hydroxybutyrate increased cardiac
output by two liters per minute or 40% with an absolute
improvement in left ventricular ejection fraction of 8%, and the
observed defects were accompanied by vasodilation with a
resultant stable systemic and pulmonary blood pressure.


Now, in the second part of the study, they studied eight HFrEF
patients examined at increasing infusion rates of
3-hydroxybutyrate and they found a dose response relationship
with a significant increase in cardiac output. And, finally, they
studied 10 HFrEF patients and 10 age-matched volunteers,
randomized in a crossover design to a three hour infusion of
3-hydroxybutyrate or placebo and they looked this time at
myocardial external energy efficiency and oxygen consumption
using 11-carbon acetate PET and what they found was
3-hydroxybutyrate increased oxygen consumption without altering
myocardial external energy efficiency. The response did not
differ between HFrEF and age-matched volunteers.


Dr Greg
Hundley:                            
Wow, Carolyn, there was a lot of data in that study. So, what's
your main take home?


Dr Carolyn
Lam:                               
In summary, 3-hydroxybutyrate, this ketone body, demonstrated
dose-dependent beneficial cardiac and hemodynamic effects in
patients with heart failure reduced ejection fraction without
deteriorating mechano-energetic coupling and without causing any
safety issues. And what's significant is that this opens the door
to modulating circulating 3-hydroxybutyrate as a novel treatment
option in patients with heart failure.


Dr Greg
Hundley:                            
Right, Carolyn, so I've got an interesting study from the world
of basic science that's looking at the role of potassium channels
as novel molecular targets and bradyarrhythmia’s and even,
perhaps, in atrial fibrillation. This is from Yoshihiro Asano
from Osaka University in Japan. So, the acetylcholine activated
potassium channel is expressed in the sinus node, atrium, and
atrioventricular node and contributes to heart rate slowing
triggered by the parasympathetic nervous system. So the
potassium, activated potassium channel is a heterotetramer of 2
inwardly rectifying potassium channel proteins encoded by two
genes, KCNJ3 and KCNJ5, respectively.


Dr Carolyn
Lam:               
               
Okay, so what did this study show?


Dr Greg
Hundley:                            
What it showed is a selective potassium acetylcholine channel
blocker effectively inhibited a mutant potassium channel and
up-regulated heart rate and bradyarrhythmias using a zebra fish
model. And this is really interesting, Carolyn, because two
conclusions are worth considering. First, future studies could
determine the prevalence of bradyarrhythmias associated with
dysfunctional mutation in this potassium channel. And, second,
results raise the possibility that pharmacologic blockade of this
channel might serve as a therapy for increasing heart rate and be
especially beneficial for bradyarrhythmias in patients with gain
of function mutations in the channel and, therefore, genetic
testing for KCNJ3 and KCNJ5 in patients with bradyarrhythmias may
provide a drug treatment option in lieu of an invasive surgical
implantation of a pacemaker.


Dr Carolyn
Lam:                               
Fascinating! Thanks, Greg. What a great issue and now onto an
even greater feature discussion.


Dr Greg
Hundley:                            
Welcome, everybody, to the second part of this interview. We've
got a very exciting paper to discuss with you. Remember this is
our backstage pass to Circulation and we've got today, Keith
Ferdinand from Tulane University in Louisiana and our Associate
Editor, our hypertensive expert, Dr Wanpen Vongpatanasin from the
University of Texas Southwestern Medical School in Dallas. We're
going to be discussing the anti-hyperglycemic and blood pressure
effects of empagliflozin in African-Americans with type two
diabetes and hypertension. Keith, we're going to start with you.
What was your hypothesis for this study? Who's the study
population? Review a little bit about your design and,
importantly, what were your results?


Dr Keith
Ferdinand:                        
Well, my hypothesis was that one of the new classes of
medications, the SGLT2 inhibitors, which have a mild diuretic
effect and a mild natriuretic effect, may have benefits in
self-described African-Americans in not only controlling glucose,
but also controlling hypertension. These medicines are approved,
of course, as medications for type 2 diabetes, but we had seen in
some earlier trials that did not include self-defined
African-Americans, that there may be a blood pressure effect. We
know that diabetes is higher in blacks, almost twice that seen in
the general population and, of course, hypertension and
uncontrolled hypertension is disproportionate. So, here's a
medication that may be even more beneficial in that population
and we wanted to study it.


Dr Greg
Hundley:                            
And tell us a little bit about who was in the study and what was
your design?


Dr Keith
Ferdinand:                        
The design was to be a placebo-controlled randomized trial using
empagliflozin starting at 10 milligrams and force-titrating to 25
milligrams versus placebo on the background of conventional
anti-hypertensive agents. Everyone was on one or more
anti-hypertensive agents. We used the gold standard for blood
pressure control with 24-hour ambulatory blood pressure and that
was the means by which patients entered the study, although the
primary endpoint was changed in hemoglobin A1c, we actually
designed and powered the study to see if there would be a change
in blood pressure. Additionally, we looked for changes in weight,
losing calories with the effects of the SGLT2 inhibitors with
glycosuria has translated in some preliminary trials to weight
loss. So, this was a study looking at a population. Most of them
had diabetes for approximately nine to 10 years, 59 years of age,
definite hypertension, obesity, a high risk population, to see if
a new class of medications would be beneficial.


Dr Greg
Hundley:            
               
And what did you find?


Dr Keith
Ferdinand:                        
Fortunately, we did find an effect. It did lower the primary
endpoint of a change in hemoglobin A1c, but remember it was
powered also by blood pressure effect and fortunately, we did see
that both with the ambulatory and clinic blood pressure, both at
12 weeks and 24 weeks. The clinic blood pressure was a trend, but
the ambulatory blood pressure was positive at 12 weeks and both
had a strong difference in terms of confidence intervals for
blood pressure lowering. About five millimeters of mercury at 12
weeks and up eight millimeters of mercury at 24 weeks for the
change in ambulatory blood pressure which, in a large population
would translate into a significant blood pressure lowering, the
hemoglobin A1c reduction was also significant. But, although that
was the primary endpoint, my concern is as a cardiologist and
cardiovascular specialist.


Dr Greg
Hundley:                            
And what dose did you select? Did you have to up-titrate this at
all and, finally, were there any side effects?


Dr Keith
Ferdinand:                        
You know, with the SGLT2 inhibitors, you have an effect both in
terms of glycosuria, some osmotic diuresis and some natriuresis,
and with the loss of body weight. But the change in body weight
really wasn't that much, about 1.2 kilos and the change in blood
pressure was discordant with the change in body weight. So, we
think that the effects in blood pressure may be from extended
diuretic effect, but it may also be from effects on endothelial
function that are outside those significantly related to
diuresis, per se. Because you're urinating glucose, glycosuria,
you would expect the potential for superficial infections,
mycotic infections and that was seen. The rates were not
prohibitive and not dissimilar to what's been seen in other
studies. So, overall, the drug was well-tolerated. It did not
have any significant adverse effects outside of a few mycotic
infections, which are basically superficial fungal infections and
that's been seen in other uses of the SGLT2 inhibitors, but
nothing that I think would be unusually disturbing in this
population.


Dr Greg
Hundley:                            
Outstanding. So, Wanpen, going to switch over to you and ask you
to help us put this in the context of treating African-American
men, women with hypertension. How do we think about using this
new finding? How would we integrate it with other therapies that
these individuals already might be taking?


Dr Wanpen
Vongpatanasin:        
Sure, so I think that this study is very intriguing and
interesting that empagliflozin to me actually had more prominent
benefit on lowering 24-hour blood pressure than the previous
study that the true analysis showed the effects of 24-hour blood
pressure is much less or almost half of four to five millimeters
of mercury and that could be that this was not that significant
in African-Americans and maybe this drug is particularly
effective and, as you know, African-Americans tend to have more
salt sensitive form of hypertension and I wonder if that could
explain the results, but I think it's very encouraging because
this drug class approved for treatment of diabetes and
medication. African-American have higher blood pressures than
other ethnic groups and having diabetes makes them prone to
having more resistant hypertension. In this particular trial,
almost 40% of the patients enrolled is already taking three or
more antihypertensive medications, so adding this on top and
having that benefit is as good as adding spironolactone, for
example, and I didn't see from the manuscript, how many patients
are taking spironolactone already, but I would be curious to see
that, as well.


But I think that is something that physicians should think about
and this drug is already FDA-approved for treating diabetes, so
if you have a patient with difficult to control blood pressure
and already needed something for diabetes, this could make a lot
of sense to use it.


Dr Greg
Hundley:                            
Keith, do you have any thoughts on Wanpen's comment regarding the
use of spironolactone in the study population?


Dr Keith
Ferdinand:                        
No, I don't have those specific data available at the time that
we're speaking now, but that's certainly something that I will
attempt to look at the database and get more information. But, I
think Wanpen is absolutely right. If you look at some of the
previous studies, for instance, EMPA-REG, the major outcomes
trial that led to the indication of a decrease in cardiovascular
death and heart failure, the blood pressure lowering wasn't that
robust, maybe 4/2, but here we saw at week 24, 10 millimeters of
mercury of blood pressure reduction and if you placebo subtract,
which is what I mentioned in my first comments, you're talking
about 8 to 8.5 millimeters of mercury reduction and that's a
significant reduction, especially for ambulatory blood pressure
measurement.


Dr Greg
Hundley:                            
Absolutely. So, I'm going to go with each of you separately, but
taking this manuscript and this work that Keith, you've
performed, we'll start with you. What do you think of the next
steps in the research in this area, both from the perspective of
using this family of agents in individuals with both diabetes and
hypertension?


Dr Keith
Ferdinand:                        
What I would hope in the future is another outcome study is done
with an SGLT2, any numbers of that class, that they particularly
target enough African-Americans to see if this robust blood
pressure reduction not only is found again, but also translates
to decreased cardiovascular events. You know, NHLBI, for instance
and ALLHAT, selectively over-represents African-Americans. They
had 35% African-Americans in ALLHAT and the reason for that is
you have a population that has a disproportionate degree of
hypertension and a disproportionate degree of associated
cardiovascular disease and renal disease, so you want to make
sure that any medication that's been shown to be effective is
effective in the higher risk population. So a future outcome
study, regardless of whether they're renal-based or related to
heart failure, I hope will target an increased population of
blacks to see some of the robust reduction we have, translates in
cardiovascular events.


My suspicion is that self-defined African-American versus a
genetic factor, describes the phenotype of patients who tend to
be more obese, have more salt sensitivity, perhaps subclinical
kidney disease and will respond to a medication that has some
diuretic natriuretic effects and effects with endothelial
dysfunction and sympathetic discharge.


Dr Greg
Hundley:                            
Very good, well I heard sympathetic discharge. Wanpen, any
comments there? That's your area.


Dr Wanpen
Vongpatanasin:         I
think that definitely needs to be studied. To my knowledge, there
was only one small study that published that tried to measure
sympathetic nerve activity directly, but unfortunately that study
after a very short-term treatment for like four or five days, so
I’m sure that there will be more studies to come and also hope
that the future study will shed light on any particular markers
with surrogate that will identify patients that will respond
better, for example, PATHWAY-2 trials that were done to test the
effects of spironolactone on resistant hypertension they found
that the lower the reading, the more likely you can have better
response to Aldactone and I wonder if this might apply to
empagliflozin and be something else. I think the fact that the
blood pressures continued to decline from the week 12 to week 24
is very, very interesting when the body weight effect doesn't
necessarily go down much further. This really tells us there's
something else beyond weight and perhaps glucose that would
explain this.


Dr Greg
Hundley:                            
Very good. Well, I certainly want to thank you both for this
outstanding discussion. Keith, we want to thank you for bringing
this manuscript to Circulation and identifying this new
application for this therapy in African-Americans. Wanpen, thank
you also for your time and comments.


On behalf of Carolyn and myself, we really appreciate you
listening. Have a great week and we look forward to seeing you
next week.


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