Circulation January 26, 2021 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
co-hosts, I'm Dr. Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, associate editor, director of the
Pauley Heart Center at VCU health in Richmond, Virginia. Well,
Carolyn, our feature discussion, actually our whole issue, is
going to involve the flozins, empa, dapa, et cetera, but that
feature discussion will get some results from the EMPEROR-Reduced
trial. Well Carolyn, how about we grab a cup of coffee and this
is your area, so we're going to let you run with it today.


Dr. Carolyn Lam:


Man, and I can't wait to talk about this. Yes, the sodium-glucose
cotransporter 2 inhibitors or SGLT2 inhibitors, are indeed now
the foundational therapies for patients with heart failure with
reduced ejection fraction. Initially developed to improve glucose
control in patients with type II diabetes, SGLT2 inhibitors have
beneficial cardiovascular and renal effects in patients with
diabetes, HFrEF, chronic kidney disease. Well, today's issue
contains two pre-specified subgroup analyses from DAPA-HF and
EMPEROR-Reduced, both trials evaluating SGLT2 inhibitor effects
on renal outcomes, as well as cardiovascular outcomes, by
baseline renal function in patients with HFrEF. The first paper
comes from Dr. Jhund and colleagues from the University of
Glasgow and it is revolving around the DAPA-HF trial.


Dr. Greg Hundley:


Ah Carolyn, tell us a little bit about DAPA-HF.


Dr. Carolyn Lam:


Gladly. In DAPA-HF, the SGLT2 inhibitor, dapagliflozin, reduced
the incidence of the primary composite outcome of cardiovascular
death or worsening heart failure in patients with HFrEF, with and
without diabetes and an estimated GFR of greater or equal to 30.
Of more than 4,700 patients with a baseline GFR, 41% had a GFR
less than 60. The effect of dapagliflozin on the primary and
secondary outcomes did not differ by GFR category or examining
GFR as a continuous variable. The pre-specified composite renal
outcomes, which in DAPA-HF was a more than 50% sustained decline
in GFR, end stage renal disease or renal death. Now this
composite renal outcome was not reduced by dapagliflozin, but the
rate of decline of GFR between days 14 and 720 was less with
dapagliflozin.


Dr. Greg Hundley:


Carolyn, what's the take home message here?


Dr. Carolyn Lam:


Dapagliflozin slowed the rate of decline in GFR in patients with
HFrEF, both in patients with and without diabetes. There was no
difference in the efficacy of dapagliflozin by baseline renal
function in preventing the risk of cardiovascular death or
worsening heart failure.


Dr. Greg Hundley:


Okay, well now how about the EMPEROR-Reduced trial?


Dr. Carolyn Lam:


All right. Well, let me remind you first that in EMPEROR-Reduced
the SGLT2 inhibitor empagliflozin also reduced cardiovascular
death or heart failure hospitalization and total heart failure
hospitalization and slowed the progressive decline in kidney
function in patients with heart failure with reduced ejection
fraction with and without diabetes. Now, more than 3,700 patients
were randomized, of whom 53% had chronic kidney disease, defined
as a GFR less than 60 or a urinary albumin to creatinine ratio
above 300 milligrams per gram. Empagliflozin reduced the primary
outcome and total heart failure hospitalizations in patients with
and without chronic kidney disease. Empagliflozin also slowed the
slope of GFR decline and the risk of the pre-specified composite
kidney outcome, now defined as a sustained, profound decline in
GFR, chronic dialysis or transplant, was reduced similarly in
patients with and without chronic kidney disease.


Dr. Carolyn Lam:


The effect of empagliflozin on the primary composite outcome of
cardiovascular death and heart failure hospitalization, as well
as the key secondary outcomes of total heart failure
hospitalization and GFR slope, were consistent across the broad
range of baseline kidney function measured by clinically relevant
GFR subgroups or by albuminuria and including patients with a GFR
as low as 20. Above all, empagliflozin was well tolerated in
these patients with chronic kidney disease. All of this is
discussed in a beautiful editorial by doctors Carnicelli and
Robert Mintz.


Dr. Carolyn Lam:


Now, can I tell you about yet another paper with the SGLT2
inhibitors? This time a pre-specified comparison of the effect of
empagliflozin in patients with and without diabetes.


Dr. Greg Hundley:


Ah, great Carolyn. What did this study find?


Dr. Carolyn Lam:


Well, this is from Dr. Stefan Anker from Berlin and colleagues,
including myself and of the more than 3,700 patients enrolled in
EMPEROR-Reduced, 50% had diabetes, 34% had pre-diabetes and 16%
had normal glycemia. Empagliflozin reduced the risk of the
primary outcome similarly in patients with and without diabetes.
Patients with and without diabetes also did not differ with
respect to the effect of empagliflozin on total heart failure
hospitalizations, on the decline in EGFR over time or on the risk
of serious adverse renal outcomes. Among these end points, the
effects of the drug did not differ in patients with pre-diabetes
or normal glycemia. When analyzed as a continuous variable,
baseline HbA1c did not significantly modify the benefits of
empagliflozin on the primary outcome. Empagliflozin also did not
lower HbA1c in patients with pre-diabetes or normal glycemia and
was not associated therefore with an increased risk of
hypoglycemia.


Dr. Greg Hundley:


Carolyn what's the take home message here?


Dr. Carolyn Lam:


Well, empagliflozin significantly improved cardiovascular and
renal outcomes in patients with HFrEF, independent of baseline
diabetes status and across the continuum of HbA1c.


Dr. Greg Hundley:


Very nice Carolyn. Well, my paper comes from professor Wai Ho
Tang and it's a basic science paper. Carolyn, aberrant expression
of circular RNA or CircRNA, contributes to human diseases.
CircRNAs regulate gene expression by sequestering specific
microRNAs. In this study, the authors investigated whether
CircMAP3K5 could act as a competing endogenous microRNA-22-3p
sponge and regulate neointimal hyperplasia.


Dr. Carolyn Lam:


Wow, that's interesting. And what were the results?


Dr. Greg Hundley:


Carolyn, the authors identified that CircMAP3K5 is a master
regulator of TET2-mediated, vascular smooth muscle
differentiation. Targeting CircMAP3K5, microRNA-22-3p and the
TET2 axis, may provide a potential therapeutic strategy for
diseases associated with intimal hyperplasia, including
restenosis as well as atherosclerosis.


Dr. Carolyn Lam:


Oh, nicely summarized. Thanks Greg. Well, we've got other papers
in today's issue. There's an ECG challenge by Dr. Frész on acute
coronary syndrome with tall R waves and inverted T waves in the
precordial leads, an ignored entity. We have an exchange of
letters between Drs. Vandecasteele and Zhao regarding the
article, Cardiac Over Expression of PDE4B Blunts β-Adrenergic
Response and Maladaptive Remodeling in Heart Failure.


Dr. Greg Hundley:


Thanks Carolyn. I have some Research Letters. The first Research
Letter is entitled, “Cardiovascular Toxicities Associated with
Loperamide: An Analysis of the World Health Organization
Pharmacovigilance Database,” and the corresponding author is Dr.
Pierre Ollitrault. The second Research Letter is entitled,
“Incessant Pericarditis as a Risk Factor for Complicated
Pericarditis and Hospital Admission,” and it comes from Professor
Massimo Imazio. And then finally, there's a White Paper
(Frontiers) for atrial fibrillation screening research priorities
from the NHLBI workshop with the corresponding author being Dr.
Emelia Benjamin from Boston University School of Medicine. Well
Carolyn, how about we jump in to more SGLT2 and another feature
discussion?


Dr. Carolyn Lam:


Yes, can't wait. Thanks Greg.


Dr. Greg Hundley:


Well listeners, we're now to our feature discussion and we have
with us today, Dr. Milton Packer from Baylor University Heart
Vascular Center in Dallas and also our own associate editor, Dr.
Justin Ezekowitz from Edmonton. Milton, welcome and wanted to ask
you first off, tell us a little bit about the background that got
you to want to perform this study. And what hypothesis did you
want to address?


Dr. Milton Packer:


Greg, first of all, I'm delighted to be here with you and Justin.
And as everyone knows, SGLT2 inhibitors have had a remarkable
track record in trials of type II diabetes, trials of chronic
kidney disease and now trials of patients with heart failure and
a reduced ejection fraction. And in these trials, SGLT2
inhibitors have had two important benefits. The first benefit has
been a reduction in serious heart failure events, primarily a
reduction in heart failure hospitalizations. And the second has
been a reduction in serious adverse renal outcomes. And that has
been now shown consistently in trial after trial in diverse
populations.


Dr. Milton Packer:


Now we carried out a trial called EMPEROR-Reduced with was the
trial in patients with heart failure and a reduced ejection
fraction. It was a sister study, so to speak, with a very
parallel trial called DAPA-HF, which was carried out with
dapagliflozin. And both DAPA-HF and EMPEROR-Reduced were studies,
were trials of SGLT2 inhibitors, dapagliflozin and empagliflozin
in people with heart failure and a reduced ejection fraction. And
they produced remarkably consistent results. And specifically a
reduction in serious heart failure events and serious adverse
renal events.


Dr. Milton Packer:


But the trial studied complimentary patient populations. We
studied patients that were a bit sicker than patients in DAPA-HF.
And Greg, what's really fun is that each trial designed its own
case report forms so that we collected information that the
investigators were really interested in and they were not
necessarily the same types of information across the two trials.
One of the things that was really interesting about
EMPEROR-Reduced was we were really interested in these heart
failure events. We wanted to understand them. We wanted to
understand whether they occurred as outpatients, inpatients. If
they occurred as inpatients, what kind of hospitalizations were
these? Were these serious hospitalizations? Were these short
term, very mild hospitalizations? This paper, the hypothesis in
this paper was to take a look at what empagliflozin did in
patients with heart failure and reduced ejection fraction,
specifically with respect to outpatient and inpatient worsening
heart failure events.


Dr. Greg Hundley:


Very nice. How many patients did you include? What were the
characteristics of the study population? And what was the design?


Dr. Milton Packer:


We enrolled, randomized 3,730 patients. All patients had heart
failure with a reduced ejection fraction. All were receiving all
appropriate treatments for heart failure. Interestingly, 20% were
receiving nephrolysin inhibitors, which is really a very high
percentage, but they were also receiving inhibitors,
renin-angiotensin system beta blockers, mineralocorticoid
receptor antagonists and they were patients who had an average
ejection fraction of about 27%, which is much lower than most
heart failure trials recently. They also had meaningfully
elevated levels of natriuretic peptides. These were sicker
patients and they had a much higher placebo event rate. They were
randomized double-blind, one to one ratio to either placebo or
empagliflozin. Dose was 10 milligrams once daily. And this was
added to all previously existing therapy and patients were
followed for double-blind therapy for an average duration of 16
months and we recorded prospectively information on outpatient
and inpatient heart failure events.


Dr. Greg Hundley:


Very nice. What did you find, Milton?


Dr. Milton Packer:


We originally reported that in this trial, there was a reduction
with empagliflozin on heart failure hospitalizations and that
reduction was about 30%. We wanted to know, well, what else was
going on with respect to these heart failure events? And so we
asked the question, well, did empagliflozin reduce urgent and
emergency room visits for heart failure? Did empagliflozin change
the types of hospitalizations? We recorded the use of positive
inotrophic drugs, vasopressor drugs, vasodilator drugs, cardiac
devices, intervention, surgical interventions. And we found out
that across the entire spectrum of heart failure outcomes, there
was a reduction in serious outcomes with empagliflozin and they
all were around a 30% reduction in risk. They varied a little bit
from about 28 to 33, but approximately all were in the same
ballpark. And what was really interesting was we had a fair
number of hospitalizations where patients required IV inotropic
drugs, vasopressors, mechanical intervention, they were reduced
by 30% with empagliflozin. Hospitalizations associated with
intensive care reduced by 30% with empagliflozin.


Dr. Milton Packer:


And then we looked at outpatient events. Outpatient
intensification of diuretics reduced by 30, 33% with
empagliflozin. We looked at New York heart class. And what was
really interesting was that patients treated with empagliflozin
had a 20 to 40% greater likelihood of showing improvement in New
York heart class and a 20 to 40% lower likelihood of showing
worsening in New York heart class. And those benefits, we're
seeing within 28 days after randomization. This early effect is
really interesting and it's generated a lot of discussion. And so
we looked at our Kaplan Meier curves for the composite of
cardiovascular death, heart failure hospitalizations, urgent
care, emergent care visits, and we found that the two curves
separated quite early and reached statistical significance only
12 days after randomization. This is a very early effect. I want
to add that this early separation of curves has been reported
previously with beta blockers, with mineralocorticoid receptor
antagonists, with neprilysin inhibitors and now we can add this
early separation with SGLT2 inhibitors.


Dr. Greg Hundley:


Very nice, Milton. Well, I'd like to turn now to our associate
editor, Dr. Justin Ezekowitz. and Justin you've seen a lot
manuscripts come pass through your hands. What attracted you to
this manuscript? And then how do you put the findings that Milton
has just described in the context with the other results that we
have been witness to regarding SGLT2 inhibitors?


Dr. Justin Ezekowitz:


Thanks Greg. And also, thanks Milton for letting us look at this
remarkable manuscript as I do think the clinical implications for
a manuscript like this are quite profound. The first thing that
really strikes me is we often get worried about looking at a
number of different end points. Within a clinical trial, we often
don't want to have too many looks at the data because of the risk
of finding something that is spurious, is high, but in this case,
the way the data was collected and the exploration is quite
valuable. We can look at any one of the combinations of clinical
end points that actually have direct clinical relevance for a
clinician and the patient. And this paper really explored that in
a lot of data, in a lot of depth and also helped us by putting
the caveats around these findings that this is exploration, but
it does anchor it in the SGLT2 world, but also the heart failure
world.


Dr. Justin Ezekowitz:


And Milton, I think one of the striking findings that you showed
and it's buried in many of the great figures and tables, is that
one in two patients had something happen in the next year. In the
next 12 months, that patient walking into an office for a routine
followup, one in two had something and the reduction was pretty
remarkable across the end point. Milton, I wanted to pick your
brain on this one, just to understand when you look at the
intensification of diuretics, that was anything from adding
another 20 milligrams of furosemide, to doubling or tripling
that. Do you think these findings are pretty ubiquitous across
the patients enrolled? Or do you think they're a niche finding in
only some patients at the highest risk?


Dr. Milton Packer:


Well, we actually looked at that. We actually looked at whether
baseline variables influenced the effect on intensification of
diuretics and it was across the board. Well, let me just say,
across the board in the patients that we studied and obviously
can't make reference to people we didn't study, but we didn't
find any particular subgroup that responded particularly well
with respect to either a hospitalizations or diuretic
intensification or New York heart class changes. But Justin,
there's one thing that you just said that is so important. And
that is, our patient population was characterized by their
physicians, 70% as having class II heart failure. And a lot of
physicians think that class II heart failure represents a stable
population, clinically stable population. And as you said, one in
two patients in our study during followup had worsening heart
failure, either represented as an inpatient or outpatient event.
A class II patient with heart failure and reduced ejection
fraction, even though they're getting optimal medical therapy, is
not a clinically stable patient.


Dr. Greg Hundley:


Very, very interesting finding. Well, just to ask each of you,
maybe Milton first and then Justin next, Milton, what do you
think is the next study that we need to perform in this patient
population using this class of drugs?


Dr. Milton Packer:


We're really excited about a new phase of heart failure research
with SGLT2 inhibitors, which is to look at the impact of these
drugs in patients with heart failure and a preserved ejection
fraction. DAPA-HF and EMPEROR-Reduced were trials of inpatients
with hard failure and a reduced ejection fraction. But we really,
about half patients with heart failure, have an ejection fraction
of greater than 40%. We really need to understand what SGLT2
inhibitors can do for these patients. And here's the good news.
And there are two large scale trials that are both nearing
completion. And the first of those trials will be reporting out
in about nine months from now with the next trial following about
six months later. We will in the next 12 to 18 months, have two
major large scale trials of these drugs in a population which is
highly different and yet complimentary to the patients who have
been studied to date.


Dr. Greg Hundley:


Justin, how about you?


Dr. Justin Ezekowitz:


Well, to compliment what Milton is suggesting, I think that's one
area. And I think the other area is in implementation science.
Now that we have four big classes or groups of drugs, is to how
to start these and how to optimize these efficiently in the first
month to two months or even three months so the patients can get
the benefit for all these medications. And I think what we need
to really study is how do we do that? Because we have the drugs
but the implementation is where we're not quite there yet. If we
get the implementation and testing, randomized strategies and how
to do it, I think we may be able to help more patients globally
than with the addition of even any new drug that may come out
onto the markets soon or in the future, as that remains one of
our challenging topics.


Dr. Greg Hundley:


Well listeners, we want to thank Dr. Milton Packer for bringing
this study to us at Circulation and also our own associate
editor, Dr. Justin Ezekowitz and really highlighting how the
initiation of this SGLT2 inhibitor, empagliflozin, at 10
milligrams per day, in a heart failure reduced ejection fraction
population with an average left ventricular ejection fraction of
27%, resulted in a 12 day, at 12 days into therapy, a separation
of the development of adverse heart failure related events that
was then sustained over the next 16 months.


Dr. Greg Hundley:


Well, on behalf of Carolyn and myself, I want to wish everyone a
great week and we will catch you next week on the run.


Dr. Greg Hundley:


This program is copyright of the American Heart Association,
2021.