Worldwide, cardiovascular
disease affects the lives of hundreds of millions
dedicated cardio nerds everywhere are working hard fight
this global epidemic. These are their stories.
Hey Cardio Nerds. This is Rick Fe ferrari
Cardiology fellow at Johns Hopkins Hospital.
Today, we are back for our second episode
on the world of sodium glucose c transporter.
You've probably heard of ST2,
but we might be talking about ST1
today just to preview a little bit, and
their impact on cardiovascular
disease.
I'm joined today as always by the tremendous
Series c chair and Director of the car
its internship, Doctor. Girl Cow, a phenomenal internal
medicine resident incoming cardiology fellow at B Women's
Hospital.
Girl, how are you doing tonight?
Thanks so much, Rick. I'm really excited tonight
to learn from this discussion about S inhibitors.
And I have the privilege of introducing doctor
Maria Bar,
an internal medicine resident at Hack Meridian Health
in the great state of New jersey
a current cardio nerd fellow an aspiring cardiologist.
Her background from Y Iran, the city which
is famous for its sweets, drives her interest
into diabetes and cardio their disease prevention. Pray
to see you here, Mary.
Thanks for
production darlene. I am so thrilled to be
here today. I have the honor of introduced
our expert faculty discussed. Doctor Wu, Water.
Doctor Var is a cardiologist
at the Bing in women hospital in Boston
massachusetts. He is a leading clinical trial is
with over 250
publications and c director of the center for
cardio
implementation science. He also hosts the podcast, don't
miss beat and heart failure and focus. Where
he critically
examine, clinical care and research with experts globally.
Doctor W,
it is an honor to have you here
with us. Welcome to Card.
Thank you so much. The honor is truly
mine. I've been a fan and really have
a great admire of the work and medical
education that you all do and champion, and
it's a real privilege to be able to
join you today.
Doctor,
as we often do, let's get it started
with the case from the car clinic.
Missus Gl is a 57 year old women
with a history of diabetes
on impact
with him hemoglobin A1c of 6.3
percent.
She is accompanied by her husband, mister Gl,
who has a history of parts failure with
ejection fraction of 35 percent. And was resilient
started on impact frozen.
During the conversation, missus Cliff explains that she
has been on
for a few years for her diabetes.
But now is unsure why her husband been
who does not have a diabetes who would
be on this as well. Doctor Barr.
Can you speak more to this
evolution in the use of S 2
inhibitors from a medication exclusively for diabetes
to now a key component of heart's failure
therapeutic management.
Thanks so much, Miriam. You know, the hidden
secret in cardiology is that
most therapies that were developed for a particular
purpose.
Actually ended up being
indicated for a vastly different reason, and so
too the S 2 inhibitors
had such a circuit
pathway to ultimately
its current indications in the Us and worldwide.
This all started back in the 2 thousands
when there was initial safety concerns about certain
classes of
anti
therapies to the point where the Us Fda
issued an industry wide guidance
requiring all new sponsors
developing therapies
for diabetes
because of its high prevalence in the community
to conduct dedicated cardiovascular
outcomes trials to exclude
excess cardiovascular risk.
This led to perhaps 1 of the greatest
growths in scientific evidence across any discipline and
we learned a tremendous amount about not only
the cardiovascular
effects,
but also
the effects on other organ systems such as
the kidney
and specifically in terms of various aspects of
the heart. The S 2 inhibitors benefited greatly
from this, and there were
really 5 large scale trials that were conducted,
specifically evaluating people
with diabetes at high cardiovascular
risk and this led to the rest of
the story quickly unfolding thereafter.
The initial signals suggested that not only were
these therapies quite safe, but in fact,
they had profound effects in preventing cardiovascular
events
specifically preventing heart failure
and in delaying kidney disease progression. Both of
these issues are, of course,
very, very important for people living with diabetes.
And so this captured broad interest amongst the
community.
And thankfully,
the sponsors that developed disease therapies.
In fact, rapidly chased those threads of information,
those
initial hints of and signals of benefit
and dedicated studies
then were pursued specifically evaluating people
with chronic kidney disease and people with heart
failure with and without diabetes.
And the fascinating thing was, we learned that
while the story started in diabetes.
It ended
in us understanding that these therapies and the
therapeutic benefits
of this class, extend well beyond diabetes in
fact reach
to chronic kidney disease and heart failure
as cornerstone of management of those conditions.
Doctor,
thank you so much for walking us through
that historical perspective and the trial data leading
to S 2 inhibitors becoming a medication outside
of just a diabetes drug, but with a
more broad indication for use. I think it's
just really remarkable to think back of how
in this field we're really able to use
data from these large scale trials and change
clinical practice and really focus in on implementation
of these therapeutics.
And S inhibitors we now have a role
within the cardiovascular system through multiple mechanisms.
Including but not limited to volume regulation, cardiac
remodeling and other cellular effect, which are still
under
investigation. Do you mind el collaborating for listeners
more on these possible mechanisms of S inhibitors
and how they work in affecting cardiovascular disease
especially how they work to improve heart failure.
G, you're asking yet another very challenging question
and in fact, this is probably the second
great secret of cardiovascular
therapeutics and drug development
is that we often don't understand central may
of how these therapies actually benefit people, while
we have this almost rosy
picture of
how drugs are development from the bench to
the bedside going through phases of development with
specific targets in mind and
almost
precision based approaches in which we design and
develop therapies,
often therapies have systemic effects that
go well beyond intended and those benefits might
actually be principally
involved in ultimately
preventing disease progression.
The S 2 inhibitors
have varied defects. S 2 is predominantly
expressed in the kidney in the proxima tub
of the kidney over 90 percent of those
transporter
are located in the proxima tub
And so it would be remiss for us
to dismiss the kidney as a central mechanism
of how these therapies
benefit
the system at large, including the cardiovascular system.
S 2 is not expressed in the my
and so the effect and benefits we see
on cardiovascular
status must be either
a myriad of factors that are systemically acting,
for instance,
Some effect on blood pressure, some effect on
volume
regulation, some effect on
metabolism in improving gl
control and all these together to improve cardiovascular
status,
or it might be
off target effects on the heart and perhaps
while it might not
influence a direct receptor or transporter present in
the my,
perhaps it has off target effects on other
ion channels, other receptors in the my cardi.
And then finally is,
that the benefits are truly outside of the
heart and the heart is benefiting second,
and that is 1 of the notions that
perhaps
The kidney really as a central actor
is improving cardiovascular
status by improving
kidney efficiency and in handling salt and water.
All these mechanisms I think are certainly credible
think mechanistic studies are very challenging to conduct
because you can do a very well conducted
study to prove or disprove 1 of these
mechanisms
but it doesn't actually speak to the other
mechanism that could be at play. So my
view is that
we
must recognize that these therapies ultimately in very
well conducted large clinical trials do benefit people,
and likely these benefits are systemic that there
multiple mechanisms
much like the statins for at atherosclerosis cardiovascular
disease we're now seeing that the s 2
inhibitors have myriad effects in improving cardio kidney
metabolic health.
Yeah. Thank you so much for that discussion.
It's really kind of the p
nature that you're talking about and what we're
still learning about these medications. Is really remarkable,
and it's been, you know, really, really a
fun time. I remember this was kind of
in the early days when I started training
and it's it's really proliferate so tremendously. And
so following that it's been has been really
a privilege.
And so to get us back to the
car clinic. Following your appointment with missus Gl,
she sends a secure message via electronic medical
record asking about her sister. Missus flows.
Who is also on
for symptomatic heart failure, but has an ef
of 55
percent as opposed to 35 percent. Can you
el more on the data and key trials
in support of the impact of these class
of medications on the management of patients with
preserved D?
It's a great question, Rick. As you know
and it has been discussed on this forum
heart failure preserved ejection fraction has been a
challenging entity to study In many cases has
been described as the graveyard of cardiovascular
therapeutics,
and some have even gone to the point
describing it as the greatest unmet need across
all of bio.
Thankfully, the S 2 inhibitors were the first
therapeutic class to definitively show cardiovascular
benefits
in this high risk population of heart failure
preserved ejection fraction.
The 2 principal trials were large scale trials
of S 2 inhibitors in the
emperor preserve trial. This was with the S
2 inhibitor amp frozen,
and then the deliver randomized clinical trial studying
the S 2 inhibitor da flows.
These were similarly designed trials
globally conducted across many, many countries involving many,
many investigators
worldwide,
but we're simply designed comparing the to inhibit
against placebo in this target population of heart
failure with mildly reduced or preserved ejection fraction,
defined as an ef above 40 percent with
elevated nat natural peptides and evidence of structural
heart disease.
Now, these therapies showed benefits
on improving cardiovascular death or heart failure events
and The effect sizes were substantial and clinically
relevant,
and their benefits were driven by both of
those components. There were some benefits seen for
even cardiovascular death and a predominant effect on
preventing
hospitalizations for heart failure and urgent heart failure
visits.
This led rapidly to labeling updates that these
therapies now are not only indicated for
people with heart failure with reduced Ef, but
for the heart failure syndrome as a whole
and actually simplified medicine in many ways.
Often were challenged by defining ejection fraction early
because in certain regions of the world, there
might be limitations and obtaining timely echo
or other modalities define
ejection fraction.
This set up a system of medicine that
simplified things that moved away from ejection fraction,
at least for this therapy
that allowed us to say
this therapy was beneficial across
the spectrum of ejection fraction and may even
be initiated before you know this specific ejection
fraction of that individual.
This also is rapidly adopted by clinical practice
guidelines and formed the first
class 1
recommendation,
4 a specific therapeutic in heart failure preserved
ejection fraction in the most recent 2023,
Es clinical practice guidelines for heart failure.
So a really, really exciting space, and I
think is just the first of therapies
to show benefit.
I think it paved a path not only
to how we can study these therapies
but also
perhaps of the types of therapies that might
be beneficial in heart failure with preserved ejection
fraction.
Heart failure preserved Ef often occurs in the
background of cardio kidney metabolic conditions. And so
perhaps these similarly
systemically acting therapies
For instance, the Gl 1 receptor
or the mineral
receptor antagonist,
maybe those are the same therapies that could
actually benefit this target population of heart failure
preserved yet. So a lot more to learn
about the syndrome,
but exciting that this was the first breakthrough
to have a definitive body of evidence to
support a class 1 recommendation in clinical practice
guidelines.
So really citing time in cardiovascular
medicine especially for heart failure preserved ejection fraction.
In my view, it not only taught us
about how we can study these therapies that
we need to conduct really
broad large scale trials
to be able to detect important effect sizes
in this heterogeneous
population, but also about the types of therapies
that might be beneficial
in heart failure preserved ef.
Half often occurs in the background of multiple
cardio kidney beam at all conditions. So perhaps
it's therapies that in fact act systemically targeting
each of these axes that may ultimately prove
to be beneficial just like the Est tune
inhibitors.
Doctor Ba gu and thanks for the nice
summary of trials. It was really interesting to
hear about
simplifying medicine. I never thought of it this
way that we can use a agility to
inhibitors without specifically defining heart failure with reduced
ejection fraction or with preserved ejection fraction as
a whole heart failure in Europe, ming slightly
away from cardiology specifically,
but to a patient population, we also see
very frequently.
I was hoping to ask about S 2
inhibitor use in patients with the renal in
efficiency. Is there any role in the management
and prevention of Ck katie?
Thanks so much, Barry. I wanna quickly touch
on that comments you made about
simplification and I recognize
as a community, we often have
This balancing act between
precision medicine,
identifying patients that may likely benefit
the most from a given therapy,
and
simplification, ability to actually implement therapies at scale.
And I think in cardiovascular medicine, we take
care of such a broad, high risk
population.
That at the present time, we are more
so
in this broad
implementation approach where we're
identifying
phenotypes
that are recognizable by all clinicians, whether they
be cardiologist for primary care doctors or ne
for endo.
And we're able to be able to treat
that cohort of people in multiple different settings
in multiple different countries.
We may actually move towards a very precise
approach to care for
some of the other phenotypes that we less
commonly see but I think in terms of
garden variety,
heart failure with preserved d or heart failure
in general,
I think this
simplified approach to implementation may actually improve our
therapeutic
uptake and may improve our familiarity with these
therapies
and our comfort with these therapies.
And perhaps
regardless of our specialty or our training, we
may feel comfortable
in using a common set of tools to
combat disease progression in heart failure.
Shifting now to chronic kidney disease, Ck has
a tremendous burden in the community
affects
about 40000000
Americans and has a tremendous footprint globally.
Ck cad is a syndrome that has been
challenging to study because it slowly progresses
and often clinically
significant events such as end stage kidney disease
requiring dialysis for transplantation,
is relatively
infrequent event during the typical time course of
a study.
The disease progression is often
asymptomatic and so
many individuals may be
undetected
or un
in the community.
And finally,
are tools that are available to actually diagnose
Ck k, such as
urine albumin cr ratio are vastly
underutilized. And so this all
and cons conspired to create a scenario in
which we vastly under diagnosed
ck circadian in the community, and we under
study this population.
The renin angiotensin system inhibitors, ace inhibitors and
or have been the cornerstone of management for
over 2 to 3 decades.
And until very recently, we haven't had great
breakthroughs in the chair of Ck.
The S 2 inhibitors were the first such
add therapy
2 background
renin angiotensin
inhibition. And have been studied in 4 separate
randomized clinical trials
that is credence, Da Ck kd,
amp kidney and scored.
These 4 trials tested each individual therapies S
2 and S12
inhibitors
in this target
population of chronic kidney disease.
2 of the randomized clinical trials,
credence and scored,
specifically studied people
with chronic kidney disease
and con conglomerate type 2 diabetes.
Most of these patients were thought to have
diabetic ne.
The other 2 trials enrolled broader
populations
including Da ck cad and amp kidney
studied populations with and without diabetes,
inclusive
of ideologies of chronic kidney disease,
unrelated to diabetic ne,
including
specific gl ne,
and other ideologies are Ck g progression.
All 4 trials showed that these therapies
modified
disease course in chronic kidney disease.
So they showed that you're able to actually
reduce clinically relevant events, such as dialysis and
transplantation,
even over a finite
duration of time,
you're able to bend the trajectory of kidney
seeds progression by slowing the decline of G
in these patient populations. And most importantly, these
benefit were seeing irrespective of diabetes status.
Irrespective of ideology
and irrespective
of the individual patient profile, for instance, if
they were high or low risk. And so
now S 2 inhibitors form
Another cornerstone of management of chronic kidney disease,
and all these patients were well treated with
background,
renin angiotensin system inhibitors,
and just like we've seen in the care
of heart failure,
we are now seeing in the care of
chronic kidney disease.
That there are now multiple therapeutics
that have been shown to delay disease progression
in Ck cad, and so much like we
consider
G
of the heart
in delaying disease progression heart failure, there's now
a very similar set of tools as a
G
for the kidney to delay disease progression ultimately
reaching
important clinical events like dialysis and
transplantation
Thank you, Doctor Var for going into more
depth about the role of S inhibitors and
chronic kidney disease. That was just really a
true master class of the child in this
patient population. And I really love that point
you made earlier about how we're going from
broad
implementation and
recognizing those broader phenotypes and moving more towards
precision medicine. And I think all this discussion
with Ck katie really speaks to the fact
that S inhibitors aren't a drug owned by
1 specialty only, is really an intersection of
cardiology ne, endo and primary care, and is
multi disc disciplinary
collaboration is needed for effective
implementation of the drug class and to get
it to the patients that would benefit from
it. The And so far, we've been talking
a lot about S 2 inhibitors, but we
know there are medications that are both S
2 and ST1
dual inhibitors.
Could you tell us a little bit more
about the trial data of those dual inhibitors
and their effectiveness across the heart failure spectrum
and other indications for their use?
Yeah. Thanks so much, Gu, and and really
all
6S2
inhibitors,
an S12
inhibitors that are now Fda approved
have varying
affinity
to either the ST1
transporter
or the S 2 transporter and So if
given in equal potent doses,
often will bind to both of these transporter,
We often call most of these therapies S
2 inhibitors because they're mostly specific to the
S to transporter.
Predominantly located in the proxima tub of kidney.
Now S 1 is also
expressed in the human system.
And that's predominantly in the brush border of
the gut and has a very similar role
in the reclamation of filtered,
glucose and sodium.
And so these transporter
both act in unison
to control
glucose homeostasis in the system,
And so its inhibition of S 1 and
2 may lead to losses not only the
kidney of glucose that's filtered. But also of
glucose in the gut lumen.
So S12
inhibitors that have more balanced effects on S
1 and 2
have also been developed and so flows is
the currently Fda approved
ST12
combined inhibitor.
This was a therapy that was studied in
2 randomized clinical trials that were in phase
3
scored and solo heart failure.
Scored was a very large trial of 10000
individuals with chronic kidney disease and type 2
diabetes.
Soul worsening heart failure was a very unique
trial
of
patients with worsening heart failure.
These are patients who are randomized either just
before or just after
hospitalization for heart failure
and so studied the role of these therapeutics
in the acute phase of illness in heart
failure.
So unfortunately,
During the conduct of these randomized clinical trials,
the primary sponsor pulled funding from scored and
sol
such that we had
curtail follow up in the case of scored,
which was fully enrolled in over 10000
individuals but had short duration follow ups, which
impacted
the actual ultimate study conclusions because
this was ultimately a Ck cad progression trial
and Ck cad progression trials
require
longer duration follow up to a crew sufficient
rare events like dialysis.
And similarly in soul worsening heart failure,
the loss of fun doing.
Restricted the number of patients actually enrolled and
that was limited now to just over a
thousand participants.
The clinical trial were quite
adapt and quite smart about this and rapidly
modified the primary outcome of these trials
recognizing that. In 1 trial, there was limited
follow in the other there was a limited
enrollment
to really a broad based point of total
cardiovascular deaths,
hospitalizations for heart failure or urgent heart failure
visits.
And in fact, in both randomized clinical trials,
actually showed that this therapy when studied in
Ck kd when studied in worsening heart failure
was able to modify that outcome of composite
cardiovascular death and heart failure events and that
was counting both first and recurrent events.
This actually led the Fda to provide
so with a specific label of
prevention of heart failure events in individuals with
chronic kidney disease and in people with worsening
heart failure. So really provided a clear pathway
how we can think about using this therapy.
Thank you for that comprehensive
review and the mechanism and the trial data
I think oliver of our discussion tonight has
really shown that there's a growing base of
Data supporting the implementation of S inhibitors.
And Doctor,
you've been such an expert in this field,
so would love to hear your perspective of
what do you think is the future advances
in S inhibitors for patient management.
We know that we recently had another S
trial presented at Acc, the impact Mi. So
we'd I'd also love to hear your thoughts
about that trial and what groups of patients
do you think might benefit
from S inhibitors that we haven't studied ed
yet? Where is the field headed?
You know, until now we've talked about cardio
protection in people with type 2 diabetes.
Primary treatment of people with heart failure irrespective
of their ejection fraction,
primary treatment of people with chronic kidney disease
of various et ideologies,
and the most recent aspect and disease state
that was studied was that after
acute myocardial infarction,
and that was studied in 2 randomized clinical
trials
Da mi and impact Mi,
and we may not have the time to
actually dive into the details of these trials
but it essentially showed that
mortality in this population was relatively
low in that Most of these people after
myocardial infarction in the contemporary era faced relatively
low
mortality events
because they're promptly rev and because standard of
care is quite quite good that are other
therapeutics
are excellent in preventing death.
However, we also recognize that patients still face
residual risk of other events such as heart
failure and so the development of post Mi
l dysfunction and heart failure is still important
even in the current era of care. And
so impact Mr Da mi
showed that you can actually
prevent heart failure
hospitalizations
in people
who
suffered from and acute myocardial infarction function, including
those who are promptly rev,
including those who are already well treated with
other dare that we know are helpful,
such as statins such as anti platelet therapies
such as
ace inhibitors, and mineral
receptor antagonist,
and
Da mi was a little bit more of
a unique trial and that it had to
be adapted in terms of its primary outcome
because it had a much lower target event
rate And so ultimately, it was
evolved into a win ratio type endpoint, and
until the learnings from that trial were a
bit more limited,
Impact Mi was conducted a bit more traditionally
was a much larger trial
and was an event driven trial. And so
we lurk that while these therapies can't bend
mortality,
which was 1 of the components of the
primary endpoint.
It does appear to prevent
hospitalization for heart failure, which is a feature
of this therapeutic class
that we've seen not just after myocardial infarction,
but across each of the disease states we
just talked about. Chronic kidney disease heart failure
patients with established disease as well as patients
with diabetes who are at high cardiovascular.
So we'll see how
regulators and guidelines
consider this data, but I think it's important
to understand that this was
therapeutic area that we've made great strides and
the S inhibitors may have a role, at
least in a selective
population at very high risk for heart failure
onset.
There are many areas that I think are
exciting ahead
we're now about 10 to 12 years after
initial labeling
of S 2 inhibitors, so many are reaching
their patent
expiration dates and in fact, we now have
generic therapeutic options in the United States.
And so I don't think we can expect
that
Principally
industry sponsored trials are going to be the
mains state of what we're gonna see moving
forward. We're gonna see federally funded studies
we're gonna see more creatively funded studies moving
ahead.
The open ended questions are how can these
therapies be a effectively combined with other therapies,
and so we now are seeing
combination medical therapy trials
including poly pills, there's a wonderful trial being
led out a few t Southwestern that's an
nih sponsored trial of a combination poly pill
in heart failure with reduced Ef.
Furthermore, there combinations with mineral cord receptor antagonists
that are being specifically studied in cardiovascular
outcomes trials in heart failure.
The other aspects are areas that were previously
excluded
For instance, people would significantly advanced chronic kidney
disease, including those
already on dialysis.
This is being now studied in large scale
trials
1 of which is called renal life cycle,
which is about a 1500 patient trial that's
being conducted globally that's studying S to inhibition
in people on dialysis
in people with significantly reduced G
and in people after kidney
transplantation.
There are some other areas that I think
are of note until now we relatively discussed
pretty high risk scenarios
People would not just type 2 diabetes, but
those who already have maybe established cardiovascular disease
or who are at very high risk for
cardiovascular events. We've discussed patients with heart failure
chronic kidney acute mi, But what about earlier
on in the disease process, including people
with
just diagnosed
type 2 diabetes
we should be learning from
1 such trial that is studying
newly diagnosed type 2 diabetes and whether S
inhibitor should be first line care, and it's
actually comparing that against
metformin in a specific trial called smartest
that's being run out of Scandinavia, so that
is another area of interest. And then finally,
of course, is
While as a field we've moved towards
combination medical therapy.
We also wanna be par in terms of
how we deliver care and so the comparative
effectiveness of these therapies
even against other mains states of care is
also of high interest and so Pe has
funded a large scale trial called precedent
that is specifically studying S to inhibitors against
Gl 1 receptor agonist,
in people with type 2 diabetes and established,
cardiovascular
disease,
This too will be an area to look
forward to
because perhaps at least in low moderate risk
individuals maybe we should be starting with 1
class and then layering on the second if
additional aspects of cardiovascular risk acc in those
individuals. So Lot to learn about this feel.
I think the core aspects of these fields
have been well studied and rapidly so it's
remarkable that all this evidence
has taken place over just about a decade,
but I think we still have about
another decade of learnings of how these therapies
can be combined, how these therapies
can be implemented in a timely basis
and how these therapies can be implemented in
people
who are previously excluded from those initial randomized
clinical trials
including some that are very, very high risk
for disease progression and clinical events.
Thank you so much for that incredible review...
I'm looking forward to going back and listening
to that again because there were a lot
of takeaways from that. You had mentioned the
Poly pill, and I'm I'm really interested in
that work, particularly
with respect to G t. And obviously, I'm
sure we've all had experienced starting many patients
on heart failure guideline directed therapy and they
can go from 0 to quite a few
medications quickly. What sort of data is there
for the Poly right now? What what kind
of progress do you think we're gonna make
in that direction?
Yeah. So I I think this is really,
really an important area because poly pills have
been showing be beneficial in many areas across
cardio metabolic medicine,
including diabetes,
in
hypertension management in other
prevention settings,
and
we've now rapidly
converged and guidelines have strongly recommended multi drug
regimen in the care of heart failure with
reduced ejection fraction, especially and even some people
would mildly reduce the. And so a poly
pill is a natural next step of what
needs to be developed.
I think until now Poly pills have been
challenging to develop and heart failure was reduced
yet
because there have been multiple sponsors of
individual therapies
that haven't actually had adjacent compounds in their
armament.
And so developing a single therapy
that encompasses all of them has been difficult.
But now we're at a unique phase in
which we're about 10 years after the development
of the core therapies, including the S inhibitors,
including
angiotensin receptor
inhibitors like
val sa. And so we do have the
potential now that generic are emerging,
that we can actually effectively combine them. So
we're at a very early stage of development
of poly pills. I don't think that they're
yet been evidence of
true poly pills in heart failure.
I mentioned that Ut South trial that I
personally am looking forward to
individual companies
are developing,
combination therapies, for instance, including 2 of the
components,
like an s inhibitor and some modulator of
the mr
receptor,
but I think a
combination of 4 drugs which were often asked
about. I think soon we'll see some attempts
of will have to understand how this will
be
taken up by the community because we are
so used to having choice in cardiovascular
choice of doses
choice of individual therapies within
combinations, for instance, a particular beta blocker or
a particular ST2
inhibitor preference are even
a particular
ace inhibitor R or ar preference. And so
that type of decision making
needs similarly be simplified when we're discussing poly
pills and the appetite of
simplification in the clinical community,
I think needs to be something that we'll
need to wrestle with. So we'll soon see
it's a very early stage even though these
therapies have been around for a long period
of time,
we're now just at the point where we're
about to see generic for all 4 core
guideline directed medical therapy. And so it is
truly a time point in which poly pills
for heart failure
are in fact possible.
Thank you so much for that. That's really
enlighten, but also in hardening and I'm really
excited to see you, what's up next for
this because we've come such a long way
as you've highlighted
via the data so far,
but there's clearly a lot of excitement on
the horizon as well.
To wrap things up here, I'd love to
ask your perspective, on some of the key
takeaways from our discussion on the data. It's
been
really a whirlwind tour here, and it's been
an really an incredible privilege to speak with
you, but what are some kind of key
points that you'd like to send to our
audience?
Thanks, Rick. This is really a remarkable drug
class that we've learned a lot about over
the last decade,
and S 2 inhibitors
today are indicated across 3 specific disease areas,
patients with type 2 diabetes,
patients with chronic kidney disease and patients with
heart failure.
In type 2 diabetes, they're indicated for their
primary glucose lowering potential,
at least in people who have preserved kidney
function because these therapies lose their glucose lowering
potential at lower G as kidney disease progresses.
And furthermore,
it's indicating people with diabetes
for cardiovascular
protection, prevention of cardiovascular
events, including
prevention of heart failure in individuals with diabetes.
In chronic kidney disease, these therapies
are now the first therapeutic class that have
been added to renin angiotensin system inhibitors
broad patient populations of chronic kidney disease inclusive
of people with and without diabetes,
And finally, in heart failure, it's been shown
that these therapies,
benefit
patients across a broad spectrum of ejection fraction
in preventing clinical events and preventing disease progression.
These therapies have been studied in
those after acute myocardial infarction
who have either L dysfunction or evidence of
congestion,
and the evidence is relatively mixed.
There's some evidence that these therapies prevent heart
failure onset after a myocardial infarction,
but there's no specific labels
for this disease area and guideline bodies
and regulators
still are digesting the very, very hot off
the press data from da at my an
impact am I.
Broadly speaking across these 4 therapeutic areas,
this
Individual therapeutic class has been studied in 16
randomized clinical trials and has led to 6
different therapies
being approved by the Us Fda in short
order,
we now have the first generic available.
And so we're hopeful
that these therapies
become more affordable,
accessible
and equitable
in terms of the implementation of them,
broadly.
Despite their now
10 years of scientific
investigation and really well conducted clinical trials, there
are many unanswered questions.
And those clinical trials are actively being
conducted
including in
populations that were previously been excluded such as
end stage kidney disease,
including
combination medical therapy, clinical trials
and about trials specifically about
implementation.
Where when and how do we implement these
therapies
to allow for the best
potential patient outcomes with their use?
So
I would say this is a paradigm of
how
therapies
that were developed in 1 area
may quite quite successful
in influencing broad patient populations.
And it's a really, really exciting time
for cardiovascular
medicine,
because this is really rein,
not just
cardiology,
but kidney medicine,
metabolic medicine
and has brought these fields really together
in studying these therapeutics even in multi orbit
conditions.
And on a personal note, I would say
that
this therapeutic class really
started
and the very first of those 16 randomized
clinical trials amp egg outcome
reported when
I was a first year cardiology fellow.
And at that point, I was relatively.
I enjoyed cardiology. I enjoyed clinical trials. I
enjoyed data science,
but this was a trial that I recognized
was outside of cardiology,
but there was some magic to this therapeutic
class, and so I invested
a lot of my early years as a
cardiology fellow
in understanding more and trying to become more
involved
in
growth of evidence
around this therapeutic class. So my main advice
is that use this as an example,
and keep your eyes open
because at whatever stage of training you're at,
there going to be surprises and
If history is going to repeat itself.
Cardiology
is a therapeutic area of serendipity,
and there will always be
a windy road ahead, and we never know
when the next
great therapeutic is going to land and
Keep your eyes open
because this is
1 of the most fascinating areas of medicine
because we have so much to learn about
cardiovascular system
and we learned it by
pathways that maybe be quite distinct from what
we're used to from phase 1 to 2
to 3 to for
investigation. Now we'd argue that most
therapeutic advances in cardiology
have taken a much, much
less well t path.
Thank you so much for just filling down
the key takeaways of S inhibitors and has
just been so exciting to hear about the
current ongoing trials and the future investigations and
the field from you. There is truly a
lot to look forward to for improving the
care of our patients that we see every
day in practice
and the road forward in improving
implementation of these therapies
and we've really been able to hear your
passion for the field in this discussion today
and great to see how you got involved
in generating the evidence for these therapies in
it. Really makes me excited as I start
cardiology fellowship and think about all there is
to still discover and learn within the field
and what therapeutic advances to lie in the
future.
For the last question for tonight, this is
something we ask all of our guest experts
on the show. We'd love to hear more
about what makes your heart flutter about heart
failure and cardio metabolic disease. It's a great
question, Gu, and to me, it is the
well of data and evidence
we have to guide care in cardio kidney
metabolism
and specifically in heart failure.
I think across disciplines of bio we have,
1 of the strongest evidence bases in heart
failure, and 1 that we should be proud
of and in fact,
many therapeutic areas
can't say the same in terms of the
survival advantages that are therapies
can afford our patients.
And so what excites me is the ability
to actually influence a disease course of a
patient population. And while we can't offer perhaps
a cure to a person with heart failure,
I think today, if implemented in a timely
and appropriate
manner.
Guideline directed medical therapies have a full potential
to completely change disease trajectory
and be able to
prevent or even delay
clinical events to the point where most people
can live very fulfilling
lives ahead, and that is
something that really really generates a lot of
excitement and rule in contributing to this field
and partnering with individuals just like yourselves,
in
combating heart failure at large.
Thank you so much for sharing. I've really
enjoyed every minute of this discussion and can't
wait to listen back to catch all of
the pearls that I may have missed and
we really went through a really thorough of
discussion of S inhibitors and their clinical trial
data.
And I think I'm also looking forward to
see how we can make these drugs affordable,
accessible and equitable like you mentioned and work
on their implementation, so we can change disease
trajectory.
And we're so grateful at Cardinal to benefit
from your wisdom. You've really been a pioneer
with all your prolific research in the field.
So it's been such an honor to learn
from your experience as a cardiologist
and a clinical trial list in this area.
So thank you so much for taking out
the time to teach us all and to
teach your audience tonight.
Thank you all. It's it's been a pleasure.
It's been a great discussion, and
Most importantly, I want to share all our
appreciation to what you do for
medical education as a whole in cardiology,
it has definitive impact, and I think it's
really, really important.
Thank you so much.
Thanks for tuning into another cartoon
episodes. The audio editing for this episode was
performed by me. Mary Bar da. I'm Cardinals
academy fellow in house toxic and the resident
at Hack Again health. Check out of the
episode page for show notes and references.
If you found this episode or the show
informative please consider subscribing to cardinals
on your favorite podcast platform and leaving us
a review. It really helps us spread the
word and further our goal to democrat cardiovascular
education. Finally, this podcast is not meant to
be used for medical advice. The View expressed
on our show inside do not reflect opinions
or policies of our employers.
All cardinals
contest his plan produced and reviewed solely by
carter's. Stay tuned for more engaging in conversation
and
exploration. In our upcoming episodes. And now it's
time to make like an S split.