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.
Welcome, everyone. This is Rick Barr. Cardiology fellow
at Johns Hopkins Hospital in c chair for
the car intervention series. We are thrilled for
today's episode, the first in a series focused
on S
inhibitors.
Today we'll be focusing on the biology of
S
and it's inhibition. I am joined today by
our c chair for this series Doctor. Gu
Cow. Cardiology fellow at the B Women's.
As well as director of the car Injured.
Thank you so much for being here, Girl
Great to Ceo. Thank you so much for
that kind introduction. We're so excited for this
episode and I'm really happy to introduce her
fit lead for today, doctor S Humber,
who is currently a cardiology fellow at the
University at Miami,
as well as cardio nerds academy faculty,
so excited to have you here today ronald.
Arlene, thank you so much for that kind
introduction, and I'm so excited to learn more
about this topic.
It is my distinct pleasure to give our
final welcome for today's expert discussion, doctor Catherine
Tu. Doctor Tu is executive director for research
at Providence healthcare,
c principal investigator of the Institute of translational
health sciences, and professor of Medicine at the
university of Washington.
Doctor Tu earned her medical degree and completed
her residency and internal medicine at Northwestern University
school of medicine. Followed by a fellowship in
metabolism and endo
at Washington university,
in Saint. Louis, and a ne mythology fellowship
training at University of Texas Health science center
in San Antonio, Texas. Doctor Total has published
over 250
original...
Contributions and served 2 terms as the associate
director for the clinical journal of the American
Society of Ne mythology and the American Journal
of Kenya. Disease. Doctor Tu is also steering
committee member for the cardio nerd supported zeus
trial, testing inter 6 inhibitor, z v for
secondary As
prevention. Doctor Tu, thank you so much for
your leadership and support of the cardio nerds
clinical trials network and for joining us today.
Well, thanks to all of you. It's really
a pleasure to join you and to have
a discussion about this super exciting topic it
that really cuts across cardiology,
ne
and diabetes.
Thank you so much, Doctor Tu. And with
That let's just dive into today's discussion.
So we'll start off with her case of
mister Ronald Nap, a 58 year old man
with a past medical history of obesity,
type 2 diabetes mel colitis and heart failure
with an ef of 32 percent, who comes
into the clinic after a recent heart failure
ex.
His current medications are metformin, Carved,
sac Val sa and act.
His relevant laboratory values are a hemoglobin a
a1c of 7.8,
Cr of 1.3
and G 48.
Doctor Total, how would you approach optimizing mister
Ne medication regimen
And what is the evidence supporting indications for
this patient to start an S 2 inhibitor
at this visit? Well, clearly, s Gl 2
inhibitors are the fourth pillar,
not only for heart failure, but for chronic
kidney disease.
He has both.
1 of the things I really like to
know is what his level of Albumin
is as the urine albumin to cr
ratio
because we think about risk based strategies in
addition to conventional cardiovascular
risk factors.
We also now recommend looking at E r
albumin, for example, in the new prevent equations.
But that said, this is enough for me
to start an ST2
inhibitor on the basis of heart failure alone.
Also, even taking into account the Ck k
angle, we know for imp kidney that even
in patients without an increase in albumin men
if G far is low, There's broad benefit
across cardiovascular
and kidney outcomes. So clearly, he needs support
pillar attitudes regimen,
His a 1 a1c is a little higher
that I'd like to see it. Ideally, we'd
like to see the a 1 a1c less
than 7 to reduce risk of diabetes
complications, heart and kidney, but also from the
standpoint of thinking more holistically
about retinopathy and neuropathy,
The
S 2 inhibitor will have only a modest
glucose lowering effect,
particularly when G r drops below 45, and
he's close to that. We see an att
continuation of the gl
efficacy, although
efficacy for heart failure and Ck
progression or preserve, But then said, I think
that it would be prudent to start the
S 2 inhibitor and then reassess him relatively
soon.
Again, from a clinical standpoint, from a heart
failure standpoint, but also reassess risk factors so
for example, if the 1 a1c stop coming
down, we may add another agent, diaz persistent
elevated albumin, we might do something else too.
Thank you so much for outlining your logic
there, doctor Tu.
Now, how about we dive into the biology
and mechanisms of S inhibitors, including both their
direct and indirect effects? We know ST2
inhibitors were initially developed as anti diabetic agents.
So to get us started, Doctor Tu, can
you please share with us how s Lt
2 inhibitors improve ac control. To be honest
with you, this goes back many years. And,
in fact, in 19 87 along with doctor
D, we gave morrison to diabetic grass.
And initially, the goal was to reduce glucose
without raising insulin.
And we were doing physiology studies, so we're
trying to prove the glucose toxicity theory that
you could lower glucose without raising insulin and
show pancreatic
preservation. But that said, Ralph and I were
also ne neurologists.
And we had a lot of discussion about
what would happen with regard kidney hem or
gl hem
because these agents cause loss of glucose in
the urine.
And this ob not only loss of glucose,
but sodium chloride.
When these agents are given, re reabsorption of
glucose is blocked to the proxima tub,
and downstream then both glucose and sodium chloride
are increased. This has profound effects on kidney
hem thermodynamics.
And it turns out that those changes
actually reduce something we call hyper filtration. Now
why am I talking to cardio nerds about
this. Well it turns out when we correct
gl molecular
filtration. There's systemic effects. That are very favorable
for the heart. There is a reduction in
blood pressure. There's reductions said that synthetic neural
activity. There's a glucose uric effect that improves
diarrhea
And then systemically, there an increase in a
wheaton, which raises red blood cells at oxygen
carrying capacity. So this culminate in a number
of favorable effects on cardiac function. Also glucose
induces a mild
ketosis by increasing free fatty acid metabolism, and
in a mild
degree, for example, increase of data hydro
is a preferred my cardio fuel. So it
turns out that very interestingly, these changes at
the level of the gl and real tub
have profound effects on the systemic
circulation that make heart function better. And I
think this is something that's really been under
underappreciated as this If you will delicate dance
between heart function and kidney function, so bottom
line is lower blood pressure less sympathetic neuro
activity, lower plasma volume,
increase for poly red cell mass and oxygen
carrying capacity, lower beta hydro,
all of which in the setting of heart
failure improves cardiac fo. Doctor Total, that was
so fantastic. You know, We have this
kind of message group that while we talk
about the episode and and there's so many
pearls that I've gotta go back and listen
to and and that we've been pulling out
here.
But 1 thing that's really obvious is I
think a lot of the time
people think of probably incorrect definitely incorrectly.
Of ne neurologists and cardiologist is is almost
antagonist. Is almost on other sides of For
example, the diuretic spectrum, but it's so cool
with these ST2
drugs that it's really all coming together to
move patient care forward, and that's really, really
cool.
So while these agents were first primarily used
for diabetes, subsequent cardiovascular outcome trial, some of
which we've already discussed have shown improved outcomes
in patients with type 2 diabetes,
and as well as independent of diabetes status.
Would you mind discussing a little bit the
background for understanding the mechanism of these medication
classes?
And specifically, how do they exert cardio protective
and renal protective benefits
outside of their effects of gl control. And
I know some of this you discussed a
little bit, but is there anything else that
you think will be worth hearing viral centers?
Well, what we're now recognizing
is there are some off target effects of
the S 2 inhibitors, but back to biology
again that's what you invited me to talk
about. 1 of the really interesting things. This
is the S 2 receptor is only found.
In the proxima convoluted tub. So the off
target effects are not receptor mediated.
So all of the effects I just described
to you that affect kidney hem
that have systemic effects to improve heart function.
Are mediated by the S 2 receptor in
the proxima tub. So again, back to what
you said, I think that what we're seeing
is synergy non antagonist in terms of both
kidney and heart protection.
Now with regard to the off target effects,
what we have learned is the S 2
inhibitors
enter a number of cells.
They enter cells by non receptor mediated mechanisms
and the cells, for example, in cardiac
with S 2 inhibitors
intra cardiac,
they actually block glucose transport into the cell,
like blocking glut 1 and 4 receptors.
They in addition reduce a signal
pathway called M torque, which not only promotes
inflammation but also promotes gl.
So long story short for cardiologist
is we see a state of reduced le
glucose intake and reduced gl, which is a
relative state of cell starvation, but that's actually
cardio protected in a sick cardiac.
Also, when we block mt torque with the
S22
inhibitor directly. There's a reduction in expression of
inflammatory meters, which is also another mechanism
of progression of heart failure and cardiomyopathy.
And then finally, at the level of the
kidney these changes are happening a number of
kidney cells. Too, so the kidney protection is
in addition to hem,
these direct effects that are intra cellular.
And 1, they'll emphasize again that's really important
is the increase in
hemoglobin is not a delusional effect. It's a
real increase in red cell mass, and this
is because in the kidney fiber, which are
not the tubular cells.
This is where a
magnet. It turns out in those fiber,
S 2 inhibitors actually have a s effect
on a signal called cert 1. And insert
1 increases expression of.
So I think it's important to recognize that
the hem of that's are probably
predominant,
but there are other off target facts in
multiple cell types of the kidney and the
heart that so far have been protective, that
if there's not been a a sign effect
if you will an off target effect that's
been found to be adverse.
At the cellular level. There are some side
effects that we'll talk about, but they're not
related to these actions.
And finally,
The other reason that these are important, S
2 inhibitors have really been the biggest gift
today for both heart failure and chronic kidney
disease.
And when we understand more about how they
work, we could even think about better drug
targets, for example, now knowing the effects of
S 2 inhibitors to block m torque. While
this gives us biological
rationale to maybe just go straight for an
m torque inhibitor 4 subsets of patients who
may progress despite the fork pillars up there.
Doctor Total, thanks for truly taking us back
to the core biology from the level of
the She to chapter in the proxima tub
to effects really related to gl to the
mt pathway.
It's really helpful to understand the potential mechanisms
through how S 2 inhibitors exert their cardio
renal protection. And so far in this discussion,
we've been really focusing in on S 2
inhibitors particularly
but we do know that there's agents studied
in clinical trials such as so
that is a dual ST1
and S 2 inhibitor.
And we had recent data from the Solo
W f and score trial that showed benefit
with so
for cardiovascular
outcomes.
Can you tell us a little bit more
about the biology of S 1 transporter?
Where are these located and does S 1
and also play a role in potential cardio
protective benefits?
Yes. That's a great question. The the rationale
for the S 1 inhibition, and by the
way, flo original agent that we used in
the route model was a combined S12
inhibitor.
And
the reason that we look for S 2
first is mainly
because of the side of that profile. I'll
come back to the rationale work returning a
combined ST12
inhibition, But I just wanna
emphasize why
we didn't do that first.
Is that S 1 receptors are found in
places of science kidney, particularly that gut
epithelium.
And 1 of the major limiting side effects
of using the agents is diarrhea, which can
be quite disabling
And now, again, originally, they were used
exclusively in diabetes
populations and in particular people who had kidney
disease or heart disease often have gas
and and autonomic neuropathy the... And the diarrhea
that resulted with adding the S 1 was
quite challenging for many patients. But be that
as it may, there was still rationale for
considering adding S 1
because there are s 1 receptors
in the kidney pro tub, not the pro
convoluted tub which is the most proxima part,
the pro tub.
So downstream
from
that convoluted
part of the tub bill so the straight
part of the proxima tub their S 1
receptors. The rationale again originally came for glucose
lowering because about 90
percent of the glucose re uptake occurs in
the proxima con tub by the ST2
receptors, But close to 10 percent is mediated
by the ST1. So the idea was you
know, maybe you can get additional glucose lowering
by blocking both receptors and hopefully people would
be able to tolerate the Gi side effects.
So that was the original rationale.
Again, back to the first question about development
of these agents for glucose.
But the idea that was as well, you
know, if these agents have greater gl
efficacy it's because there's greater
and back again, the first question. The reason
is
important from the standpoint of heart and kidney
protection is could we get more complete
restoration or normalization of or hem that then
in turn would translate
into even better
systemic of effects that flow from improving gl
hem.
So, yes, in those 2 trials, There were
favorable cardiovascular
benefits. The question though is that they haven't
really even studied head to head versus an
S 2. And it, you know, between trials,
you really can't make direct comparisons. So I
think the real question is if there is
a gain from it.
Is it gonna be worth the side effect,
particularly the management, the Gi side effects?
Doctor Tu, thank you so much for breaking
down, not just the complex biological mechanisms of
these drugs, but also providing some historical context
to the decisions to
study certain drugs prior her to others. But
as you've alluded to a few times, as
clinicians whenever we prescribe any class of medications,
we really have to be very thoughtful of
the potential side effects and what to counsel
patients regarding. Doctor Tu, would you please be
able to tell us a little bit more
about the common side effects of the S
2 inhibitors and the dual ST1
and 2 inhibitors and the mechanisms behind them?
And to that same point, are there certain
patient populations that are at higher risk for
these side effects?
Sure. And I guess just because mary it
started with the ST1.
The mechanism behind the diarrhea
is because they're
actually is less glucose reabsorption
in the gut. So basically, it's an os
type of diarrhea, like the os
dia.
So that's the main
additional sign effect of the S
1 car. With regard to S 2, there's
are some important side effects and almost all
of them relate to the.
So most common what we see are gen
urinary infection because having glucose in the urine
is fodder for
bacteria fungus. And in fact, what most common
or gen psychotic such and they can occur
in men as well as women, and women
about 4 to 5 percent, but in men,
it's about half that that's still 2 to
3 percent.
So all patients need to be counsel about
h genetic measures and in studies where patients
have received counseling
about daily bathing and clean close those risks
can be reduced and have.
Most of the time they're mild and we
can treat through them and keep them on
life saving therapy without having to stop them.
But in some cases it may be severe
and that can be a limitation to use
of these agents,
especially in people who may be I compromised
example.
The other 1 can be volume depletion. Now
on our fields where we're dealing with volume
overload and more commonly than that, the raises
is often a welcome side effect, but there
are some patients who do have tenuous volume
status and then those people we have to
be cautious.
About volume depletion,
and might even consider proactively
reducing a diuretic dose.
Ahead of starting an S 2 inhibitor, and
I think this brings up another issue about
S twos is as opposed to say statins.
These aren't really fire forget therapies. People do
need to be managed on those. And after
starting an S 2 inhibitor At least at
our practice, we see people back within 2
to 4 weeks to recheck labs, E our
of potassium, in particular,
but also,
a good clinical
evaluation for volume status and blood pressure. And
that brings up the other things. Some people
because of the diuretic effect can become hypo.
And this brings up this issue with the
G deck. So up to 30 percent decline
in G is a dip that we attribute
to reducing gl hyper filtration,
har back to the physiology that we talked
about, in which case, it's a good thing.
It's actually a read for therapeutic
responsiveness fitness, so like in da Ck arcadia
and credence,
G dips up to 30 percent actually predicted
benefit
on kidney and cardiovascular
outcomes. However,
if there's more than a 30 percent decline,
then we need to think about other issues.
Usually, it's volume depletion or hypotension, and most
people will
improve by simply backing off diuretics or other
anti.
Then the other big side effect that gets
a lot of place the so called
keto.
This occurs most commonly in people with type
2 diabetes, long standing insulin users.
In those
individuals, it's the gl,
the resulting increase in free fatty acid oxidation
that leads to mild ketosis.
But in those individuals,
especially with stress of acute illness, whether it's
a viral infection or something else can tip
them into a keto
without
severe hyper.
And here the best defense against keto
is maintaining some insulin board.
So even if they have a lowering of
glucose if you have to back off it's
something you could actually reduce the ST2
inhibitor.
Because the ST2
inhibitor benefit on heart and kidney,
protection is not dose dependent, but glucose lowering
is. So there we recommend keep a little
insulin on,
and reduce the ST2,
but keep the S 2 on board. It
is very rare to seek keto acidosis in
non diabetic
individuals But again, even in people without diabetes,
starvation, ketosis of other things can happen, which
is why we recommend these s day rules
to stop the s jolt 2 temporarily drink
periods
of acute illness,
but the important thing is remember to restart
because 1 of the problems we have with
the implementation of these therapies is they get
stopped, let's say we're an acute all, but
they don't get restarted. So we have to
remember it to restart these agents once a
person's recovered, usually about a week of recovery
is enough, and they can go back on.
The other thing that came up with can
frozen and the canvas cardiovascular
outcome portfolio of trials was at increased risk
of amp.
Of that has not been seen in any
of the other trials, and it may have
been a play of chance, but that said,
it's still a good practice to remember to
advise patients about good foot care. And again,
this is why these are not fire forget
therapies part of grooming a patient on these
agents should be taking their shoes and socks
on. It's very simple to look at their
feet, and that's why we need to do
clinical
evaluations as well.
But with daily foot, self exams and regular
foot exams at, clinical visits, it's very rare
amp computations, And then finally hypoglycemia
only rarely occurs, and usually, this is in
people with well preserved G r But again,
we sometimes have to back off other glucose
soaring agents,
and I'll reiterate the caution if someone is
on insulin to not completely eliminate it
maintain at least 10 units or so long
acting insulin to help prevent keto.
Wow, doctor total such a wealth of information
there? Well, I, you know, I I particularly
wanted to come back to that point you
made about statins as compared to ST2
and inhibitors errors and how These are really
medications where we need to monitor patients and
bring them back and and do a little
bit more hand holding with respect to the
medication and Everything you outlined there is is
such a road map of doing so that
I think I might need to print it
out and put it on the walls. My
office or something like that. It was that
incredible. That wonderful background aside, potential applications and
indications for S 2 inhibitors
continue to be areas of
active
investigation and recent trial examining the value of
s
inhibitors,
specifically flows and with the recent impact of
my trial.
As 1 example, but many others. Doctor Total,
could you share your perspective on next steps
for investigation of ST2
war 1 as you had mentioned already? And
questions we should be thinking about as these
research in this field be. Well, I think
3 things. 1, I think we really need
to move much more ex sleeve of evidence
to
implementation because we have these highly effective therapies
that truly do state life and kidneys. But
they're being markedly under underutilized.
That's a very active area of investigation. There
are multiple barriers
everything from the more complex clinical mandates, which
that we just talked about to cost
to
education of clinicians and patients,
And the other thing too is health care
systems support for doing this kind of care
because these really aren't 15 minute visits,
and we haven't really been resourced to give
this more comprehensive
care. And so that's a real paradigm shift
and it hasn't been very well addressed or
supported.
More so with for,
advanced heart clinic programs
but not so much, I think in general
clinical practice of cardiology or ne,
and I think this needs to be an
area where we really do put a lot
more emphasis and resources because people only benefit
from treatment say or see, and we need
to do a better job.
And then with regard to
implementation, you've probably all heard about the phenomena
at clinical
inertia, which is where we sort of gl
gag around starting these meds and trying to
get the back every 3 or 4 months
and start new med. But especially if you
look at the heart failure outcomes
We know that, whether we look at a
heart failure population or a Ct
population, in particular,
the heart failure outcomes occur early,
they're frequent in both of those populations, and
we see almost an immediate benefit on reducing
risk of
heart failure
hospitalization or urgent visits. So we can't wait
6 months to get everybody on board here.
And this is again, white not fire forget
therapy. We need to rapidly escalate therapies.
What that means, I think it also needs
research, You know, what therapies when how fast.
But, you know, that is important because these
patients are very high risk of death, and
they die of heart failure, Again, whether they
come through the heart failure portable or the
Ck portal. That's what takes both groups of
patients out, but they're not really both groups
of patients. They're largely the same people. Just
depends on which portal you come in through.
So for example, in light practice, most people
have an E afar ejection fraction the same,
both less than 30. That a heart failure
patient with loan G in a Ck patient
with low ejection fraction. Let's really ample.
And so we need to recognize the enormous
risk of death and that we have treatments
that very quickly reduce that risk substantially.
So
implementation and then no inertia end much more
rapid
escalation of therapy.
And then finally, back to the science again,
we're learning a lot more about how S
2 inhibitors work and how we
stumbled on this almost by accident although, not
completely because when we first gave flu into
those routes. So we
envisioned that at least the gl mer hem
if that could occur, although I don't think
we imagined it would have such profound effects
on heart failure. But that said,
Some of the mechanisms that we're discovering really
could lead us to new targets that might
even be safer and more effective. So for
example, if we could target torque directly
then we might not have a lot of
side center real into Across Area.
Doctor Total. Thank you so much for
noting everything that you just mentioned, I think
that your points are so well taken particularly
with regards to mentioning the barriers to implementation
of this science when all of the investigations
are moving so quickly and we're learning so
much about these drugs. I think it's really
just such an important
perspective to maintain that we really need to
figure out how to figure out how to
get these medications to patients. So thanks so
much for mentioning that. Now given everything that
we discussed doctor Tu, would you please be
able to summarize for our audience, some of
the key takeaways
that our listeners should remember regarding S t
inhibitors?
Well, I think these really are transformative
therapies,
and they address
very important risks in patient populations.
For example, in heart failure particulate preserved ejection
fraction in chronic kidney disease, which were rather
hopeless
conditions until these agents appeared on the scene.
And now we truly have drugs that save
lives hearts and kidneys. And I think we
need to have a sense of urgency
about getting all people on unleash their piece
suzanne benefit.
Also think that as we go forward, we
probably should do a better job of if
you will clinically
patients for which therapy
and prioritizing
those that have the greatest benefits.
For example, with regard to ST2
inhibitors
In addition to getting them on therapy. I'd
also like to comment that we should take
people off with potential harmful therapies like non
steroid anti inflammatory drugs and proton pump inhibitors,
So please put people on guideline directed medical
therapy, S 2 inhibitors, truly have been a
guest there is life saving for patients who
have very few options here to 4 and
also remember to get rid of the things
that undo the good we're doing. With these
agents such as giving non str inflammatory drugs
which are not good for either heart failure
or kidney disease.
Thanks for really dis it down to these
key takeaways for listeners and putting that clinical
perspective of how to get patients on the
right drugs and off of the wrong 1.
Something that we always like to ask our
guest expert on cardio is, what makes your
heart flutter about S inhibitors and the future
for science in this field?
Well, I think that the S 2 inhibitors
really burst open an entirely new era for
heart failure and Ck cad. And I think
as I mentioned, we have a lot to
worry about how to implement and apply these
therapies,
how to learn from the mechanisms
involved in S 2 heart and kidney protection
to make better treatments,
but the other thing it did is that
ushered in a new era of interest in
heart failure Ck that's really unprecedented.
And so in addition to S 2, we
now have other breakthrough therapies?
And a pipeline of therapies that may help
to ratchet down residual risk, but then I
just wanna emphasize the other we need to
do is then figure out who gets what
drug does everybody need everything all the time
and get rid of potentially harmful things. But
what makes my heart flutter is that hopeless
diseases have now become very hopeful, and these
are all really good problems to have? To
have therapies so that we can even ask
these questions
about order therapies
combination of therapies, ph,
implementations I welcome the challenges, and I'm so
glad I can go to clinic now and
say, we have treatment. We have treatment that
saves lines hearts and kidneys and be really
excited
and patience are so grateful, and especially in
ne mythology,
many of them used to come feeling so
disillusioned. And now it's a completely different vibe,
and it's so wonderful to see them happy
about the idea that they could actually get
better, not just continue to slowly get worse.
Doctor total your passion for the fields and
patient care really shines through, and it's been
such a master class learning from you about
S inhibitors
from the basic biology
and beyond. I was just thinking back to
when we first learned about Cl inhibitors during
the preclinical years of med school. And at
that time, I think we just learned about
it as a diabetes
medication, it's just remarkable to see that since
then there's been all of this data for
the cardiovascular effects, the renal protective effects, and
how it's become a pillar of therapy for
both heart failure and chronic kidney disease. And
It really speaks to the fighting advances in
this field to how to help take care
of her patients, which is the ultimate goal
for all of us. In both medicine and
research. And it's really great to see how
it can be done in collaboration with cardiologist
working with ne pathologist and endo
than other physicians and also other health care
professionals. So we really wanna thank you for
taking out time to teach us today and
really sharing your for expertise. I'll definitely have
to listen back to absorb all of the
pearls that you've reviewed and the mechanisms of
action and the biology behind these agents.
Thank you so much. We're really excited to
share this with our listeners.
Well, thanks for including me. It's wonderful to
see the future of cardiology and medicine so
bright is reflected in all of you.
So
go forth and set the world empire, see
Thank you so much for tuning into this
cardio nerds episode. The audio editing for this
episode was performed by me, Cri.
I'm an intern in the Cardio Nerds Academy
and a senior at Boston University.
Check out the episode page for the show
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