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Worldwide, cardiovascular

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disease affects the lives of hundreds of millions

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dedicated cardio nerds everywhere are working hard fight

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this global epidemic. These are their stories.

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Hey Cardio Nerds. This is Rick Fe ferrari

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Cardiology fellow at Johns Hopkins Hospital.

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Today, we are back for our second episode

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on the world of sodium glucose c transporter.

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You've probably heard of ST2,

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but we might be talking about ST1

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today just to preview a little bit, and

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their impact on cardiovascular

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disease.

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I'm joined today as always by the tremendous

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Series c chair and Director of the car

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its internship, Doctor. Girl Cow, a phenomenal internal

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medicine resident incoming cardiology fellow at B Women's

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Hospital.

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Girl, how are you doing tonight?

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Thanks so much, Rick. I'm really excited tonight

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to learn from this discussion about S inhibitors.

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And I have the privilege of introducing doctor

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Maria Bar,

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an internal medicine resident at Hack Meridian Health

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in the great state of New jersey

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a current cardio nerd fellow an aspiring cardiologist.

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Her background from Y Iran, the city which

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is famous for its sweets, drives her interest

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into diabetes and cardio their disease prevention. Pray

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to see you here, Mary.

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Thanks for

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production darlene. I am so thrilled to be

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here today. I have the honor of introduced

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our expert faculty discussed. Doctor Wu, Water.

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Doctor Var is a cardiologist

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at the Bing in women hospital in Boston

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massachusetts. He is a leading clinical trial is

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with over 250

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publications and c director of the center for

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cardio

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implementation science. He also hosts the podcast, don't

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miss beat and heart failure and focus. Where

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he critically

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examine, clinical care and research with experts globally.

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Doctor W,

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it is an honor to have you here

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with us. Welcome to Card.

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Thank you so much. The honor is truly

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mine. I've been a fan and really have

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a great admire of the work and medical

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education that you all do and champion, and

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it's a real privilege to be able to

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join you today.

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Doctor,

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as we often do, let's get it started

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with the case from the car clinic.

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Missus Gl is a 57 year old women

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with a history of diabetes

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on impact

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with him hemoglobin A1c of 6.3

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percent.

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She is accompanied by her husband, mister Gl,

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who has a history of parts failure with

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ejection fraction of 35 percent. And was resilient

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started on impact frozen.

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During the conversation, missus Cliff explains that she

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has been on

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for a few years for her diabetes.

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But now is unsure why her husband been

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who does not have a diabetes who would

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be on this as well. Doctor Barr.

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Can you speak more to this

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evolution in the use of S 2

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inhibitors from a medication exclusively for diabetes

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to now a key component of heart's failure

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therapeutic management.

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Thanks so much, Miriam. You know, the hidden

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secret in cardiology is that

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most therapies that were developed for a particular

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purpose.

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Actually ended up being

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indicated for a vastly different reason, and so

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too the S 2 inhibitors

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had such a circuit

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pathway to ultimately

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its current indications in the Us and worldwide.

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This all started back in the 2 thousands

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when there was initial safety concerns about certain

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classes of

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anti

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therapies to the point where the Us Fda

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issued an industry wide guidance

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requiring all new sponsors

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developing therapies

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for diabetes

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because of its high prevalence in the community

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to conduct dedicated cardiovascular

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outcomes trials to exclude

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excess cardiovascular risk.

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This led to perhaps 1 of the greatest

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growths in scientific evidence across any discipline and

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we learned a tremendous amount about not only

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the cardiovascular

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effects,

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but also

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the effects on other organ systems such as

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the kidney

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and specifically in terms of various aspects of

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the heart. The S 2 inhibitors benefited greatly

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from this, and there were

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really 5 large scale trials that were conducted,

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specifically evaluating people

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with diabetes at high cardiovascular

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risk and this led to the rest of

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the story quickly unfolding thereafter.

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The initial signals suggested that not only were

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these therapies quite safe, but in fact,

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they had profound effects in preventing cardiovascular

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events

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specifically preventing heart failure

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and in delaying kidney disease progression. Both of

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these issues are, of course,

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very, very important for people living with diabetes.

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And so this captured broad interest amongst the

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community.

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And thankfully,

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the sponsors that developed disease therapies.

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In fact, rapidly chased those threads of information,

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those

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initial hints of and signals of benefit

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and dedicated studies

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then were pursued specifically evaluating people

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with chronic kidney disease and people with heart

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failure with and without diabetes.

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And the fascinating thing was, we learned that

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while the story started in diabetes.

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It ended

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in us understanding that these therapies and the

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therapeutic benefits

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of this class, extend well beyond diabetes in

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fact reach

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to chronic kidney disease and heart failure

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as cornerstone of management of those conditions.

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Doctor,

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thank you so much for walking us through

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that historical perspective and the trial data leading

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to S 2 inhibitors becoming a medication outside

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of just a diabetes drug, but with a

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more broad indication for use. I think it's

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just really remarkable to think back of how

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in this field we're really able to use

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data from these large scale trials and change

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clinical practice and really focus in on implementation

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of these therapeutics.

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And S inhibitors we now have a role

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within the cardiovascular system through multiple mechanisms.

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Including but not limited to volume regulation, cardiac

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remodeling and other cellular effect, which are still

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under

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investigation. Do you mind el collaborating for listeners

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more on these possible mechanisms of S inhibitors

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and how they work in affecting cardiovascular disease

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especially how they work to improve heart failure.

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G, you're asking yet another very challenging question

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and in fact, this is probably the second

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great secret of cardiovascular

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therapeutics and drug development

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is that we often don't understand central may

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of how these therapies actually benefit people, while

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we have this almost rosy

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picture of

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how drugs are development from the bench to

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the bedside going through phases of development with

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specific targets in mind and

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almost

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precision based approaches in which we design and

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develop therapies,

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often therapies have systemic effects that

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go well beyond intended and those benefits might

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actually be principally

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involved in ultimately

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preventing disease progression.

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The S 2 inhibitors

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have varied defects. S 2 is predominantly

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expressed in the kidney in the proxima tub

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of the kidney over 90 percent of those

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transporter

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are located in the proxima tub

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And so it would be remiss for us

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to dismiss the kidney as a central mechanism

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of how these therapies

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benefit

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the system at large, including the cardiovascular system.

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S 2 is not expressed in the my

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and so the effect and benefits we see

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on cardiovascular

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status must be either

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a myriad of factors that are systemically acting,

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for instance,

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Some effect on blood pressure, some effect on

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volume

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regulation, some effect on

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metabolism in improving gl

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control and all these together to improve cardiovascular

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status,

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or it might be

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off target effects on the heart and perhaps

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while it might not

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influence a direct receptor or transporter present in

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the my,

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perhaps it has off target effects on other

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ion channels, other receptors in the my cardi.

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And then finally is,

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that the benefits are truly outside of the

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heart and the heart is benefiting second,

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and that is 1 of the notions that

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perhaps

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The kidney really as a central actor

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is improving cardiovascular

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status by improving

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kidney efficiency and in handling salt and water.

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All these mechanisms I think are certainly credible

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think mechanistic studies are very challenging to conduct

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because you can do a very well conducted

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study to prove or disprove 1 of these

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mechanisms

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but it doesn't actually speak to the other

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mechanism that could be at play. So my

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view is that

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we

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must recognize that these therapies ultimately in very

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well conducted large clinical trials do benefit people,

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and likely these benefits are systemic that there

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multiple mechanisms

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much like the statins for at atherosclerosis cardiovascular

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disease we're now seeing that the s 2

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inhibitors have myriad effects in improving cardio kidney

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metabolic health.

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Yeah. Thank you so much for that discussion.

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It's really kind of the p

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nature that you're talking about and what we're

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still learning about these medications. Is really remarkable,

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and it's been, you know, really, really a

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fun time. I remember this was kind of

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in the early days when I started training

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and it's it's really proliferate so tremendously. And

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so following that it's been has been really

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a privilege.

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And so to get us back to the

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car clinic. Following your appointment with missus Gl,

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she sends a secure message via electronic medical

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record asking about her sister. Missus flows.

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Who is also on

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for symptomatic heart failure, but has an ef

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of 55

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percent as opposed to 35 percent. Can you

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el more on the data and key trials

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in support of the impact of these class

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of medications on the management of patients with

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preserved D?

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It's a great question, Rick. As you know

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and it has been discussed on this forum

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heart failure preserved ejection fraction has been a

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challenging entity to study In many cases has

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been described as the graveyard of cardiovascular

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therapeutics,

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and some have even gone to the point

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describing it as the greatest unmet need across

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all of bio.

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Thankfully, the S 2 inhibitors were the first

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therapeutic class to definitively show cardiovascular

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benefits

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in this high risk population of heart failure

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preserved ejection fraction.

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The 2 principal trials were large scale trials

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of S 2 inhibitors in the

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emperor preserve trial. This was with the S

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2 inhibitor amp frozen,

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and then the deliver randomized clinical trial studying

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the S 2 inhibitor da flows.

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These were similarly designed trials

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00:11:43,103 --> 00:11:46,518
globally conducted across many, many countries involving many,

283
00:11:46,676 --> 00:11:47,573
many investigators

284
00:11:48,026 --> 00:11:48,264
worldwide,

285
00:11:48,900 --> 00:11:52,251
but we're simply designed comparing the to inhibit

286
00:11:52,251 --> 00:11:55,272
against placebo in this target population of heart

287
00:11:55,272 --> 00:11:58,452
failure with mildly reduced or preserved ejection fraction,

288
00:11:59,261 --> 00:12:02,115
defined as an ef above 40 percent with

289
00:12:02,115 --> 00:12:05,603
elevated nat natural peptides and evidence of structural

290
00:12:05,603 --> 00:12:06,078
heart disease.

291
00:12:06,969 --> 00:12:09,226
Now, these therapies showed benefits

292
00:12:09,605 --> 00:12:12,981
on improving cardiovascular death or heart failure events

293
00:12:13,360 --> 00:12:17,273
and The effect sizes were substantial and clinically

294
00:12:17,273 --> 00:12:17,750
relevant,

295
00:12:18,386 --> 00:12:20,533
and their benefits were driven by both of

296
00:12:20,533 --> 00:12:23,407
those components. There were some benefits seen for

297
00:12:23,407 --> 00:12:27,454
even cardiovascular death and a predominant effect on

298
00:12:27,454 --> 00:12:27,954
preventing

299
00:12:28,724 --> 00:12:31,598
hospitalizations for heart failure and urgent heart failure

300
00:12:31,598 --> 00:12:31,836
visits.

301
00:12:32,710 --> 00:12:36,205
This led rapidly to labeling updates that these

302
00:12:36,205 --> 00:12:38,850
therapies now are not only indicated for

303
00:12:39,318 --> 00:12:41,539
people with heart failure with reduced Ef, but

304
00:12:41,539 --> 00:12:43,942
for the heart failure syndrome as a whole

305
00:12:44,315 --> 00:12:46,933
and actually simplified medicine in many ways.

306
00:12:47,662 --> 00:12:51,738
Often were challenged by defining ejection fraction early

307
00:12:51,794 --> 00:12:54,099
because in certain regions of the world, there

308
00:12:54,099 --> 00:12:57,397
might be limitations and obtaining timely echo

309
00:12:57,852 --> 00:12:59,705
or other modalities define

310
00:13:00,081 --> 00:13:00,798
ejection fraction.

311
00:13:01,514 --> 00:13:04,514
This set up a system of medicine that

312
00:13:05,113 --> 00:13:07,266
simplified things that moved away from ejection fraction,

313
00:13:07,425 --> 00:13:08,723
at least for this therapy

314
00:13:09,259 --> 00:13:11,035
that allowed us to say

315
00:13:11,732 --> 00:13:13,906
this therapy was beneficial across

316
00:13:14,299 --> 00:13:16,936
the spectrum of ejection fraction and may even

317
00:13:16,936 --> 00:13:19,892
be initiated before you know this specific ejection

318
00:13:19,892 --> 00:13:21,090
fraction of that individual.

319
00:13:21,745 --> 00:13:24,704
This also is rapidly adopted by clinical practice

320
00:13:24,704 --> 00:13:26,884
guidelines and formed the first

321
00:13:27,345 --> 00:13:28,245
class 1

322
00:13:28,784 --> 00:13:29,024
recommendation,

323
00:13:29,758 --> 00:13:32,939
4 a specific therapeutic in heart failure preserved

324
00:13:32,939 --> 00:13:36,042
ejection fraction in the most recent 2023,

325
00:13:36,614 --> 00:13:39,491
Es clinical practice guidelines for heart failure.

326
00:13:40,050 --> 00:13:42,767
So a really, really exciting space, and I

327
00:13:42,767 --> 00:13:45,185
think is just the first of therapies

328
00:13:45,579 --> 00:13:46,535
to show benefit.

329
00:13:47,173 --> 00:13:50,303
I think it paved a path not only

330
00:13:50,360 --> 00:13:52,853
to how we can study these therapies

331
00:13:53,482 --> 00:13:54,300
but also

332
00:13:54,673 --> 00:13:57,293
perhaps of the types of therapies that might

333
00:13:57,293 --> 00:14:00,231
be beneficial in heart failure with preserved ejection

334
00:14:00,231 --> 00:14:00,548
fraction.

335
00:14:01,183 --> 00:14:04,536
Heart failure preserved Ef often occurs in the

336
00:14:04,536 --> 00:14:08,353
background of cardio kidney metabolic conditions. And so

337
00:14:08,353 --> 00:14:09,648
perhaps these similarly

338
00:14:10,500 --> 00:14:12,114
systemically acting therapies

339
00:14:12,584 --> 00:14:14,519
For instance, the Gl 1 receptor

340
00:14:14,976 --> 00:14:15,875
or the mineral

341
00:14:16,412 --> 00:14:17,130
receptor antagonist,

342
00:14:17,688 --> 00:14:20,161
maybe those are the same therapies that could

343
00:14:20,161 --> 00:14:23,548
actually benefit this target population of heart failure

344
00:14:23,607 --> 00:14:26,161
preserved yet. So a lot more to learn

345
00:14:26,161 --> 00:14:27,039
about the syndrome,

346
00:14:27,518 --> 00:14:30,333
but exciting that this was the first breakthrough

347
00:14:30,392 --> 00:14:33,434
to have a definitive body of evidence to

348
00:14:33,434 --> 00:14:37,413
support a class 1 recommendation in clinical practice

349
00:14:37,413 --> 00:14:37,811
guidelines.

350
00:14:38,368 --> 00:14:41,278
So really citing time in cardiovascular

351
00:14:41,657 --> 00:14:44,534
medicine especially for heart failure preserved ejection fraction.

352
00:14:45,253 --> 00:14:47,751
In my view, it not only taught us

353
00:14:47,890 --> 00:14:50,691
about how we can study these therapies that

354
00:14:50,691 --> 00:14:52,225
we need to conduct really

355
00:14:52,918 --> 00:14:55,168
broad large scale trials

356
00:14:55,479 --> 00:14:58,105
to be able to detect important effect sizes

357
00:14:58,105 --> 00:14:59,560
in this heterogeneous

358
00:14:59,936 --> 00:15:03,039
population, but also about the types of therapies

359
00:15:03,039 --> 00:15:04,813
that might be beneficial

360
00:15:05,204 --> 00:15:06,882
in heart failure preserved ef.

361
00:15:07,602 --> 00:15:10,819
Half often occurs in the background of multiple

362
00:15:10,878 --> 00:15:14,235
cardio kidney beam at all conditions. So perhaps

363
00:15:14,235 --> 00:15:18,334
it's therapies that in fact act systemically targeting

364
00:15:18,391 --> 00:15:21,735
each of these axes that may ultimately prove

365
00:15:21,735 --> 00:15:24,383
to be beneficial just like the Est tune

366
00:15:24,383 --> 00:15:24,782
inhibitors.

367
00:15:25,501 --> 00:15:27,419
Doctor Ba gu and thanks for the nice

368
00:15:27,419 --> 00:15:30,535
summary of trials. It was really interesting to

369
00:15:30,535 --> 00:15:31,309
hear about

370
00:15:31,828 --> 00:15:34,062
simplifying medicine. I never thought of it this

371
00:15:34,062 --> 00:15:37,434
way that we can use a agility to

372
00:15:37,573 --> 00:15:41,490
inhibitors without specifically defining heart failure with reduced

373
00:15:41,490 --> 00:15:44,673
ejection fraction or with preserved ejection fraction as

374
00:15:44,673 --> 00:15:47,299
a whole heart failure in Europe, ming slightly

375
00:15:47,299 --> 00:15:49,488
away from cardiology specifically,

376
00:15:49,866 --> 00:15:51,942
but to a patient population, we also see

377
00:15:51,942 --> 00:15:52,740
very frequently.

378
00:15:53,139 --> 00:15:55,614
I was hoping to ask about S 2

379
00:15:55,614 --> 00:15:57,904
inhibitor use in patients with the renal in

380
00:15:58,182 --> 00:16:01,063
efficiency. Is there any role in the management

381
00:16:01,198 --> 00:16:02,785
and prevention of Ck katie?

382
00:16:03,499 --> 00:16:06,039
Thanks so much, Barry. I wanna quickly touch

383
00:16:06,039 --> 00:16:08,139
on that comments you made about

384
00:16:08,511 --> 00:16:10,438
simplification and I recognize

385
00:16:10,968 --> 00:16:13,767
as a community, we often have

386
00:16:14,394 --> 00:16:16,732
This balancing act between

387
00:16:17,510 --> 00:16:18,250
precision medicine,

388
00:16:19,668 --> 00:16:22,165
identifying patients that may likely benefit

389
00:16:22,479 --> 00:16:24,230
the most from a given therapy,

390
00:16:25,026 --> 00:16:25,526
and

391
00:16:26,379 --> 00:16:29,962
simplification, ability to actually implement therapies at scale.

392
00:16:30,773 --> 00:16:34,115
And I think in cardiovascular medicine, we take

393
00:16:34,115 --> 00:16:36,923
care of such a broad, high risk

394
00:16:37,378 --> 00:16:37,537
population.

395
00:16:38,509 --> 00:16:41,386
That at the present time, we are more

396
00:16:41,386 --> 00:16:41,886
so

397
00:16:42,265 --> 00:16:44,044
in this broad

398
00:16:44,663 --> 00:16:46,521
implementation approach where we're

399
00:16:47,060 --> 00:16:47,560
identifying

400
00:16:47,875 --> 00:16:48,375
phenotypes

401
00:16:49,154 --> 00:16:52,914
that are recognizable by all clinicians, whether they

402
00:16:52,914 --> 00:16:55,815
be cardiologist for primary care doctors or ne

403
00:16:55,875 --> 00:16:56,615
for endo.

404
00:16:57,327 --> 00:16:59,073
And we're able to be able to treat

405
00:16:59,073 --> 00:17:02,804
that cohort of people in multiple different settings

406
00:17:02,804 --> 00:17:04,233
in multiple different countries.

407
00:17:05,044 --> 00:17:08,574
We may actually move towards a very precise

408
00:17:08,712 --> 00:17:10,488
approach to care for

409
00:17:10,945 --> 00:17:13,338
some of the other phenotypes that we less

410
00:17:13,338 --> 00:17:15,820
commonly see but I think in terms of

411
00:17:15,820 --> 00:17:16,853
garden variety,

412
00:17:17,409 --> 00:17:20,587
heart failure with preserved d or heart failure

413
00:17:20,587 --> 00:17:21,302
in general,

414
00:17:21,954 --> 00:17:22,773
I think this

415
00:17:23,152 --> 00:17:26,664
simplified approach to implementation may actually improve our

416
00:17:26,664 --> 00:17:27,164
therapeutic

417
00:17:27,542 --> 00:17:30,576
uptake and may improve our familiarity with these

418
00:17:30,576 --> 00:17:31,076
therapies

419
00:17:31,468 --> 00:17:33,218
and our comfort with these therapies.

420
00:17:33,695 --> 00:17:34,911
And perhaps

421
00:17:35,445 --> 00:17:38,388
regardless of our specialty or our training, we

422
00:17:38,388 --> 00:17:39,604
may feel comfortable

423
00:17:39,994 --> 00:17:42,871
in using a common set of tools to

424
00:17:42,871 --> 00:17:45,428
combat disease progression in heart failure.

425
00:17:46,307 --> 00:17:49,674
Shifting now to chronic kidney disease, Ck has

426
00:17:49,674 --> 00:17:52,322
a tremendous burden in the community

427
00:17:52,697 --> 00:17:53,197
affects

428
00:17:53,572 --> 00:17:54,845
about 40000000

429
00:17:55,084 --> 00:17:58,440
Americans and has a tremendous footprint globally.

430
00:17:59,314 --> 00:18:01,460
Ck cad is a syndrome that has been

431
00:18:01,460 --> 00:18:04,821
challenging to study because it slowly progresses

432
00:18:05,607 --> 00:18:07,140
and often clinically

433
00:18:07,514 --> 00:18:10,056
significant events such as end stage kidney disease

434
00:18:10,056 --> 00:18:12,042
requiring dialysis for transplantation,

435
00:18:12,694 --> 00:18:13,512
is relatively

436
00:18:13,889 --> 00:18:17,075
infrequent event during the typical time course of

437
00:18:17,075 --> 00:18:17,554
a study.

438
00:18:18,191 --> 00:18:20,125
The disease progression is often

439
00:18:20,740 --> 00:18:22,117
asymptomatic and so

440
00:18:22,428 --> 00:18:24,201
many individuals may be

441
00:18:24,735 --> 00:18:25,235
undetected

442
00:18:25,610 --> 00:18:26,348
or un

443
00:18:26,803 --> 00:18:27,598
in the community.

444
00:18:28,314 --> 00:18:28,951
And finally,

445
00:18:29,363 --> 00:18:32,561
are tools that are available to actually diagnose

446
00:18:33,013 --> 00:18:34,704
Ck k, such as

447
00:18:35,077 --> 00:18:38,528
urine albumin cr ratio are vastly

448
00:18:39,380 --> 00:18:41,550
underutilized. And so this all

449
00:18:42,640 --> 00:18:45,106
and cons conspired to create a scenario in

450
00:18:45,106 --> 00:18:47,514
which we vastly under diagnosed

451
00:18:48,063 --> 00:18:50,207
ck circadian in the community, and we under

452
00:18:50,207 --> 00:18:51,398
study this population.

453
00:18:52,113 --> 00:18:55,290
The renin angiotensin system inhibitors, ace inhibitors and

454
00:18:55,290 --> 00:18:57,609
or have been the cornerstone of management for

455
00:18:57,609 --> 00:18:59,758
over 2 to 3 decades.

456
00:19:00,475 --> 00:19:03,580
And until very recently, we haven't had great

457
00:19:03,580 --> 00:19:05,513
breakthroughs in the chair of Ck.

458
00:19:06,303 --> 00:19:09,253
The S 2 inhibitors were the first such

459
00:19:09,253 --> 00:19:10,391
add therapy

460
00:19:10,848 --> 00:19:11,747
2 background

461
00:19:12,124 --> 00:19:13,341
renin angiotensin

462
00:19:14,356 --> 00:19:17,747
inhibition. And have been studied in 4 separate

463
00:19:18,125 --> 00:19:19,345
randomized clinical trials

464
00:19:19,803 --> 00:19:22,280
that is credence, Da Ck kd,

465
00:19:23,092 --> 00:19:24,924
amp kidney and scored.

466
00:19:25,879 --> 00:19:30,440
These 4 trials tested each individual therapies S

467
00:19:30,657 --> 00:19:32,750
2 and S12

468
00:19:32,750 --> 00:19:33,250
inhibitors

469
00:19:33,710 --> 00:19:34,690
in this target

470
00:19:34,990 --> 00:19:36,349
population of chronic kidney disease.

471
00:19:37,230 --> 00:19:39,150
2 of the randomized clinical trials,

472
00:19:39,802 --> 00:19:40,996
credence and scored,

473
00:19:41,950 --> 00:19:43,325
specifically studied people

474
00:19:43,700 --> 00:19:45,313
with chronic kidney disease

475
00:19:45,688 --> 00:19:47,756
and con conglomerate type 2 diabetes.

476
00:19:48,486 --> 00:19:50,710
Most of these patients were thought to have

477
00:19:50,710 --> 00:19:51,846
diabetic ne.

478
00:19:52,775 --> 00:19:55,340
The other 2 trials enrolled broader

479
00:19:55,714 --> 00:19:56,214
populations

480
00:19:56,763 --> 00:19:59,016
including Da ck cad and amp kidney

481
00:19:59,392 --> 00:20:02,203
studied populations with and without diabetes,

482
00:20:03,297 --> 00:20:03,797
inclusive

483
00:20:04,108 --> 00:20:06,334
of ideologies of chronic kidney disease,

484
00:20:07,050 --> 00:20:08,663
unrelated to diabetic ne,

485
00:20:09,912 --> 00:20:10,412
including

486
00:20:10,945 --> 00:20:12,876
specific gl ne,

487
00:20:13,584 --> 00:20:16,373
and other ideologies are Ck g progression.

488
00:20:17,409 --> 00:20:20,459
All 4 trials showed that these therapies

489
00:20:21,408 --> 00:20:21,908
modified

490
00:20:22,365 --> 00:20:24,438
disease course in chronic kidney disease.

491
00:20:25,155 --> 00:20:27,787
So they showed that you're able to actually

492
00:20:27,787 --> 00:20:31,890
reduce clinically relevant events, such as dialysis and

493
00:20:32,188 --> 00:20:32,427
transplantation,

494
00:20:33,065 --> 00:20:34,522
even over a finite

495
00:20:35,059 --> 00:20:35,937
duration of time,

496
00:20:36,495 --> 00:20:38,808
you're able to bend the trajectory of kidney

497
00:20:38,808 --> 00:20:42,591
seeds progression by slowing the decline of G

498
00:20:43,366 --> 00:20:47,191
in these patient populations. And most importantly, these

499
00:20:47,191 --> 00:20:50,153
benefit were seeing irrespective of diabetes status.

500
00:20:51,348 --> 00:20:52,804
Irrespective of ideology

501
00:20:53,340 --> 00:20:54,477
and irrespective

502
00:20:54,869 --> 00:20:57,906
of the individual patient profile, for instance, if

503
00:20:57,906 --> 00:21:00,623
they were high or low risk. And so

504
00:21:00,623 --> 00:21:03,280
now S 2 inhibitors form

505
00:21:03,755 --> 00:21:06,394
Another cornerstone of management of chronic kidney disease,

506
00:21:06,955 --> 00:21:09,515
and all these patients were well treated with

507
00:21:09,515 --> 00:21:10,015
background,

508
00:21:10,555 --> 00:21:12,714
renin angiotensin system inhibitors,

509
00:21:13,368 --> 00:21:16,144
and just like we've seen in the care

510
00:21:16,144 --> 00:21:17,096
of heart failure,

511
00:21:17,572 --> 00:21:19,872
we are now seeing in the care of

512
00:21:19,872 --> 00:21:20,983
chronic kidney disease.

513
00:21:21,712 --> 00:21:24,276
That there are now multiple therapeutics

514
00:21:24,649 --> 00:21:27,110
that have been shown to delay disease progression

515
00:21:27,110 --> 00:21:29,833
in Ck cad, and so much like we

516
00:21:29,889 --> 00:21:30,389
consider

517
00:21:30,699 --> 00:21:31,199
G

518
00:21:31,578 --> 00:21:32,478
of the heart

519
00:21:33,017 --> 00:21:36,453
in delaying disease progression heart failure, there's now

520
00:21:36,453 --> 00:21:39,250
a very similar set of tools as a

521
00:21:39,330 --> 00:21:39,830
G

522
00:21:40,463 --> 00:21:44,548
for the kidney to delay disease progression ultimately

523
00:21:44,844 --> 00:21:45,344
reaching

524
00:21:45,880 --> 00:21:48,371
important clinical events like dialysis and

525
00:21:48,747 --> 00:21:49,247
transplantation

526
00:21:49,719 --> 00:21:51,953
Thank you, Doctor Var for going into more

527
00:21:51,953 --> 00:21:54,587
depth about the role of S inhibitors and

528
00:21:54,587 --> 00:21:56,902
chronic kidney disease. That was just really a

529
00:21:56,902 --> 00:21:59,147
true master class of the child in this

530
00:21:59,147 --> 00:22:01,453
patient population. And I really love that point

531
00:22:01,453 --> 00:22:03,283
you made earlier about how we're going from

532
00:22:03,283 --> 00:22:03,783
broad

533
00:22:04,158 --> 00:22:04,769
implementation and

534
00:22:05,367 --> 00:22:08,018
recognizing those broader phenotypes and moving more towards

535
00:22:08,076 --> 00:22:10,307
precision medicine. And I think all this discussion

536
00:22:10,307 --> 00:22:12,059
with Ck katie really speaks to the fact

537
00:22:12,059 --> 00:22:15,020
that S inhibitors aren't a drug owned by

538
00:22:15,020 --> 00:22:17,799
1 specialty only, is really an intersection of

539
00:22:17,799 --> 00:22:21,689
cardiology ne, endo and primary care, and is

540
00:22:21,689 --> 00:22:22,838
multi disc disciplinary

541
00:22:23,211 --> 00:22:24,823
collaboration is needed for effective

542
00:22:25,196 --> 00:22:27,021
implementation of the drug class and to get

543
00:22:27,021 --> 00:22:29,164
it to the patients that would benefit from

544
00:22:29,164 --> 00:22:31,326
it. The And so far, we've been talking

545
00:22:31,326 --> 00:22:33,872
a lot about S 2 inhibitors, but we

546
00:22:33,872 --> 00:22:36,202
know there are medications that are both S

547
00:22:36,418 --> 00:22:37,691
2 and ST1

548
00:22:37,691 --> 00:22:38,407
dual inhibitors.

549
00:22:38,979 --> 00:22:40,169
Could you tell us a little bit more

550
00:22:40,169 --> 00:22:42,073
about the trial data of those dual inhibitors

551
00:22:42,073 --> 00:22:45,088
and their effectiveness across the heart failure spectrum

552
00:22:45,088 --> 00:22:46,674
and other indications for their use?

553
00:22:47,564 --> 00:22:50,137
Yeah. Thanks so much, Gu, and and really

554
00:22:50,276 --> 00:22:50,776
all

555
00:22:51,312 --> 00:22:52,828
6S2

556
00:22:52,828 --> 00:22:53,147
inhibitors,

557
00:22:53,785 --> 00:22:55,061
an S12

558
00:22:55,061 --> 00:22:57,269
inhibitors that are now Fda approved

559
00:22:57,787 --> 00:22:58,606
have varying

560
00:22:59,061 --> 00:22:59,561
affinity

561
00:23:00,017 --> 00:23:01,928
to either the ST1

562
00:23:01,928 --> 00:23:02,428
transporter

563
00:23:03,441 --> 00:23:06,800
or the S 2 transporter and So if

564
00:23:06,800 --> 00:23:08,868
given in equal potent doses,

565
00:23:09,504 --> 00:23:12,550
often will bind to both of these transporter,

566
00:23:13,419 --> 00:23:16,476
We often call most of these therapies S

567
00:23:17,015 --> 00:23:20,372
2 inhibitors because they're mostly specific to the

568
00:23:20,451 --> 00:23:21,671
S to transporter.

569
00:23:22,864 --> 00:23:25,740
Predominantly located in the proxima tub of kidney.

570
00:23:26,300 --> 00:23:28,798
Now S 1 is also

571
00:23:29,176 --> 00:23:30,615
expressed in the human system.

572
00:23:31,109 --> 00:23:33,269
And that's predominantly in the brush border of

573
00:23:33,269 --> 00:23:35,670
the gut and has a very similar role

574
00:23:35,670 --> 00:23:37,750
in the reclamation of filtered,

575
00:23:38,549 --> 00:23:39,670
glucose and sodium.

576
00:23:40,242 --> 00:23:42,251
And so these transporter

577
00:23:42,862 --> 00:23:44,474
both act in unison

578
00:23:45,006 --> 00:23:46,141
to control

579
00:23:46,991 --> 00:23:48,737
glucose homeostasis in the system,

580
00:23:49,388 --> 00:23:52,737
And so its inhibition of S 1 and

581
00:23:52,737 --> 00:23:55,288
2 may lead to losses not only the

582
00:23:55,288 --> 00:23:59,130
kidney of glucose that's filtered. But also of

583
00:23:59,130 --> 00:24:00,566
glucose in the gut lumen.

584
00:24:01,124 --> 00:24:03,278
So S12

585
00:24:03,278 --> 00:24:06,569
inhibitors that have more balanced effects on S

586
00:24:06,707 --> 00:24:07,640
1 and 2

587
00:24:07,998 --> 00:24:11,422
have also been developed and so flows is

588
00:24:11,422 --> 00:24:13,753
the currently Fda approved

589
00:24:14,208 --> 00:24:15,982
ST12

590
00:24:16,534 --> 00:24:17,493
combined inhibitor.

591
00:24:18,292 --> 00:24:20,769
This was a therapy that was studied in

592
00:24:20,769 --> 00:24:24,045
2 randomized clinical trials that were in phase

593
00:24:24,045 --> 00:24:24,545
3

594
00:24:25,017 --> 00:24:27,164
scored and solo heart failure.

595
00:24:27,880 --> 00:24:30,765
Scored was a very large trial of 10000

596
00:24:31,140 --> 00:24:33,944
individuals with chronic kidney disease and type 2

597
00:24:33,944 --> 00:24:34,424
diabetes.

598
00:24:35,224 --> 00:24:37,784
Soul worsening heart failure was a very unique

599
00:24:37,784 --> 00:24:38,284
trial

600
00:24:38,664 --> 00:24:39,164
of

601
00:24:39,464 --> 00:24:41,544
patients with worsening heart failure.

602
00:24:42,039 --> 00:24:45,475
These are patients who are randomized either just

603
00:24:45,475 --> 00:24:47,174
before or just after

604
00:24:48,671 --> 00:24:50,050
hospitalization for heart failure

605
00:24:50,443 --> 00:24:53,150
and so studied the role of these therapeutics

606
00:24:53,150 --> 00:24:55,777
in the acute phase of illness in heart

607
00:24:55,777 --> 00:24:56,095
failure.

608
00:24:57,050 --> 00:24:57,926
So unfortunately,

609
00:24:58,418 --> 00:25:00,961
During the conduct of these randomized clinical trials,

610
00:25:01,358 --> 00:25:04,934
the primary sponsor pulled funding from scored and

611
00:25:04,934 --> 00:25:05,434
sol

612
00:25:05,824 --> 00:25:07,121
such that we had

613
00:25:07,498 --> 00:25:09,650
curtail follow up in the case of scored,

614
00:25:09,809 --> 00:25:13,099
which was fully enrolled in over 10000

615
00:25:13,396 --> 00:25:16,710
individuals but had short duration follow ups, which

616
00:25:16,850 --> 00:25:17,350
impacted

617
00:25:17,730 --> 00:25:20,630
the actual ultimate study conclusions because

618
00:25:20,930 --> 00:25:24,154
this was ultimately a Ck cad progression trial

619
00:25:24,289 --> 00:25:25,980
and Ck cad progression trials

620
00:25:26,433 --> 00:25:26,933
require

621
00:25:27,307 --> 00:25:30,189
longer duration follow up to a crew sufficient

622
00:25:30,578 --> 00:25:32,273
rare events like dialysis.

623
00:25:33,128 --> 00:25:35,757
And similarly in soul worsening heart failure,

624
00:25:36,315 --> 00:25:37,430
the loss of fun doing.

625
00:25:38,084 --> 00:25:40,960
Restricted the number of patients actually enrolled and

626
00:25:40,960 --> 00:25:43,677
that was limited now to just over a

627
00:25:43,677 --> 00:25:44,875
thousand participants.

628
00:25:45,769 --> 00:25:48,109
The clinical trial were quite

629
00:25:48,410 --> 00:25:51,630
adapt and quite smart about this and rapidly

630
00:25:51,849 --> 00:25:54,670
modified the primary outcome of these trials

631
00:25:55,303 --> 00:25:58,254
recognizing that. In 1 trial, there was limited

632
00:25:58,254 --> 00:26:00,349
follow in the other there was a limited

633
00:26:00,487 --> 00:26:00,987
enrollment

634
00:26:01,683 --> 00:26:05,445
to really a broad based point of total

635
00:26:05,445 --> 00:26:06,400
cardiovascular deaths,

636
00:26:07,276 --> 00:26:09,981
hospitalizations for heart failure or urgent heart failure

637
00:26:09,981 --> 00:26:10,299
visits.

638
00:26:11,095 --> 00:26:13,880
And in fact, in both randomized clinical trials,

639
00:26:14,292 --> 00:26:16,751
actually showed that this therapy when studied in

640
00:26:16,910 --> 00:26:19,789
Ck kd when studied in worsening heart failure

641
00:26:19,845 --> 00:26:23,533
was able to modify that outcome of composite

642
00:26:23,669 --> 00:26:26,606
cardiovascular death and heart failure events and that

643
00:26:26,606 --> 00:26:29,703
was counting both first and recurrent events.

644
00:26:30,514 --> 00:26:33,328
This actually led the Fda to provide

645
00:26:33,706 --> 00:26:36,121
so with a specific label of

646
00:26:36,499 --> 00:26:39,778
prevention of heart failure events in individuals with

647
00:26:39,778 --> 00:26:43,273
chronic kidney disease and in people with worsening

648
00:26:43,273 --> 00:26:46,395
heart failure. So really provided a clear pathway

649
00:26:46,863 --> 00:26:48,852
how we can think about using this therapy.

650
00:26:49,568 --> 00:26:50,863
Thank you for that comprehensive

651
00:26:51,238 --> 00:26:53,647
review and the mechanism and the trial data

652
00:26:53,799 --> 00:26:55,470
I think oliver of our discussion tonight has

653
00:26:55,470 --> 00:26:57,061
really shown that there's a growing base of

654
00:26:57,141 --> 00:27:00,561
Data supporting the implementation of S inhibitors.

655
00:27:01,134 --> 00:27:01,453
And Doctor,

656
00:27:02,251 --> 00:27:03,686
you've been such an expert in this field,

657
00:27:03,925 --> 00:27:05,760
so would love to hear your perspective of

658
00:27:05,760 --> 00:27:07,696
what do you think is the future advances

659
00:27:08,153 --> 00:27:10,487
in S inhibitors for patient management.

660
00:27:11,119 --> 00:27:13,372
We know that we recently had another S

661
00:27:13,749 --> 00:27:16,936
trial presented at Acc, the impact Mi. So

662
00:27:16,936 --> 00:27:18,211
we'd I'd also love to hear your thoughts

663
00:27:18,211 --> 00:27:20,382
about that trial and what groups of patients

664
00:27:20,382 --> 00:27:21,521
do you think might benefit

665
00:27:22,060 --> 00:27:24,137
from S inhibitors that we haven't studied ed

666
00:27:24,137 --> 00:27:25,815
yet? Where is the field headed?

667
00:27:26,469 --> 00:27:28,804
You know, until now we've talked about cardio

668
00:27:28,942 --> 00:27:30,797
protection in people with type 2 diabetes.

669
00:27:31,653 --> 00:27:34,605
Primary treatment of people with heart failure irrespective

670
00:27:34,605 --> 00:27:35,801
of their ejection fraction,

671
00:27:36,772 --> 00:27:39,317
primary treatment of people with chronic kidney disease

672
00:27:39,317 --> 00:27:40,669
of various et ideologies,

673
00:27:41,385 --> 00:27:44,580
and the most recent aspect and disease state

674
00:27:44,580 --> 00:27:46,352
that was studied was that after

675
00:27:46,726 --> 00:27:48,315
acute myocardial infarction,

676
00:27:48,871 --> 00:27:51,334
and that was studied in 2 randomized clinical

677
00:27:51,334 --> 00:27:51,834
trials

678
00:27:52,462 --> 00:27:54,850
Da mi and impact Mi,

679
00:27:55,487 --> 00:27:57,238
and we may not have the time to

680
00:27:57,238 --> 00:27:59,649
actually dive into the details of these trials

681
00:28:00,279 --> 00:28:02,375
but it essentially showed that

682
00:28:03,390 --> 00:28:05,566
mortality in this population was relatively

683
00:28:05,943 --> 00:28:09,248
low in that Most of these people after

684
00:28:09,305 --> 00:28:12,671
myocardial infarction in the contemporary era faced relatively

685
00:28:12,887 --> 00:28:13,387
low

686
00:28:14,002 --> 00:28:15,298
mortality events

687
00:28:15,847 --> 00:28:18,870
because they're promptly rev and because standard of

688
00:28:18,870 --> 00:28:21,756
care is quite quite good that are other

689
00:28:21,893 --> 00:28:22,393
therapeutics

690
00:28:22,783 --> 00:28:25,252
are excellent in preventing death.

691
00:28:26,208 --> 00:28:29,893
However, we also recognize that patients still face

692
00:28:30,030 --> 00:28:32,200
residual risk of other events such as heart

693
00:28:32,200 --> 00:28:35,319
failure and so the development of post Mi

694
00:28:35,319 --> 00:28:38,440
l dysfunction and heart failure is still important

695
00:28:38,440 --> 00:28:41,332
even in the current era of care. And

696
00:28:41,332 --> 00:28:43,743
so impact Mr Da mi

697
00:28:44,119 --> 00:28:45,733
showed that you can actually

698
00:28:46,666 --> 00:28:47,883
prevent heart failure

699
00:28:48,497 --> 00:28:48,997
hospitalizations

700
00:28:49,308 --> 00:28:50,126
in people

701
00:28:50,659 --> 00:28:51,159
who

702
00:28:51,771 --> 00:28:54,472
suffered from and acute myocardial infarction function, including

703
00:28:54,472 --> 00:28:56,322
those who are promptly rev,

704
00:28:56,855 --> 00:28:59,570
including those who are already well treated with

705
00:28:59,570 --> 00:29:01,556
other dare that we know are helpful,

706
00:29:02,032 --> 00:29:04,836
such as statins such as anti platelet therapies

707
00:29:04,892 --> 00:29:05,710
such as

708
00:29:06,499 --> 00:29:08,517
ace inhibitors, and mineral

709
00:29:09,135 --> 00:29:10,014
receptor antagonist,

710
00:29:10,573 --> 00:29:11,073
and

711
00:29:11,452 --> 00:29:13,624
Da mi was a little bit more of

712
00:29:13,624 --> 00:29:15,858
a unique trial and that it had to

713
00:29:15,858 --> 00:29:18,753
be adapted in terms of its primary outcome

714
00:29:18,891 --> 00:29:21,366
because it had a much lower target event

715
00:29:21,366 --> 00:29:23,711
rate And so ultimately, it was

716
00:29:24,166 --> 00:29:27,428
evolved into a win ratio type endpoint, and

717
00:29:27,428 --> 00:29:29,416
until the learnings from that trial were a

718
00:29:29,416 --> 00:29:30,291
bit more limited,

719
00:29:31,180 --> 00:29:33,796
Impact Mi was conducted a bit more traditionally

720
00:29:33,796 --> 00:29:35,485
was a much larger trial

721
00:29:35,936 --> 00:29:38,889
and was an event driven trial. And so

722
00:29:38,889 --> 00:29:41,706
we lurk that while these therapies can't bend

723
00:29:42,484 --> 00:29:42,884
mortality,

724
00:29:43,363 --> 00:29:44,801
which was 1 of the components of the

725
00:29:44,801 --> 00:29:45,440
primary endpoint.

726
00:29:46,094 --> 00:29:47,868
It does appear to prevent

727
00:29:48,324 --> 00:29:51,431
hospitalization for heart failure, which is a feature

728
00:29:51,431 --> 00:29:52,967
of this therapeutic class

729
00:29:53,279 --> 00:29:56,400
that we've seen not just after myocardial infarction,

730
00:29:56,799 --> 00:29:58,799
but across each of the disease states we

731
00:29:58,799 --> 00:30:02,112
just talked about. Chronic kidney disease heart failure

732
00:30:02,169 --> 00:30:05,750
patients with established disease as well as patients

733
00:30:05,750 --> 00:30:07,761
with diabetes who are at high cardiovascular.

734
00:30:08,694 --> 00:30:10,069
So we'll see how

735
00:30:10,936 --> 00:30:12,470
regulators and guidelines

736
00:30:13,401 --> 00:30:16,103
consider this data, but I think it's important

737
00:30:16,103 --> 00:30:18,193
to understand that this was

738
00:30:18,981 --> 00:30:22,324
therapeutic area that we've made great strides and

739
00:30:22,324 --> 00:30:24,712
the S inhibitors may have a role, at

740
00:30:24,712 --> 00:30:25,929
least in a selective

741
00:30:27,118 --> 00:30:29,696
population at very high risk for heart failure

742
00:30:29,835 --> 00:30:29,995
onset.

743
00:30:30,714 --> 00:30:32,791
There are many areas that I think are

744
00:30:32,791 --> 00:30:34,010
exciting ahead

745
00:30:34,322 --> 00:30:37,997
we're now about 10 to 12 years after

746
00:30:38,212 --> 00:30:39,029
initial labeling

747
00:30:39,561 --> 00:30:42,919
of S 2 inhibitors, so many are reaching

748
00:30:43,149 --> 00:30:44,048
their patent

749
00:30:44,505 --> 00:30:46,759
expiration dates and in fact, we now have

750
00:30:47,057 --> 00:30:49,211
generic therapeutic options in the United States.

751
00:30:50,008 --> 00:30:52,241
And so I don't think we can expect

752
00:30:52,241 --> 00:30:52,741
that

753
00:30:53,295 --> 00:30:53,795
Principally

754
00:30:54,335 --> 00:30:56,975
industry sponsored trials are going to be the

755
00:30:56,975 --> 00:30:58,735
mains state of what we're gonna see moving

756
00:30:58,735 --> 00:31:01,955
forward. We're gonna see federally funded studies

757
00:31:02,269 --> 00:31:05,696
we're gonna see more creatively funded studies moving

758
00:31:05,696 --> 00:31:05,936
ahead.

759
00:31:06,733 --> 00:31:09,603
The open ended questions are how can these

760
00:31:09,603 --> 00:31:12,747
therapies be a effectively combined with other therapies,

761
00:31:13,203 --> 00:31:14,898
and so we now are seeing

762
00:31:15,354 --> 00:31:17,447
combination medical therapy trials

763
00:31:18,077 --> 00:31:20,939
including poly pills, there's a wonderful trial being

764
00:31:20,939 --> 00:31:22,927
led out a few t Southwestern that's an

765
00:31:22,927 --> 00:31:26,439
nih sponsored trial of a combination poly pill

766
00:31:26,439 --> 00:31:28,027
in heart failure with reduced Ef.

767
00:31:28,901 --> 00:31:32,950
Furthermore, there combinations with mineral cord receptor antagonists

768
00:31:32,950 --> 00:31:35,848
that are being specifically studied in cardiovascular

769
00:31:36,226 --> 00:31:37,742
outcomes trials in heart failure.

770
00:31:38,381 --> 00:31:41,834
The other aspects are areas that were previously

771
00:31:42,451 --> 00:31:42,951
excluded

772
00:31:43,422 --> 00:31:46,758
For instance, people would significantly advanced chronic kidney

773
00:31:46,758 --> 00:31:47,972
disease, including those

774
00:31:48,346 --> 00:31:49,402
already on dialysis.

775
00:31:49,934 --> 00:31:52,079
This is being now studied in large scale

776
00:31:52,079 --> 00:31:52,579
trials

777
00:31:53,049 --> 00:31:55,444
1 of which is called renal life cycle,

778
00:31:56,002 --> 00:31:58,717
which is about a 1500 patient trial that's

779
00:31:58,717 --> 00:32:02,045
being conducted globally that's studying S to inhibition

780
00:32:02,323 --> 00:32:03,777
in people on dialysis

781
00:32:04,469 --> 00:32:07,353
in people with significantly reduced G

782
00:32:07,887 --> 00:32:09,976
and in people after kidney

783
00:32:10,509 --> 00:32:10,669
transplantation.

784
00:32:11,637 --> 00:32:13,626
There are some other areas that I think

785
00:32:13,626 --> 00:32:16,728
are of note until now we relatively discussed

786
00:32:16,728 --> 00:32:18,262
pretty high risk scenarios

787
00:32:18,653 --> 00:32:20,800
People would not just type 2 diabetes, but

788
00:32:20,800 --> 00:32:24,300
those who already have maybe established cardiovascular disease

789
00:32:24,300 --> 00:32:26,704
or who are at very high risk for

790
00:32:26,704 --> 00:32:30,848
cardiovascular events. We've discussed patients with heart failure

791
00:32:30,848 --> 00:32:34,634
chronic kidney acute mi, But what about earlier

792
00:32:34,775 --> 00:32:37,275
on in the disease process, including people

793
00:32:37,654 --> 00:32:38,154
with

794
00:32:38,695 --> 00:32:39,674
just diagnosed

795
00:32:40,055 --> 00:32:40,955
type 2 diabetes

796
00:32:41,428 --> 00:32:43,041
we should be learning from

797
00:32:43,415 --> 00:32:45,743
1 such trial that is studying

798
00:32:46,277 --> 00:32:49,479
newly diagnosed type 2 diabetes and whether S

799
00:32:49,694 --> 00:32:52,804
inhibitor should be first line care, and it's

800
00:32:52,804 --> 00:32:54,731
actually comparing that against

801
00:32:55,341 --> 00:32:58,221
metformin in a specific trial called smartest

802
00:32:58,608 --> 00:33:00,908
that's being run out of Scandinavia, so that

803
00:33:00,908 --> 00:33:03,843
is another area of interest. And then finally,

804
00:33:03,923 --> 00:33:05,137
of course, is

805
00:33:05,923 --> 00:33:08,258
While as a field we've moved towards

806
00:33:08,795 --> 00:33:10,151
combination medical therapy.

807
00:33:10,868 --> 00:33:14,059
We also wanna be par in terms of

808
00:33:14,059 --> 00:33:17,045
how we deliver care and so the comparative

809
00:33:17,102 --> 00:33:18,637
effectiveness of these therapies

810
00:33:19,013 --> 00:33:22,437
even against other mains states of care is

811
00:33:22,437 --> 00:33:26,031
also of high interest and so Pe has

812
00:33:26,031 --> 00:33:28,755
funded a large scale trial called precedent

813
00:33:29,367 --> 00:33:33,599
that is specifically studying S to inhibitors against

814
00:33:34,068 --> 00:33:35,659
Gl 1 receptor agonist,

815
00:33:36,136 --> 00:33:38,761
in people with type 2 diabetes and established,

816
00:33:39,397 --> 00:33:39,897
cardiovascular

817
00:33:40,352 --> 00:33:40,511
disease,

818
00:33:41,243 --> 00:33:43,395
This too will be an area to look

819
00:33:43,395 --> 00:33:44,373
forward to

820
00:33:44,830 --> 00:33:48,518
because perhaps at least in low moderate risk

821
00:33:48,576 --> 00:33:51,222
individuals maybe we should be starting with 1

822
00:33:51,222 --> 00:33:54,434
class and then layering on the second if

823
00:33:55,051 --> 00:33:58,183
additional aspects of cardiovascular risk acc in those

824
00:33:58,241 --> 00:34:00,572
individuals. So Lot to learn about this feel.

825
00:34:01,132 --> 00:34:03,689
I think the core aspects of these fields

826
00:34:03,689 --> 00:34:07,099
have been well studied and rapidly so it's

827
00:34:07,537 --> 00:34:09,230
remarkable that all this evidence

828
00:34:09,684 --> 00:34:13,103
has taken place over just about a decade,

829
00:34:13,660 --> 00:34:15,465
but I think we still have about

830
00:34:16,141 --> 00:34:18,949
another decade of learnings of how these therapies

831
00:34:19,325 --> 00:34:21,815
can be combined, how these therapies

832
00:34:22,190 --> 00:34:25,078
can be implemented in a timely basis

833
00:34:25,547 --> 00:34:28,487
and how these therapies can be implemented in

834
00:34:28,487 --> 00:34:28,987
people

835
00:34:29,361 --> 00:34:33,096
who are previously excluded from those initial randomized

836
00:34:33,096 --> 00:34:33,993
clinical trials

837
00:34:34,462 --> 00:34:37,507
including some that are very, very high risk

838
00:34:37,564 --> 00:34:40,269
for disease progression and clinical events.

839
00:34:41,318 --> 00:34:43,148
Thank you so much for that incredible review...

840
00:34:43,625 --> 00:34:45,057
I'm looking forward to going back and listening

841
00:34:45,057 --> 00:34:46,489
to that again because there were a lot

842
00:34:46,489 --> 00:34:48,814
of takeaways from that. You had mentioned the

843
00:34:48,893 --> 00:34:51,052
Poly pill, and I'm I'm really interested in

844
00:34:51,052 --> 00:34:52,031
that work, particularly

845
00:34:52,410 --> 00:34:54,328
with respect to G t. And obviously, I'm

846
00:34:54,328 --> 00:34:56,406
sure we've all had experienced starting many patients

847
00:34:56,406 --> 00:34:58,813
on heart failure guideline directed therapy and they

848
00:34:58,813 --> 00:35:00,664
can go from 0 to quite a few

849
00:35:00,719 --> 00:35:02,943
medications quickly. What sort of data is there

850
00:35:02,943 --> 00:35:04,770
for the Poly right now? What what kind

851
00:35:04,770 --> 00:35:06,438
of progress do you think we're gonna make

852
00:35:06,438 --> 00:35:07,073
in that direction?

853
00:35:08,121 --> 00:35:10,349
Yeah. So I I think this is really,

854
00:35:10,508 --> 00:35:14,110
really an important area because poly pills have

855
00:35:14,897 --> 00:35:18,012
been showing be beneficial in many areas across

856
00:35:18,384 --> 00:35:20,048
cardio metabolic medicine,

857
00:35:20,445 --> 00:35:21,420
including diabetes,

858
00:35:22,364 --> 00:35:22,864
in

859
00:35:23,164 --> 00:35:24,625
hypertension management in other

860
00:35:25,005 --> 00:35:25,724
prevention settings,

861
00:35:26,284 --> 00:35:26,784
and

862
00:35:27,484 --> 00:35:28,784
we've now rapidly

863
00:35:29,085 --> 00:35:32,215
converged and guidelines have strongly recommended multi drug

864
00:35:32,215 --> 00:35:34,932
regimen in the care of heart failure with

865
00:35:34,932 --> 00:35:38,141
reduced ejection fraction, especially and even some people

866
00:35:38,141 --> 00:35:40,934
would mildly reduce the. And so a poly

867
00:35:40,934 --> 00:35:43,648
pill is a natural next step of what

868
00:35:43,648 --> 00:35:44,606
needs to be developed.

869
00:35:45,338 --> 00:35:47,641
I think until now Poly pills have been

870
00:35:47,641 --> 00:35:50,420
challenging to develop and heart failure was reduced

871
00:35:50,420 --> 00:35:50,920
yet

872
00:35:51,452 --> 00:35:54,414
because there have been multiple sponsors of

873
00:35:55,121 --> 00:35:55,939
individual therapies

874
00:35:56,394 --> 00:35:59,973
that haven't actually had adjacent compounds in their

875
00:35:59,973 --> 00:36:00,473
armament.

876
00:36:01,739 --> 00:36:04,545
And so developing a single therapy

877
00:36:04,920 --> 00:36:08,182
that encompasses all of them has been difficult.

878
00:36:08,834 --> 00:36:11,072
But now we're at a unique phase in

879
00:36:11,072 --> 00:36:13,789
which we're about 10 years after the development

880
00:36:13,789 --> 00:36:16,826
of the core therapies, including the S inhibitors,

881
00:36:17,145 --> 00:36:17,645
including

882
00:36:18,278 --> 00:36:19,336
angiotensin receptor

883
00:36:19,793 --> 00:36:20,771
inhibitors like

884
00:36:21,388 --> 00:36:24,338
val sa. And so we do have the

885
00:36:24,338 --> 00:36:26,731
potential now that generic are emerging,

886
00:36:27,304 --> 00:36:30,014
that we can actually effectively combine them. So

887
00:36:30,014 --> 00:36:32,485
we're at a very early stage of development

888
00:36:32,485 --> 00:36:34,876
of poly pills. I don't think that they're

889
00:36:34,876 --> 00:36:37,141
yet been evidence of

890
00:36:37,596 --> 00:36:39,901
true poly pills in heart failure.

891
00:36:40,458 --> 00:36:43,161
I mentioned that Ut South trial that I

892
00:36:43,161 --> 00:36:44,933
personally am looking forward to

893
00:36:45,719 --> 00:36:46,617
individual companies

894
00:36:47,070 --> 00:36:47,967
are developing,

895
00:36:49,293 --> 00:36:52,550
combination therapies, for instance, including 2 of the

896
00:36:52,550 --> 00:36:52,868
components,

897
00:36:53,598 --> 00:36:56,698
like an s inhibitor and some modulator of

898
00:36:56,698 --> 00:36:57,596
the mr

899
00:36:57,970 --> 00:36:58,288
receptor,

900
00:36:59,162 --> 00:37:00,298
but I think a

901
00:37:00,673 --> 00:37:03,308
combination of 4 drugs which were often asked

902
00:37:03,308 --> 00:37:07,039
about. I think soon we'll see some attempts

903
00:37:07,039 --> 00:37:09,579
of will have to understand how this will

904
00:37:09,579 --> 00:37:10,079
be

905
00:37:10,389 --> 00:37:13,102
taken up by the community because we are

906
00:37:13,102 --> 00:37:15,757
so used to having choice in cardiovascular

907
00:37:16,534 --> 00:37:17,672
choice of doses

908
00:37:18,303 --> 00:37:20,795
choice of individual therapies within

909
00:37:21,331 --> 00:37:24,518
combinations, for instance, a particular beta blocker or

910
00:37:24,518 --> 00:37:26,111
a particular ST2

911
00:37:26,111 --> 00:37:27,567
inhibitor preference are even

912
00:37:27,879 --> 00:37:28,779
a particular

913
00:37:29,238 --> 00:37:32,535
ace inhibitor R or ar preference. And so

914
00:37:32,754 --> 00:37:34,613
that type of decision making

915
00:37:34,992 --> 00:37:38,837
needs similarly be simplified when we're discussing poly

916
00:37:38,837 --> 00:37:41,327
pills and the appetite of

917
00:37:41,862 --> 00:37:43,294
simplification in the clinical community,

918
00:37:43,851 --> 00:37:46,080
I think needs to be something that we'll

919
00:37:46,080 --> 00:37:48,402
need to wrestle with. So we'll soon see

920
00:37:48,402 --> 00:37:50,628
it's a very early stage even though these

921
00:37:50,628 --> 00:37:52,615
therapies have been around for a long period

922
00:37:52,615 --> 00:37:53,171
of time,

923
00:37:53,887 --> 00:37:56,289
we're now just at the point where we're

924
00:37:56,289 --> 00:37:59,418
about to see generic for all 4 core

925
00:37:59,635 --> 00:38:02,742
guideline directed medical therapy. And so it is

926
00:38:02,742 --> 00:38:05,308
truly a time point in which poly pills

927
00:38:05,308 --> 00:38:06,288
for heart failure

928
00:38:06,666 --> 00:38:07,945
are in fact possible.

929
00:38:08,903 --> 00:38:11,320
Thank you so much for that. That's really

930
00:38:12,032 --> 00:38:14,579
enlighten, but also in hardening and I'm really

931
00:38:14,579 --> 00:38:17,047
excited to see you, what's up next for

932
00:38:17,047 --> 00:38:18,799
this because we've come such a long way

933
00:38:18,799 --> 00:38:19,538
as you've highlighted

934
00:38:20,008 --> 00:38:21,280
via the data so far,

935
00:38:22,076 --> 00:38:23,826
but there's clearly a lot of excitement on

936
00:38:23,826 --> 00:38:24,780
the horizon as well.

937
00:38:25,735 --> 00:38:27,246
To wrap things up here, I'd love to

938
00:38:27,246 --> 00:38:29,655
ask your perspective, on some of the key

939
00:38:29,655 --> 00:38:32,614
takeaways from our discussion on the data. It's

940
00:38:32,614 --> 00:38:33,114
been

941
00:38:33,494 --> 00:38:35,734
really a whirlwind tour here, and it's been

942
00:38:35,734 --> 00:38:37,494
an really an incredible privilege to speak with

943
00:38:37,494 --> 00:38:39,188
you, but what are some kind of key

944
00:38:39,188 --> 00:38:40,626
points that you'd like to send to our

945
00:38:40,626 --> 00:38:40,946
audience?

946
00:38:42,385 --> 00:38:46,060
Thanks, Rick. This is really a remarkable drug

947
00:38:46,060 --> 00:38:48,221
class that we've learned a lot about over

948
00:38:48,221 --> 00:38:49,333
the last decade,

949
00:38:50,206 --> 00:38:51,977
and S 2 inhibitors

950
00:38:52,510 --> 00:38:57,059
today are indicated across 3 specific disease areas,

951
00:38:58,254 --> 00:38:59,710
patients with type 2 diabetes,

952
00:39:00,883 --> 00:39:04,012
patients with chronic kidney disease and patients with

953
00:39:04,403 --> 00:39:05,121
heart failure.

954
00:39:06,079 --> 00:39:08,711
In type 2 diabetes, they're indicated for their

955
00:39:08,711 --> 00:39:10,786
primary glucose lowering potential,

956
00:39:11,598 --> 00:39:15,126
at least in people who have preserved kidney

957
00:39:15,184 --> 00:39:18,474
function because these therapies lose their glucose lowering

958
00:39:18,691 --> 00:39:22,625
potential at lower G as kidney disease progresses.

959
00:39:23,425 --> 00:39:24,324
And furthermore,

960
00:39:24,625 --> 00:39:26,484
it's indicating people with diabetes

961
00:39:26,798 --> 00:39:27,617
for cardiovascular

962
00:39:28,389 --> 00:39:30,081
protection, prevention of cardiovascular

963
00:39:30,456 --> 00:39:31,512
events, including

964
00:39:31,966 --> 00:39:35,384
prevention of heart failure in individuals with diabetes.

965
00:39:36,354 --> 00:39:38,527
In chronic kidney disease, these therapies

966
00:39:39,302 --> 00:39:42,489
are now the first therapeutic class that have

967
00:39:42,489 --> 00:39:45,698
been added to renin angiotensin system inhibitors

968
00:39:46,728 --> 00:39:49,999
broad patient populations of chronic kidney disease inclusive

969
00:39:49,999 --> 00:39:52,813
of people with and without diabetes,

970
00:39:54,004 --> 00:39:56,559
And finally, in heart failure, it's been shown

971
00:39:56,559 --> 00:39:57,538
that these therapies,

972
00:39:58,315 --> 00:39:58,815
benefit

973
00:39:59,353 --> 00:40:01,828
patients across a broad spectrum of ejection fraction

974
00:40:01,828 --> 00:40:05,677
in preventing clinical events and preventing disease progression.

975
00:40:06,316 --> 00:40:08,414
These therapies have been studied in

976
00:40:08,873 --> 00:40:11,610
those after acute myocardial infarction

977
00:40:11,924 --> 00:40:14,792
who have either L dysfunction or evidence of

978
00:40:14,792 --> 00:40:15,110
congestion,

979
00:40:15,668 --> 00:40:17,660
and the evidence is relatively mixed.

980
00:40:18,456 --> 00:40:21,347
There's some evidence that these therapies prevent heart

981
00:40:21,347 --> 00:40:24,303
failure onset after a myocardial infarction,

982
00:40:24,942 --> 00:40:27,040
but there's no specific labels

983
00:40:27,353 --> 00:40:30,241
for this disease area and guideline bodies

984
00:40:30,696 --> 00:40:31,435
and regulators

985
00:40:31,890 --> 00:40:34,755
still are digesting the very, very hot off

986
00:40:34,755 --> 00:40:37,338
the press data from da at my an

987
00:40:37,395 --> 00:40:37,951
impact am I.

988
00:40:39,619 --> 00:40:42,797
Broadly speaking across these 4 therapeutic areas,

989
00:40:43,432 --> 00:40:43,885
this

990
00:40:44,482 --> 00:40:47,690
Individual therapeutic class has been studied in 16

991
00:40:48,545 --> 00:40:51,833
randomized clinical trials and has led to 6

992
00:40:51,890 --> 00:40:52,948
different therapies

993
00:40:53,499 --> 00:40:56,376
being approved by the Us Fda in short

994
00:40:56,376 --> 00:40:56,775
order,

995
00:40:57,414 --> 00:41:00,370
we now have the first generic available.

996
00:41:01,425 --> 00:41:02,644
And so we're hopeful

997
00:41:03,025 --> 00:41:04,085
that these therapies

998
00:41:04,704 --> 00:41:05,664
become more affordable,

999
00:41:06,224 --> 00:41:06,724
accessible

1000
00:41:07,264 --> 00:41:08,324
and equitable

1001
00:41:08,639 --> 00:41:10,872
in terms of the implementation of them,

1002
00:41:11,989 --> 00:41:12,467
broadly.

1003
00:41:13,584 --> 00:41:14,722
Despite their now

1004
00:41:15,259 --> 00:41:16,716
10 years of scientific

1005
00:41:17,412 --> 00:41:20,862
investigation and really well conducted clinical trials, there

1006
00:41:20,862 --> 00:41:22,540
are many unanswered questions.

1007
00:41:23,179 --> 00:41:26,556
And those clinical trials are actively being

1008
00:41:26,935 --> 00:41:27,435
conducted

1009
00:41:28,068 --> 00:41:29,127
including in

1010
00:41:29,824 --> 00:41:32,377
populations that were previously been excluded such as

1011
00:41:32,377 --> 00:41:33,574
end stage kidney disease,

1012
00:41:34,691 --> 00:41:35,191
including

1013
00:41:36,063 --> 00:41:38,721
combination medical therapy, clinical trials

1014
00:41:39,500 --> 00:41:42,716
and about trials specifically about

1015
00:41:43,255 --> 00:41:43,495
implementation.

1016
00:41:44,148 --> 00:41:46,860
Where when and how do we implement these

1017
00:41:46,860 --> 00:41:47,360
therapies

1018
00:41:47,977 --> 00:41:50,551
to allow for the best

1019
00:41:50,928 --> 00:41:53,321
potential patient outcomes with their use?

1020
00:41:54,214 --> 00:41:54,714
So

1021
00:41:55,173 --> 00:41:57,730
I would say this is a paradigm of

1022
00:41:57,730 --> 00:41:58,230
how

1023
00:41:58,848 --> 00:41:59,348
therapies

1024
00:41:59,887 --> 00:42:01,905
that were developed in 1 area

1025
00:42:02,539 --> 00:42:04,556
may quite quite successful

1026
00:42:04,934 --> 00:42:07,568
in influencing broad patient populations.

1027
00:42:08,207 --> 00:42:11,661
And it's a really, really exciting time

1028
00:42:11,974 --> 00:42:12,795
for cardiovascular

1029
00:42:13,094 --> 00:42:13,494
medicine,

1030
00:42:14,614 --> 00:42:16,474
because this is really rein,

1031
00:42:17,574 --> 00:42:18,394
not just

1032
00:42:18,775 --> 00:42:19,275
cardiology,

1033
00:42:19,734 --> 00:42:20,787
but kidney medicine,

1034
00:42:21,345 --> 00:42:22,244
metabolic medicine

1035
00:42:22,701 --> 00:42:25,195
and has brought these fields really together

1036
00:42:25,572 --> 00:42:29,103
in studying these therapeutics even in multi orbit

1037
00:42:29,401 --> 00:42:29,640
conditions.

1038
00:42:30,451 --> 00:42:32,831
And on a personal note, I would say

1039
00:42:32,831 --> 00:42:33,331
that

1040
00:42:33,704 --> 00:42:36,030
this therapeutic class really

1041
00:42:36,721 --> 00:42:37,221
started

1042
00:42:37,688 --> 00:42:40,871
and the very first of those 16 randomized

1043
00:42:40,871 --> 00:42:43,043
clinical trials amp egg outcome

1044
00:42:43,657 --> 00:42:44,873
reported when

1045
00:42:45,184 --> 00:42:47,729
I was a first year cardiology fellow.

1046
00:42:48,445 --> 00:42:50,615
And at that point, I was relatively.

1047
00:42:52,198 --> 00:42:55,217
I enjoyed cardiology. I enjoyed clinical trials. I

1048
00:42:55,217 --> 00:42:56,091
enjoyed data science,

1049
00:42:57,124 --> 00:43:00,241
but this was a trial that I recognized

1050
00:43:00,241 --> 00:43:01,697
was outside of cardiology,

1051
00:43:02,553 --> 00:43:05,126
but there was some magic to this therapeutic

1052
00:43:05,344 --> 00:43:07,757
class, and so I invested

1053
00:43:08,149 --> 00:43:10,147
a lot of my early years as a

1054
00:43:10,147 --> 00:43:11,366
cardiology fellow

1055
00:43:11,745 --> 00:43:14,962
in understanding more and trying to become more

1056
00:43:15,181 --> 00:43:15,681
involved

1057
00:43:16,060 --> 00:43:16,560
in

1058
00:43:17,352 --> 00:43:18,411
growth of evidence

1059
00:43:19,027 --> 00:43:22,477
around this therapeutic class. So my main advice

1060
00:43:22,695 --> 00:43:25,246
is that use this as an example,

1061
00:43:26,217 --> 00:43:27,673
and keep your eyes open

1062
00:43:28,050 --> 00:43:30,361
because at whatever stage of training you're at,

1063
00:43:30,919 --> 00:43:33,251
there going to be surprises and

1064
00:43:33,563 --> 00:43:35,553
If history is going to repeat itself.

1065
00:43:36,747 --> 00:43:37,247
Cardiology

1066
00:43:37,782 --> 00:43:40,351
is a therapeutic area of serendipity,

1067
00:43:40,965 --> 00:43:42,898
and there will always be

1068
00:43:43,849 --> 00:43:47,050
a windy road ahead, and we never know

1069
00:43:47,050 --> 00:43:48,030
when the next

1070
00:43:48,570 --> 00:43:51,309
great therapeutic is going to land and

1071
00:43:51,624 --> 00:43:52,762
Keep your eyes open

1072
00:43:53,139 --> 00:43:54,198
because this is

1073
00:43:54,575 --> 00:43:57,547
1 of the most fascinating areas of medicine

1074
00:43:57,925 --> 00:44:00,079
because we have so much to learn about

1075
00:44:00,079 --> 00:44:01,296
cardiovascular system

1076
00:44:01,687 --> 00:44:03,536
and we learned it by

1077
00:44:04,068 --> 00:44:06,926
pathways that maybe be quite distinct from what

1078
00:44:06,926 --> 00:44:09,545
we're used to from phase 1 to 2

1079
00:44:09,545 --> 00:44:10,934
to 3 to for

1080
00:44:11,468 --> 00:44:13,798
investigation. Now we'd argue that most

1081
00:44:14,809 --> 00:44:16,742
therapeutic advances in cardiology

1082
00:44:17,197 --> 00:44:19,367
have taken a much, much

1083
00:44:19,757 --> 00:44:21,428
less well t path.

1084
00:44:22,065 --> 00:44:24,054
Thank you so much for just filling down

1085
00:44:24,054 --> 00:44:26,934
the key takeaways of S inhibitors and has

1086
00:44:26,934 --> 00:44:28,612
just been so exciting to hear about the

1087
00:44:28,612 --> 00:44:31,648
current ongoing trials and the future investigations and

1088
00:44:31,648 --> 00:44:33,645
the field from you. There is truly a

1089
00:44:33,645 --> 00:44:35,726
lot to look forward to for improving the

1090
00:44:35,726 --> 00:44:37,472
care of our patients that we see every

1091
00:44:37,472 --> 00:44:38,289
day in practice

1092
00:44:38,742 --> 00:44:40,590
and the road forward in improving

1093
00:44:41,121 --> 00:44:42,256
implementation of these therapies

1094
00:44:42,803 --> 00:44:44,390
and we've really been able to hear your

1095
00:44:44,390 --> 00:44:46,532
passion for the field in this discussion today

1096
00:44:46,532 --> 00:44:48,277
and great to see how you got involved

1097
00:44:48,277 --> 00:44:50,657
in generating the evidence for these therapies in

1098
00:44:50,657 --> 00:44:52,744
it. Really makes me excited as I start

1099
00:44:52,744 --> 00:44:55,775
cardiology fellowship and think about all there is

1100
00:44:55,775 --> 00:44:57,690
to still discover and learn within the field

1101
00:44:57,690 --> 00:45:00,481
and what therapeutic advances to lie in the

1102
00:45:00,481 --> 00:45:00,641
future.

1103
00:45:01,293 --> 00:45:03,124
For the last question for tonight, this is

1104
00:45:03,124 --> 00:45:04,955
something we ask all of our guest experts

1105
00:45:04,955 --> 00:45:07,264
on the show. We'd love to hear more

1106
00:45:07,264 --> 00:45:09,587
about what makes your heart flutter about heart

1107
00:45:09,587 --> 00:45:12,606
failure and cardio metabolic disease. It's a great

1108
00:45:12,606 --> 00:45:15,465
question, Gu, and to me, it is the

1109
00:45:15,465 --> 00:45:17,475
well of data and evidence

1110
00:45:18,023 --> 00:45:21,307
we have to guide care in cardio kidney

1111
00:45:21,364 --> 00:45:21,864
metabolism

1112
00:45:22,239 --> 00:45:23,909
and specifically in heart failure.

1113
00:45:24,959 --> 00:45:28,145
I think across disciplines of bio we have,

1114
00:45:28,543 --> 00:45:31,251
1 of the strongest evidence bases in heart

1115
00:45:31,251 --> 00:45:33,402
failure, and 1 that we should be proud

1116
00:45:33,402 --> 00:45:34,851
of and in fact,

1117
00:45:35,806 --> 00:45:37,182
many therapeutic areas

1118
00:45:38,116 --> 00:45:40,984
can't say the same in terms of the

1119
00:45:40,984 --> 00:45:42,918
survival advantages that are therapies

1120
00:45:43,308 --> 00:45:44,500
can afford our patients.

1121
00:45:45,135 --> 00:45:47,700
And so what excites me is the ability

1122
00:45:47,756 --> 00:45:51,568
to actually influence a disease course of a

1123
00:45:51,568 --> 00:45:55,012
patient population. And while we can't offer perhaps

1124
00:45:55,012 --> 00:45:57,887
a cure to a person with heart failure,

1125
00:45:58,527 --> 00:46:01,670
I think today, if implemented in a timely

1126
00:46:01,804 --> 00:46:02,701
and appropriate

1127
00:46:03,074 --> 00:46:03,470
manner.

1128
00:46:04,105 --> 00:46:08,174
Guideline directed medical therapies have a full potential

1129
00:46:08,324 --> 00:46:11,378
to completely change disease trajectory

1130
00:46:11,995 --> 00:46:13,373
and be able to

1131
00:46:13,910 --> 00:46:16,006
prevent or even delay

1132
00:46:16,398 --> 00:46:19,438
clinical events to the point where most people

1133
00:46:19,732 --> 00:46:21,502
can live very fulfilling

1134
00:46:21,875 --> 00:46:23,804
lives ahead, and that is

1135
00:46:24,114 --> 00:46:26,755
something that really really generates a lot of

1136
00:46:26,755 --> 00:46:30,054
excitement and rule in contributing to this field

1137
00:46:30,355 --> 00:46:33,074
and partnering with individuals just like yourselves,

1138
00:46:33,729 --> 00:46:34,229
in

1139
00:46:34,766 --> 00:46:36,362
combating heart failure at large.

1140
00:46:37,160 --> 00:46:39,155
Thank you so much for sharing. I've really

1141
00:46:39,155 --> 00:46:41,803
enjoyed every minute of this discussion and can't

1142
00:46:41,803 --> 00:46:43,558
wait to listen back to catch all of

1143
00:46:43,558 --> 00:46:45,494
the pearls that I may have missed and

1144
00:46:45,552 --> 00:46:47,945
we really went through a really thorough of

1145
00:46:47,945 --> 00:46:50,657
discussion of S inhibitors and their clinical trial

1146
00:46:50,657 --> 00:46:50,976
data.

1147
00:46:51,469 --> 00:46:52,980
And I think I'm also looking forward to

1148
00:46:52,980 --> 00:46:54,729
see how we can make these drugs affordable,

1149
00:46:55,126 --> 00:46:57,670
accessible and equitable like you mentioned and work

1150
00:46:57,670 --> 00:47:00,215
on their implementation, so we can change disease

1151
00:47:00,215 --> 00:47:00,612
trajectory.

1152
00:47:01,262 --> 00:47:03,481
And we're so grateful at Cardinal to benefit

1153
00:47:03,481 --> 00:47:05,803
from your wisdom. You've really been a pioneer

1154
00:47:05,937 --> 00:47:07,918
with all your prolific research in the field.

1155
00:47:08,409 --> 00:47:09,835
So it's been such an honor to learn

1156
00:47:09,835 --> 00:47:11,682
from your experience as a cardiologist

1157
00:47:12,054 --> 00:47:14,194
and a clinical trial list in this area.

1158
00:47:14,670 --> 00:47:16,514
So thank you so much for taking out

1159
00:47:16,514 --> 00:47:18,514
the time to teach us all and to

1160
00:47:18,514 --> 00:47:19,634
teach your audience tonight.

1161
00:47:20,674 --> 00:47:22,994
Thank you all. It's it's been a pleasure.

1162
00:47:23,234 --> 00:47:25,255
It's been a great discussion, and

1163
00:47:25,569 --> 00:47:29,505
Most importantly, I want to share all our

1164
00:47:29,883 --> 00:47:32,460
appreciation to what you do for

1165
00:47:32,852 --> 00:47:35,253
medical education as a whole in cardiology,

1166
00:47:35,704 --> 00:47:38,556
it has definitive impact, and I think it's

1167
00:47:38,556 --> 00:47:39,349
really, really important.

1168
00:47:39,998 --> 00:47:40,713
Thank you so much.

1169
00:47:42,459 --> 00:47:44,785
Thanks for tuning into another cartoon

1170
00:47:45,159 --> 00:47:48,016
episodes. The audio editing for this episode was

1171
00:47:48,016 --> 00:47:51,716
performed by me. Mary Bar da. I'm Cardinals

1172
00:47:51,853 --> 00:47:54,744
academy fellow in house toxic and the resident

1173
00:47:55,201 --> 00:47:58,160
at Hack Again health. Check out of the

1174
00:47:58,160 --> 00:48:00,647
episode page for show notes and references.

1175
00:48:01,180 --> 00:48:03,563
If you found this episode or the show

1176
00:48:03,563 --> 00:48:06,389
informative please consider subscribing to cardinals

1177
00:48:06,765 --> 00:48:09,795
on your favorite podcast platform and leaving us

1178
00:48:09,795 --> 00:48:12,266
a review. It really helps us spread the

1179
00:48:12,266 --> 00:48:16,046
word and further our goal to democrat cardiovascular

1180
00:48:16,661 --> 00:48:19,449
education. Finally, this podcast is not meant to

1181
00:48:19,449 --> 00:48:22,728
be used for medical advice. The View expressed

1182
00:48:22,728 --> 00:48:26,172
on our show inside do not reflect opinions

1183
00:48:26,627 --> 00:48:28,616
or policies of our employers.

1184
00:48:29,188 --> 00:48:30,088
All cardinals

1185
00:48:30,545 --> 00:48:33,576
contest his plan produced and reviewed solely by

1186
00:48:33,576 --> 00:48:37,404
carter's. Stay tuned for more engaging in conversation

1187
00:48:37,404 --> 00:48:37,904
and

1188
00:48:38,361 --> 00:48:41,553
exploration. In our upcoming episodes. And now it's

1189
00:48:41,553 --> 00:48:43,775
time to make like an S split.