Kevin Sheth: Innovation Toward a Healthier Brain

Transcript

Harlan Krumholz: Welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We’re physicians and professors at Yale University. We’re trying to get closer to the truth about health and healthcare. Our guest today is Dr. Kevin Sheth. But first, we always check in on current hot topics in health and healthcare. And Harlan, I know this is probably a different topic for us to talk about, but what do you have for us?

Harlan Krumholz: Yeah, this has been a tough week for me. I have the most wonderful mother-in-law, loving, kind. And she’s probably in her last days now. She had a major heart attack just a couple days ago and I’ve just, in the last 48 hours, experienced as a family member the healthcare system. Every time we experience the healthcare system, it teaches us a lot. And I don’t want to make this about me, but I did think ... I would tell you some of the amazing, marvelous things I saw and some of the things that weren’t so marvelous. And what it teaches us about healthcare a little bit.

She woke up at five in the morning, had fallen, and she lives in assisted living, so she pulled a string in her room. And before she knew it, she was taken to Newton-Wellesley Hospital. She’s in Boston. They don’t do primary PCI and they immediately diagnosed a—

Howard Forman: Just explain for them what PCI is because I think—

Harlan Krumholz: Oh, gosh, thanks. Yeah.

Howard Forman: Yup.

Harlan Krumholz: Well, let me just say, she took the hospital and they diagnosed a certain heart attack that would do better if they immediately put in a stent and did a percutaneous coronary intervention, where they open the artery again. These are the kind of heart attacks where there’s an immediate blockage.

So I’m going to go with a lowlight and then a highlight. Lowlight is that she’s in this community hospital. I spent my career trying to make sure people could get treated quickly. And it’s like a fumble. They call Beth Israel to transfer her. They don’t accept primary PCIs because their ICU is full. So they’ve got to call around. Meanwhile, minutes are passing. Then they’re able to finally get her accepted at Mass General, but it’s like our system should be set up, so if somebody comes in within a constellation of hospitals with referral patterns, you know immediately what hospitals are available, where to send somebody. So that was certainly a lowlight.

On transfer, she developed shock. So it’s taken so long, she developed a shock. A highlight was that the interventional team, the cardiologist who took care of her here, were wonderful, kind, capable. And it was very difficult. She had a long procedure, and it took—

Howard Forman: And you’re physically at Mass General right now.

Harlan Krumholz: I was in Boston for a meeting, so I was able to come right over. And... so that was a highlight. And it just reminds us, I think, and we all see this every day, but the kind of dedication, and real commitment, and excellence among so many people in our profession who, when called on to do something, they really deliver. And we see this all the time, of course. But when you’re the patient’s family, it means so much more.

Then a lowlight was, you wouldn’t believe the absence of communication sitting in the waiting room. There was no effort to update what’s going on. The procedure takes a long time. When I was at Yale New Haven with my wife, who needed elective surgery, they’re texting me every 15 minutes, “Hey, this surgery is this, this is what’s going on.” Here, it was like six hours of no communication, essentially, having to beg for information. And then she got transferred to the CCU [cardiac care unit]. It was like entering a different country.

A highlight was, the CCU was incredible, marvelous. It’s the spirit, the culture. It was like you had crossed from one land to another. The procedural piece where there was a paucity of information and a lack of humanity, honestly. Even though I’m sure there were people there who were dedicated and hardworking, but they didn’t have the work processes to make sure that people were in the loop and they felt comforted and supported and knew what was happening. And then you walked into the CCU and, for some reason, they had fostered a culture of positivity, communication, embrace.

And we’ve seen that, too, in our CCUs and ICUs, there’s a similar kind of spirit. And it’s just so interesting to see how you’re unable to harmonize that kind of spirit across the entire institution. And so we’ve been struggling last couple days, just to finish this, with... she’s on maximum therapy. She really never wanted a lot of aggressive end-of-life care, but now here we are and trying to make these very tough decisions. But it just reminds me, in an era of AI or technology and cost and policy, you and I get embroiled in these conversations, the kind of humanity that can exist within the healthcare system, when teams are actually trying to help you struggle with the most human of problems, when to start, when to slow, how hard to go... it’s breathtaking to see that kind of excellence and commitment to patient care that ... you know, so those highlights will stay with me.

And then the lowlights, I’ll try to remember. Even at our own place, how can we avoid that kind of thing? But, yeah, that’s what’s going on, so it’s been hard. But the nice thing is the whole family pulled together and it’s been a moment to try to support each other.

Howard Forman: Yeah. All I can say is having been a patient for like 63 days in the hospital in my life, I have a long—

Harlan Krumholz: Oh my God. I forgot that you endured that.

Howard Forman: Yeah, I have a long list of highlights and lowlights. And I excuse most of the lowlights because I see them. It’s so easy to see how they happen. It’s a fast-paced world where everybody seems focused on one thing and not all things. And it’s easy to imagine how the family becomes a casualty of that.

Harlan Krumholz: But the highlights are breathtaking. And I think our goal really needs to be to foster those highlights. And again, in medicine, we so much talk about mortality, hospitalizations, events, but this experience that people have is also enduring and so important. And we all carry it with us afterwards because there were such consequential decisions and issues. And it’s such an important part of care, how we experience it.

Howard Forman: I’ll just say as a last point, because I think our listeners should know this, your work has dramatically not only reduced door-to-balloon time, the treatment time for patients like this, but you’ve also dramatically narrowed the variation that exists while reducing it. So what you’re talking about happening at Newton-Wellesley and other places is much more of an aberration today than it was 30 years ago. And you’ve shown this.

Harlan Krumholz: Well, you’re so kind, Howie, and it was so many people. But let me just tell you, the thing that did go right about it was once they made the transfer, there was no stopping in the emergency department, which went straight to the cath lab. I mean, those processes were very much in place. It was just that little bit of fumble at the beginning. It’s just, every minute counts.

Howard Forman: Yes.

Harlan Krumholz: And when you’re trying to, “Oh, can’t go here and then need to call somebody else,” just shouldn’t happen that way. But there’s a lot still that they did right. And just being able to go straight to the cath lab without any pause, that was good. That was good.

All right. Hey, let’s get on to Kevin Sheth. Terrific guest this week and I didn’t want to miss it. So let’s go.

Howard Forman: Dr. Kevin Sheth is the Vice Chair for Clinical and Translational Research in Neurology and Neurosurgery at Yale and a founding director of the Yale Center for Brain & Mind Health. He practices as a critical care neurologist and as a professor of neurology and neurosurgery at the Yale School of Medicine. As a chief medical advisor for Astrocyte Pharmaceuticals, Dr. Sheth collaborates with pharmaceuticals and medical device startups to develop innovative solutions in neurological disease.

His research focuses on advancing therapies for acute brain injury, including stroke and hemorrhage, and he has served as principal investigator or co-principal investigator for eight multicenter clinical trials in stroke. He received his bachelor’s degree in neuroscience from Johns Hopkins University and earned his medical degree from the University of Pennsylvania School of Medicine before going on to complete his neurology residency, as well as his fellowship in vascular neurology and neurocritical care at Massachusetts General and Brigham and Women’s Hospitals.

We’re really excited to have you join us today. I want to just highlight, though, that you are a true scholar with a large accumulation of research and contributions to the neurology and neurosurgical literature, and you are an innovator, as we mentioned. And we’re going to go into some of those innovations that you’re involved with, but I wanted to hear from you, you work really at the translational junction with patients, like how do we take science and make it applicable to patients. And one of your startups is Alva, which is a company that is trying to help patients detect stroke at the earliest possible moment. And I thought maybe that would be a good launching-off point for you to just discuss both the challenges of innovation, but also the importance to identify stroke early.

Kevin Sheth: Yeah. First of all, thanks for having me on the podcast. Ultimately, the answer, I think, that any question you’re going to ask from my perspective is just about people, actually. And one of the reasons I love this podcast is because you’re hearing the stories of both individuals and the work they do. It’s about people. We’re taking care of patients and trying to make patients and individuals’ lives better, longer, healthier. And so it’s about people. It’s all about people. I mean, it’s really that simple, in my view.

Alva Health represents exactly what you’re talking about, which is the idea of using innovation and technology to bring to bear on very common and important and otherwise devastating problems. So the fundamental problem in stroke is that we actually have highly effective therapies that have been available for decades actually, which is to basically break open blood clots in the brain and try to prevent some of the disability that people might have when they’re having a stroke. The challenge fundamentally is that when you think about things that get someone to call 911—for any medical condition, actually—one of the most powerful motivators is pain, actually, pain from appendicitis, pain from a heart attack, pain from a broken bone, whatever it may be.

Most strokes actually don’t cause pain. Strokes are also confusing because neurological symptoms are confusing. And sometimes the disability that results from strokes prevents you from picking up the phone and calling 911. So you can imagine all of those things converge to move people in the opposite direction, not engaging with the health system immediately. So what’s happened over decades, I would say the last 20 years, one of the exciting things is, is to try to bring the medical system closer to patients. And the way we’ve done that is we say, “Okay, we’ll have stroke doctors in the emergency department.” Okay, what we’ll do is we’ll set up a telemedicine system so that stroke neurologists can work with ER doctors in the community as patients present there.

We’ve even started to put in CT scanners into ambulances so we can diagnose stroke in the field, taking the system closer to the patient. But actually, the realization that we came to many years ago is that if you had a blank sheet of paper, what you would really try to do is just turn the whole system upside down and start from the patient in the moment that a stroke started because you had these barriers. And how would you do that? Well, you would want a passive system to diagnose stroke or any medical condition in real time automatically, actually. You would want to flip the whole thing on its head. So that was the fundamental concept, and that’s what Alva’s trying to do.

Howard Forman: And just as a quick follow-up, because I think it’s a nice story for Yale, how did you come to meet Sandra Saldana, who is our EMBA graduate from about 10 years ago?

Kevin Sheth: Yeah. So what ended up happening is, I had this idea, which I’d been carrying around in my head, actually, probably for five years before that and training in my early years as a faculty member. Finally, really, there was an engineering pitch night just about any concepts. So I had a fundamental idea of how, once you had this idea, it basically became an engineering problem, a sensitivity, specificity, detection problem, if you could diagnose a stroke and we could get into that.

And basically, so I went to an engineering pitch night where I met an engineer here at Yale that was also interested in neuroscience. We teamed up. And then basically shortly after that, we started talking to anybody that we could. At the time, what was the precursor for Yale Ventures, and then over at the Yale School of Management, where we met Sandra, who had a PhD in cancer biology but was really interested in attacking a hard problem through innovation. She was a recent graduate and very involved in the ecosystem. And she said, “I’m the perfect person to be your CEO.”

Howard Forman: That’s awesome.

Kevin Sheth: We said, “No way, you’re not qualified. You have no experience.” We talked to several other people, but for a number of reasons, her perseverance, her tenacity, her ambition, she became our CEO, and she’s done an incredible job.

Howard Forman: That’s great.

Harlan Krumholz: What a great story. So many people go to these hackathon-like events and try to meet up with people who might be like-minded to be able to find a group and make that go. That’s amazing.

Look, Kevin, you’re one of the stars at Yale. We’re so lucky to have you here. You have such a positive energy. You’re one of the few people I’ve seen who can really combine outstanding clinical acumen and care, real care for patients, an ability to teach, real accomplishment, and research. And I’ll say the fourth one. We often talk about these three-legged stools, but the fourth one is really administration. You execute. You know how to execute. You’ve been a big part of this new initiative we’re going to have to emphasize neuroscience at Yale and at Yale New Haven Health.

I was wondering, as you reflect, and I think you’re in your prime, your best work is still ahead of you. You’ve been so creative so much and accomplished. But as you’ve looked at what you’ve done, what are you most proud of? What’s a thing, if you could name one thing, that you say like, “I’ve done so far that really gives me the most pride?”

Kevin Sheth: First of all, Harlan, that’s the tallest praise one could ask for, especially the part about bringing it back to patients. So I really appreciate that. The one thing is always a tough question, but I would say if there’s one thing, one common thread, and one thing I’m proud of, at least when it’s gone well, has been working with other people. And I can’t think, I have been unable my entire career to think about how to tackle an important problem without working with other people, without collaborating.

And so I would say if you say one thing, one thing is working across disciplines at the borderlands, which is sometimes a lonely, tough space of fields but where the most exciting stuff happens. And I think the examples where that has gone well, both well in terms of the actual collaboration but in terms of execution and actually a material deliverable, that to me is the most satisfying.

Harlan Krumholz: Do you think you were always predisposed of that because your personality is so positive, but it’s actually something I’ve often thought we want to teach, we want people to develop skills in, because sometimes our enterprise, our academic environment, reward stars and actually tells people, “Wow, you’re collaborating? No, you have to ‘show independence.’ You have to separate from those other people you’re working from, especially any senior people, because you have to ‘show your independence.’”

So we’re actually pushing people apart. We’re saying any one research group should never get so large without people down sprouting out. And the idea that we can actually put together teams where everyone’s getting the credit they deserve but taking pride in the accomplishment of the whole is not something that comes natural to an environment that wants to name a Nobel Prize winner, a single Nobel Prize winner, a single person who came up with an idea. I mean, my experience, it never happens that way. I mean, all great accomplishments take a whole team. How do you think about that as you role-model for others. What we should be doing?

Kevin Sheth: Well, thanks for asking about this. I mean, I think I’ve been trying to think about this for a long time. And a couple of answers, and I think not false humility, but just the truth. First of all, I mean, I think it’s ... I would say the inverse. If you’re showing me ... and I know, that has been, I think, the historical piece for many decades; it’s moved a lot, but not nearly as much as it could. The idea that it was one molecule, one person, one lab. I mean, that has been the historical context.

And I think, show me one person in one lab, and I will show you a problem that’s not that important, actually. I’ll go out on a limb and say that. I think anything that really matters, by definition, if you need to land on the moon, you need a team. There’s no getting around that. So that’s number one. Number two, what I would say is that no false humility here. I don’t know that I’m capable of solving anything that matters by myself, even if I’m an expert in something. So I’m actually more interested in solving big problems. And so you need to work with others.

Number three is what I would say is that, Harlan, you mentioned the Nobel Prize thing as an example, which totally makes sense. Can you name the last 10 Nobel Prize winners? I don’t think you can. Maybe you can, but I’d be surprised. And so once you realize ... I mean, just to me, that kind of a question, it should give all of us, all of us have ego, but it should give us instant humility, because if you can’t even name the last 10 or the last five Nobel Prize winners, the pinnacle, there’s no better evidence to just say that when you do that, it’s yesterday’s news. It’s going to be yesterday’s news right away. Armed with that humility, it should unlock you to say, the only durable thing is going to be whether or not you really delivered on something.

The final thing I’ll say is, is that I didn’t think I was going to really succeed by being the smartest math guy in the room or ... So early on in some of my projects ... Actually, there was a New England Journal perspective about this a few years ago. It was called the peer buddy swimming system. And basically, in some of my projects, I pulled in a co-PI or a partner who was a peer, actually. And everybody would say, “Well, whose credit? Who’s really driving all of these things that mattered?” But the reality is, I got a buddy, actually, that was in the project! There was more than enough credit to go around and a “grow the pie and split the pie” rather than “split the pie.” And we actually got more done. It was more fun, and it’s totally the way to go.

The multi-PI system, for example, at the NIH, huge step forward for team science, but we all know that the idea of giving just the contact PI and their department and their institution the credit totally does not facilitate team science. And every time we say, “Oh, we’re number X on the rankings at any level,” actually, we reinforce, I think, the system we’re not really trying to reinforce. And so I think that comes down to a leadership thing.

Howard Forman: I want to take a step way back and ask you about how you got so interested in neuroscience so early on, because there’s a lot of people that do a neuroscience major and very few of them go on to be specialized as you are. What first drew you to the field, really, at a stage that most people probably don’t even understand what neuroscience is?

Kevin Sheth: I didn’t understand what neuroscience was. You know, the ’90s were the decade of the brain—I think officially, there was an act of Congress. There’s a “decade of the brain.” There was massive investment that was made. I was an undergraduate at Johns Hopkins, and at the time, as became quite prevalent later, I was one of the first neuroscience majors at Hopkins, but I didn’t go in thinking that I would be a neuroscience major. Actually, I was really interested in people. I took psychology courses, which I loved. I think I was more discreetly organized in terms of being quantitative, and I liked the tangible part of being molecular.

So I started taking those classes as a result, but what drew me in was the psychology in the first place. And I got really interested. I’ll tell you, when I went to medical school, I thought that was all nice, but if you were to just look at me from central casting at the time, and I looked at myself, I said, “Oh, I’m going to be a cardiologist,” and for a lot of reasons. But I’ll tell you, when I went into the neurology clerkships, what I saw was still this era where you were diagnosing people, there wasn’t a lot to offer. And to me—that drew a lot of people away—to me, I said, “This is a huge opportunity. These are important problems. There’s no way we’re going to go the next 50, 100 years.”

So exciting stuff is going to happen. And explaining to patients just these things that are actually not that complicated, but seem mysterious, that was fun. You could actually deliver value there. So when I saw those things, and I saw the people, my teachers doing those things, I said, “This might be pretty cool.”

Harlan Krumholz: So one of the things I want to jump in with is, there are few people that have such a view of the future as you do. You’re always thinking about what’s next and what’s out there, and also, you have a curiosity that’s infectious. There’s almost no field moving faster than neurology and neuroscience. Project out for me five, 10 years, I mean, what’s going to be the difference? I mean, I have a hunch that it’s going to be very different than what it’s been for the last 50 years, but give us a glimpse of what you think is ... what are going to be the biggest differences in the next 10 years in neurology?

Kevin Sheth: I can’t ... What’s the famous baseball player quotes about prediction?

Harlan Krumholz: Yogi Berra. Yeah.

Kevin Sheth: Yeah, yeah, Yogi Berra quotes. I got to be careful about that.

Harlan Krumholz: Yeah.

Kevin Sheth: But I’ll tell you, having said that, here’s what I think. Not that the 21st century is not, but if the 20th century was about protecting the heart, then I think the 21st century is going to be about preserving the brain. It’s not about ... you can’t have aging and healthy aging without having healthy neurological aging. And that’s why we’re in large part, not exclusively, but talking about not just lifespan but also health span. And, obviously, we all care as we age about our brain and to live full, healthy lives.

And I think what we’re going to see, I hope we see, and I think we are going there in neurology, is this idea of population and patient-level screening of risk factor–based identifications of patients, and using and leveraging technology and molecular diagnostics to do so in a way that’s risk-stratifying and -identifying earlier, pre-disease—disease, early disease, and pre-disease. In some ways, I think what we’re doing for cardiovascular health today, and doing better and better every week, I think we’re going to start doing it a step change for neurology.

Harlan Krumholz: But tell me what that looks like. You go to your primary care doc or what? You’re just going to Walgreens or CVS, and you’re just getting a panel that’s saying ... and then what’s going to be actionable about it? What’s that going to change for folks, do you think?

Kevin Sheth: Yeah. Well, first of all, Harlan, let’s just look at current state. If you’re 55 years old today and you go to see your primary care physician for a routine checkup, what are we doing today for the brain? I mean, I would argue absolutely nothing.

Harlan Krumholz: Nothing. We’re not even doing a baseline cognitive assessment, really.

Kevin Sheth: It watches you when you walk in the room and walk out of the room, and that’s about it, actually. Yeah. Now the question is, that doesn’t mean you should do more because what does doing more lead to? And I think that’s, in a sense, the question that you’re asking. And I think that’s the piece we don’t exactly know.

I do think we have some hints at the future. We do now have hints that, number one, actually, we are able to use plasma-based markers that are with very high operating characteristics, identifying people that are vulnerable to brain-specific vascular decline for brain vascular independent decline, neurodegenerative disease, Alzheimer’s. Just within the last one to five years, there’s been very excited data from multiple cohorts around the world that are showing this. And I think we’re going to start ... and we’re already seeing that in digital health as well. So that’s number one.

Number two, those programs are setting up now the window for therapeutic interventions, some of which may be early disease or pre-disease. We’re seeing this with giving vaccines potentially for multiple sclerosis, even in pre-MS. And there are trials now that are testing, for example, some of these anti-amyloid therapies. There’s been a lot of controversy about that and ... actually, even early or pre-symptomatic disease and Alzheimer’s. Whether or not those trials work, it’s going to set the stage for other interventions like that. So the case has to be proven, that’s the work to be done.

The last piece that I’ll say about that, Harlan, is that I think there’s a bigger question, not just for neurological health, broader health, as to whether or not this happens in the clinic. I think for a variety of reasons, platforms and access, this may be happening even adjacent or outside the clinic direct to patients. That’s where I think we’re going to go.

Howard Forman: I want to ask ... Because your career has coincided with dramatic process changes around stroke. And you alluded to this before when you talked about being able to do a CT scan in an ambulance and so on, but we do, and I say “we,” because it’s a lot of different specialties, a lot to get a patient quickly through the clinical encounter, the imaging diagnosis and treatment when appropriate for our patients with stroke right now. Are we doing it well enough? Are there things we could be doing better? What’s the next step there? Because while I agree that the better opportunity is to prevent this, we have a lot of strokes that we deal with.

Kevin Sheth: Yeah. We certainly have a lot to do with prevention, but I think if I understand your question, you’re asking me, do we have significant places to make step change improvements in acute stroke? Is that correct?

Howard Forman: Correct.

Kevin Sheth: Yeah. The answer is, yeah, there are a lot of things that we do well, we can do them better. I think it’s somewhat incremental if you really take a step back, but there are improvements. I will say one area of improvements is that there continues to be dramatic variation when you look at rural/urban environments, different levels of hospitals, et cetera. So I think to get some of these proven therapeutics like endovascular thrombectomy, taking someone to the cath lab and taking a blood clot out, I mean, that whole system works really well at some places, not as well at other places, and that’s just in the United States. So globally, even more so.

So I think we know how to do those things. We have to implement them. There’s a lot of work to be done there. But I would say two areas there. Number one, we don’t do that nearly as well for brain hemorrhage, actually, and I think that’s a big frontier. And there are things that are now proven that are not implemented. So we could talk about the value of implementation and quality of care. I mean, this is work Harlan did 25 years ago and others. So I mean, I think we can do this.

And the second thing that I think is, I think we are going to see more technology and diagnostics go closer to the patient setting. So I think we’re going to do more in the pre-hospital space. For years, I think all of us were very cynical and nihilistic about high-quality blood tests in an ambulance that could differentiate an ischemic stroke for hemorrhagic stroke, but I’m willing to go out on a limb in saying that is going to come online. It may not be by itself. It may be in combination in a multimodal way with other diagnostics, but we do nothing in the field right now in the ambulance, even though we have all the technology and diagnostics. I think that’s going to change.

Harlan Krumholz: I have a quick question for you about brain wellness. So lots of people are talking about actively training and protecting brain health through cognitive exercise and a whole range of other things. A whole range of other things make a lot of sense, lifestyle factors like physical exercise, quality sleep, stress management, social connections, all that stuff should be recommended anyway. But some people are being recommended to do things like learning new skills, learning a language, doing puzzles.

What’s your view on whether there’s really evidence that people should be exercising their brains in the same way they exercise their bodies in order to maintain the cognitive function and wellness? Does it create a cognitive reserve? Is there resilience generated by that or is that a leap of faith right now until we actually generate more evidence?

Kevin Sheth: Yeah. And Harlan, in answering your question, I’ll also say the somewhat artificial distinction potentially between reserve and delaying health and enhancing health, actually, but we won’t go there. I would tell you, and this is just my sense of the field, I don’t know that we have in hand yet high-quality information to suggest that what you just said is true. I’d like to believe it. I think there’s lots of good biological plausibility for it, but in terms of the evidence, I’m not sure that it’s there. I would buy—

Harlan Krumholz: So you’re not prescribing puzzles yet?

Kevin Sheth: I’m not prescribing puzzles yet. But I will tell you, for a number of different reasons, I mean, I’ll say this here, I always wanted to as a kid, and I never had the opportunity to pick up a musical instrument. I’m not musically inclined, but I was really ... like a lot of people. And a few years ago, I started taking piano lessons. And I wonder, I wonder about whether or not it’ll be good for my brain, but I’ll tell you, it is good for my humility and my soul, and that’s a reason to do it.

Harlan Krumholz: That’s great. I love that. That’s so great to hear.

Howard Forman: That is great. Well, look, I know we’re getting to the end. I want to just ask you one final question. You’ve been involved in innovation on multiple projects, and we’ve mentioned a couple of them, but there are even more. Do you want to just say a word about how difficult innovation is or even how easy it is? I mean, whatever, in terms of what it’s been like for you, because I feel like sometimes people only see home runs, and they don’t realize that a lot goes into that.

Kevin Sheth: Yeah. I don’t know how many home runs we had. If you look at the batting average, I mean, it’s probably like 100 or 150. I mean ... so it is one of these, you want to pick the best stocks you can, but you got to pick a bunch of tries to try to do it. I think the way I look at the innovation thing is that I don’t believe that people should do something different for the sake of doing something different, but I don’t think it’s possible very often outside of things like implementation to really chart a new course by doing the same thing.

And the way I looked at it, and it goes back to the earlier conversations about teamwork, and credit, and humility, and these things, I mean, I think I’ve thought, “I just want to get my hands on the craziest, biggest-bang ideas that we can possibly get our hands on to take a crack at it.” And that’s just been the approach because doing the opposite, you know at the beginning, the best-case scenario is incremental. And that just seems like a lot of waste of time, and not fun, and not a good use of the investment that’s been made in me by others.

Howard Forman: Well, we need people like you to take these chances and make the effort. We just appreciate everything you do.

Harlan Krumholz: What a delight to have you on, Kevin. You’re such a ... it’s incredible.

Kevin Sheth: Thank you so much.

Harlan Krumholz: Thank you. This is a great conversation and we look forward to continue to work with you and ...

Howard Forman: Many years to come.

Harlan Krumholz: ... also, keep watching what you’re doing. Thanks.

Kevin Sheth: Thank you both. I look up to you both, and I really appreciate the invitation. Thank you.

Howard Forman: Thank you. Oh, that was great. That was great.

Harlan Krumholz: Yeah, Kevin Sheth. What a terrific guest. He’s a great communicator.

Howard Forman: Yeah.

Harlan Krumholz: So smart and humble. This is terrific to have him.

Howard Forman: Absolutely.

Harlan Krumholz: But let’s ... look, this is one of my favorite parts of the show is to hear what’s on your mind this week. So what’s going on, Howie?

Howard Forman: Well, this is one of your topics, but a different angle. So for much of the last three years, the obesity drug news, the GLP-1 news has mostly been about efficacy, safety, and expanded applications. And you, Harlan, and many of our guests have done an incredible job highlighting the numerous benefits of GLP-1 drugs in certain high-risk populations, weight loss, diabetes, cardiovascular disease, and myriad other related and unrelated conditions.

The risks from the drugs have been relatively muted, but we do know that they are not without side effects, and at least at the moment should require substantial consultation with a physician. The last few months have seen a different phenomenon taking shape. Prices are finally falling, competition is increasing, and oral forms of these effective injectables are becoming increasingly available and effective. Novo Nordisk, the maker of semaglutide, Wegovy, and Ozempic, cut their list prices by 50% and more recently. While that may not have a huge impact because it’s the list price, since that doesn’t necessarily change the retail or insured prices, it still sends a signal that the sky is not the limit for these drugs.

And Wegovy oral version is now roughly $200 per month without insurance, dramatically lower than earlier prices when only injectable doses were available. And now Walgreens has announced a new program to provide telemedicine consultations for obesity, ultimately also selling GLP-1s at a similar steep discount, competing directly with Hims & Hers in the market for approved drugs. Walgreens will be charging $49 for a consultation with a physician or nurse practitioner with the usual starting doses of Wegovy being $149. This would be less than $200 for the first few months and possibly less once you no longer need the physician or nurse check-ins.

The options now available for GLP-1s are vast. They’re the mainstream companies like Hims & Hers and Ro, and now the even more mainstream like Walgreens. And there are a lot of compounding companies offering GLP-1 knockoffs or unauthorized compounded versions. And there are medical spas in other infusion centers that will offer some version of GLP-1 under the least regulated circumstances. To the average consumer, I’m not sure there’s always a difference. So I’m just raising a few concerns here.

First, are people getting the drug they think they’re getting? Are they getting appropriate medical advice? And do we have the systems in place to monitor real-world effectiveness in this new wild world of GLP-1s?

Harlan Krumholz: Well, Howie, you’ve hit on such an important point. I have to say, I applaud the increased access. In the beginning, it was just people of means, people who had resources, people who had really good insurance. We’re in a position to be able to do this. People who are living week to week on salaries with high deductibles—

Howard Forman: It’s crazy. It was a thousand a month or more.

Harlan Krumholz: We published an article that showed this discordance between the people who needed it and the people who could probably afford it, and how this was going to maybe contribute to disparities in health. I think you’re raising a really good point, though, which is, there’s an art to the use of these. There’s an important consent process, but there’s also a slow titration. And I’ve noticed that some patients, they don’t actually start low and go slow.

Howard Forman: Right.

Harlan Krumholz: They’re actually eager to get the weights off and are going at much higher levels. And that’s where I think you really get into trouble. And there are things to watch out for. There’s also not enough research, I believe, in the real world to say exactly what are people experiencing, what can you attribute to the drugs, because there’s a lot of hearsay out there about these drugs.

So you know me, I’m actually very pro about them. They lower blood pressure by more than most antihypertensives. They lower inflammation. They certainly improve cardiometabolic biomarkers. And almost every study that’s looking at cardiovascular outcomes is at least suggesting that there’s all benefits going in the right direction. And for heart failure with preserved ejection fraction, heart failure when your heart is actually squeezing normally, but the pressures are still elevated and you get in trouble for which we had almost no treatments, these drugs seem to help people feel better.

And so I’m reigning enthusiast for the potential for these to really turn the corner on us. And it’s not about how you look, it’s really about your cardiometabolic health at least, let alone orthopedic health and others, but there’s so much more to learn. You know what’s so amazing to me, Howie, is we still don’t exactly know how these drugs work. And so there’s a lot more to learn. I applaud the fact that people are going to have an easier access, but like you said, you need to make sure they have access to healthcare, too, in order to help them on this journey.

Howard Forman: And I don’t want to exaggerate this because I get to see unique cases in the ER, but there is a lot of presentation to the ER from patients that are coming onto these drugs and experiencing side effects, not lethal side effects, not even side effects that may mean they’re going to come off the drug, but it is important to monitor patients. So when patients are experiencing such severe nausea or abdominal pain as to warrant coming to the emergency room, it makes me think like you should at least have a primary care doctor aware of what’s going on with you.

Harlan Krumholz: Yeah, that’s right. And I just wonder for many of those people, whether or not ... what routine did they follow? Did they follow best practice or not? So, like you said, it’s the Wild West out there, lots still to learn, lots to optimize, but it’s exciting to have drugs like these that seemingly everything goes in the right direction when it goes right, when it goes right.

Howard Forman: That’s right. And the price is coming down. We will see more access and there’s going to be new drugs as well.

Harlan Krumholz: And many, many, many drugs in the pipeline.

Howard Forman: Yeah.

Harlan Krumholz: Well, thanks, Howie. I really appreciate you sharing. You’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So how did we do? To give us your feedback or to keep the conversation going, email us at health.veritas@yale.edu or follow us on any of social media, including our Instagram account.

Harlan Krumholz: Yeah, we look forward to feedback. You can talk to us directly or it’s better if you leave comments, helps people find us. And you should know our numbers are going up every week, Howie. It’s really great.

Howard Forman: We’re very happy to have more listeners, and it’s great to talk to people.

Harlan Krumholz: And somehow we must be doing something right.

Howard Forman: It was nice to hear Kevin also tell us that he enjoys the podcast. I like that.

Harlan Krumholz: Yeah, yeah.

Howard Forman: Health & Veritas is produced with the Yale School of Management and the Yale School of Public Health. To learn about Yale SOM’s MBA for Executives program, visit som.yale.edu/emba. And to learn about YSPH’s Executive Master of Public Health program, visit sph.yale.edu/emph.

Harlan Krumholz: And we always want to give a shout-out to our superstar undergrads. Now we have Donovan Brown joining Tobias Liu and Gloria Beck, our outstanding producer, Miranda Shafer, and I get to work with the best in the business, Howie Forman.

Howard Forman: You’re very kind, Harlan, and I wish, and I send the best to your family at this difficult time.

Harlan Krumholz: Thanks so much, Howie. Talk to you soon.

Howard Forman: Thanks, Harlan. Talk to you soon.