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welcome to this special edition focused on obesity, the changing landscape. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. This special edition of Diabetes Core Update is sponsored by AstraZeneca. Obesity affects approximately 40% of the United States population, with actually another third of the population being overweight. The consequences of obesity range from cardiometabolic consequences, hypertension, high cholesterol, diabetes, to the downstream consequences of those cardiometabolic abnormalities that include things like coronary disease, chronic kidney disease, heart failure, and mass metabolic associated steatotic hepatitis. There are also biomechanical consequences, often that we forget about, but are really important that include sleep apnea and arthritis, as well as the psychological effects of obesity on many people. Our understanding and approach to obesity have changed enormously over the last decade and our understanding and approaches continue to evolve and advance. Joining us today to discuss this evolving science and cardiometabolic diseases associated with obesity is Dr. Mikhail Kosaburad. Dr. Kosaburad is senior Vice President, Late stage Development, Cardiovascular, Renal and Metabolism Biopharmaceuticals Research and Development at AstraZeneca. He is an internationally recognized physician for his work in cardiometabolic and cardiorenal disease and he has led numerous large scale global clinical trials and outcomes research programs that have really shaped how these conditions are understood and how they're managed. Mikal welcome back to our podcast.
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Neil, thanks so much for having me. It's a real pleasure to see you and to be back and talking about really interesting and exciting things that are going on in disease.
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It really is. And Mikaela, what's pretty amazing is you got interested in this before it was even a field. Can you, before we dive into the topic, tell us a little bit about how you got interested in this area because it wasn't even named yet as an area of interest when you started.
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Yeah, thanks Neil. Indeed, this story goes all the way back to actually late 90s and early 2000s. And at the time I was just studying my cardiology fellowship and I think part of what influenced my interest in what we call today cardiometabolic field, of course there was no such name back then. I would say a constellation of two key things. First was that I was, you know, back in those days, if you were a cardiologist fellow, 80 to 90% of your time you dealt with acute myocardial infarction and its complications and you consistently, and I consistently as a fellow at the time saw patients with diabetes having larger, more severe events and having worse outcomes. And we did not understand why that was. And I really wanted to understand what it is about type 2 diabetes, or diabetes in general, for that matter, that influences in such a compelling way the outcomes of patients that develop cardiovascular complications and why it leads to a higher risk of complications to begin with. So that was one, I would say, driver of my interest. And the second was a very personal one, which is I had actually two very close family members, one that had type 1 diabetes and some that had type 2 diabetes and also cardiovascular disease that actually Both diagnosis type 1 and type 2 in two different family members happened within a very short period of time of one another. And so there were some things going on on the personal side that really, I think, almost subconsciously kind of compelled me to try to ask and answer some questions about why that is. I will tell you, as a, you know, matter of curiosity, is that back in those days, if you were a cardiology fellow, you were really, really cool if you were interested in things like angioplasty and you wanted to be an inferential cardiologist, maybe a little bit less so if you had interest in other parts of cardiology, but trying to be kind of a cardiometabolic cardiologist and understands the relationship between diabetes and heart disease was not cool at all. On the hierarchy of things, that was the lowest, if you will. And it's personally very heartening for me to see how much the field has evolved. Several of us made a prediction about 15 years ago that going forward in the future, addressing metabolic arrangements and metabolic therapies will be the leading treatments for heart disease. And everybody thought we were crazy. It's very good to see that, in fact, that prediction turned out to be correct in many ways.
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Mikhail, it's really remarkable as I listen to this, when we look at the way knowledge has changed throughout world history, it doesn't happen by people following in the footsteps of everyone else who's doing all the usual things. It take someone who can follow their curiosity. And you use that word, curiosity. I was thinking that when you were saying it, following their curiosity and having the confidence to go in a path that isn't the same as everyone else. If you're going to. If you're going to pave new ground, you've got to follow a path of your own, right?
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Yes, absolutely. In fact, I was giving a talk recently and to cardiology fellows, actually, one of them asked me a question. It's like, what are some of the things that you've learned in your career and that you think we should think about as we continue through our own personal development. And one of the things I mentioned was you've gotta challenge conventional wisdom. You know, I mean, I was taught many things when I was in medical school. Many of them turned out to be wrong. Those were absolute truths. And if you don't challenge it, if you don't ask the right questions, you'll never find out what the truth actually is. And that pursuit of out of the box ideas and challenging conventional wisdom is frankly how we make the biggest leaps in medicine. It is.
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We always have to be open to changes. I actually did a Medscape piece recently on things we used to think were true that now we know aren't. One of them that quickly comes to mind is when I trained, they said you shouldn't use beta blockers in people with heart failure. Right. And lo and behold, so science is fascinating because it takes courage, it takes curiosity, and it takes being open to things changing. One of the things that has changed that we're here to talk about is this new field of cardiovascular kidney metabolic health. And you are actually one of the co authors of the presidential advisory from the American Heart association that had that name in the title, Cardiovascular kidney metabolic Health. Now, even though the advisory came out a couple of years ago, this is still a new concept for many clinicians. Can you define for us the concept of cardiovascular kidney metabolic syndrome, CKM for short, and how it came to be recognized and why it matters for us to understand it?
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Yeah, I would say the key behind the concept is a realization which one could argue we should have come to a bit earlier than we did, that these common cardiovascular kidney metabolic conditions, you know, things like atherosclerotic cardiovascular disease, heart failure, kidney disease, liver disease, MASH that you mentioned before and many others. If you look at the patients we see in practice, there are very few patients that have just one of these things. Vast majority of patients have 2, 3, 4 or more. Of course, these are very common conditions that affect millions of people. There are millions of people early that we treat in practice that have constellation of these conditions. And the question is, is it really a surprise that that's the case? And it shouldn't be a surprise because if you look at the risk factors that lead to these complications, there is a huge amount of overlap between them as well. So there are common root causes, common key drivers that ultimately influence the development of these complications. And if we are to be successful in managing these conditions, we can treat them in isolation. We have to understand the reasons that we need to develop treatment paradigms and interventions that address more than one or two things at a time is because if we are to be successful with that, address the key drivers, the root causes of the disease. There are several fundamental root causes and key drivers that need to be addressed. And if you address them, you actually will be able to treat not just one, but but multiple chronic conditions at the same time. And if you address several of those fundamental drivers of disease, several foundational drivers, you could actually treat many chronic conditions at the same time. So I think part of it is kind of how we think about the root causes and downstream effects. Part of it is how we think about interventions and trying to do more than one thing at a time. Part of it also comes from the mindset of a specialist treating one set of problems in isolation versus treating a patient as a whole. Right. So the traditional paradigm really has been the cardiologist runs the heart and endocrinologist runs the hemoglobin A1C in the pancreas. Right. Nephrologist runs the kidney and frequently don't talk to one another. Vertif. We each of us need to understand that we actually treating the entire patient. And doesn't matter who the specialist is, doesn't matter what the issue is that you're seeing the patient for. If you have that holistic approach, you're actually going to be able to help the patient to a much greater extent, especially if you have the treatments that accomplish multiple things at the same time. So I would say a big. The reason I think the CKM framework is so useful is that allows us to integrate all of these concepts, root causes and downstream effects, the holistic approach to patient care and interrelated CKM conditions, if you will. And also, what's most relevant to what I'm doing now, of course, becomes drug development and interventions and how to develop interventions that can really deliver value to patients and clinicians by treating not one, but addressing not one, but multiple drivers of disease and thereby treating not one, but multiple chronic conditions at the same time.
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That makes so much sense. And can you distinguish for our listeners how CKM is different than or adds to what we've talked about for years, which is metabolic syndrome.
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Yeah, I think the metabolic syndrome question is very interesting. Right. Because we all lived through that kind of chapter in the history of medicine. And I think where the metabolic syndrome concept was useful is that it gave a name to a constellation of things that we're observing more and more in clinical practice. But I think what was missing is this whole. At the time was this whole concept of what's actually causing that and what's the most effective treatment. Right. This whole concept of root cause, gear driver and downstream effect. It was a good descriptor of a patient phenotype, but it was not especially useful at the time in terms of how we approach patient care in a comprehensive way. And I think that was just a chapter in medical history because we also didn't have very effective treatments for the patient phenotype and we didn't quite understand what the key drivers of metabolic syndrome were. I mean, here, for example, of course, we know today, right. Obesity is a kind of the big. The by far the biggest driver of that phenotype. So obesity and insulin resistance. I don't think that in general there was that understanding of the link between the two at the time.
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Yeah. And so can you talk about where exactly that. So where does obesity now fit into the CKM syndrome? And why is it seen as, in a way, an upstream driver of disease progression rather than just another component of the condition?
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Yeah, to my mind, obesity is one of the absolute key fundamental root causes and key drivers of CKM syndrome. Yes. But also, I would say even going beyond that, if you look at what is the number one public health threat in the world today, both in this country and well beyond, it's overweight. And obesity is. And it's not just because it's common, but it's also because in this hierarchy of root causes and downstream effect is probably the biggest root cause. Why is that? So I kind of think about it as you can call it an upstream. I sometimes talk about a kind of a cardiometabolic volcano where you have magma at the bottom of the volcano, which is obesity and insulin resistance. Dysfunctional adiposity. Whichever way you think about it, if you have root cause and key driver. Right. So obesity, dysfunctional adiposity, insulin resistance, ultimately cause a number of pathobiologic. There's a trigger, a number of pathobiologic processes which include things like inflammation, things like vascular damage, things like salted water retention, and of course, hypertension and cholesterol abnormalities and many, many others that ultimately kind of erupt in a entire range of complications. Of course, the one most near and dear to me are the cardiologists, cardiovascular disease and ACVD and heart failure and atrial fibrillation, things like that. But of course, there are so many others. Type 2 diabetes, right. Kidney disease, liver disease, sleep apnea, osteoarthritis and many other complications. That you mentioned already, Neil, in the beginning of the podcast. This is why obesity is now linked, I believe, to more than 200 complications. So if you want to talk about hierarchy, it is the reason that's the biggest public health threat. It's not just how common it is, it's how many problems it causes. And I think what we missed up until very recently of the medical community is seeing all of these epidemics of all these conditions that I've just mentioned and many others go up and up and up over time. And also seeing the obesity epidemic evolve over time at a breathtaking pace. And not putting two and two together, heart failure, heart failure or obesity related card failure is a great example of that. Of course, that's something that I had very personal experience with because of the program I led some years ago. You know, obesity related heart failure. But what, what we saw epidemiologically was that 4 out of 5 people with heart failure and preserved ejection fraction, which is now more than half of all people with heart failure had overweight obesity. But we didn't put two and two together. We didn't say, well, it's not just an accident that this is the case. Maybe, just maybe, overweight and obesity is actually what's causing heart failure in my patient. That's a root cause and we have to target, we have to treat obesity in order to be successful in treating heart failure. And of course that more or less what we ultimately found is that in fact that the right hypothesis was proven to be correct. And of course that evolved across many other complications too. Acvd now, osteoarthritis, sleep apnea. Right. We have data to say that if you actually target obesity, you can improve the complications.
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You know, it's fascinating. There's this saying there are no perceptions without conceptions that you don't see what's in front of you until you begin to conceive that it can be so. And we were seeing a lot of fpef. And as, as you said, until we connected the dots, we didn't even notice that it was, that there was that relationship. Let's shift a little bit now and talk about the advances in our scientific understanding of obesity and weight regulation and how that's reshaped our view of obesity and how it's moved obesity from just a risk factor for things to an actual chronic disease.
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Yeah, I think, Neil, if you look at the last four or five years, there were kind of several key aha moments, if you will, that we led us to where we are today. And I think that one of the kind of key moments, at least in my professional career was at the end of 2023, I think it was December of 23 that the Science magazine named GLP1 receptor agonist is a scientific breakthrough of the year. And keep in mind that science magazines, this is not a small accomplishment, Right. Because Science magazine doesn't just deal with medicine, it deals with the entirety of science. So competing with things like, you know, black holes and nuclear fusion and many others. Right. And yet a class of medicines is actually named a science breakthrough of the year. That's quite an accomplishment. So why did that happen? We talked about the enormity of obesity as a, as an issue for us as a society. Right. You know, it's the number one public health threat for reasons we've stated. The realization, number one, aha moment number one was it's a chronic disease. It's not a lifestyle choice. It's not a failure of willpower. It's a chronic disease that has biologic determinants just like many other chronic conditions, chronic diseases, too. And I think the science was very, very clear on that front, that most of our body weight and our body composition actually is genetically encoded. You know, not all of it, but a lot of it is. Right. So a lot of it is biology. And so if we need, if we're going to treat it as a chronic disease, we need to first acknowledge that it's a chronic disease that's not just as important, but more important cause of how common it is and how many complications have caused it. So that's high. Moment number two, what we've talked about before is this root causes and downstream effects, right? Obesity and everything that comes with it as a root cause that causes so many complications. And in order to effectively treat the complications, you have to address the root cause. And then aha moment number three, of course, is emergence of treatments that can be very effective targeting obesity both in terms of what, what they do as far as effective weight loss is concerned, but also, of course, in reducing the complications that we all care about to enable patients to live longer, feel better, be able to do more. And now that avalanche of data is building and will continue to build over the next number of years. Right? So I think if you kind of just think about where we were in the past and where we are now, we've learned a huge amount. And all of these aha moments that I just told you about, these are huge leaps, which is exactly why the Science magazine did what it did in 2023. Now that's kind of here and now. But I will say that the field is entirely in its infancy still. And there is still a lot that we're going to be learning and still a lot to look forward to. In fact, I think the next five, seven years we'll see enormous progress and further evolution in this space.
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So you say the field is in its infancy. So we now have treatments, GLP1s and the dual agonist GIP, GLP1. And we're familiar with their mechanism as incretins. They work in the hypothalamus, on the appetite center. They've been amazing. Why do you say that this is in its infancy and what are we looking forward to here? What sort of changes are going on at a research level?
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Yeah, so the reason I say it's in its infancy is because we've discovered admittedly an incredibly important mechanism, predominantly based on GLP1 agonism that does a number of really foundational things. Not only effective weight loss, but probably depending on the complication, some more weight loss related informatic complications, mostly weight loss uncoupled benefits that GLP agonism does likely above and beyond the weight loss that we see. So incredibly important foundational mechanism will continue to be foundational because of all the outcome benefits that we've now seen with this class. And when I say class, I mean not just pure jilt agonists, but some of the dual agonists and others that are emerging. Obviously some of it remains to be seen about what additional receptor engagement beyond GLP1, what that brings to the table. That said, it's one mechanism and we know today there are many others. And I think the idea that a single mechanism is going to solve the problem, the worldwide problem with obesity is naive. It's the beginning of the story. It's certainly not the end of the story. What was that? It's, it's not the end, it's not even the beginning of the end, but it's end of the beginning. I think the quote, it's kind of where we are now. It's just one mechanism. And that mechanism, at least when we're talking body weight, really has to do with reduction in the caloric intake. Right? I mean that's, that's predominantly how this mechanism works. But we know that there are others. Energy expenditure, for example, the calorie independent effects on visceral adiposities that we see with some of the novel mechanisms in development. There is a lot of talk, of course about lean body mass preservation. How important is that? Yeah, it's a fascinating scientific debate. I don't think we know the answer to that question at this point just yet. So there are lots and lots of other mechanisms and I think there is enormous amount of work and frankly enormous amount of investment that's going on across this entire space. And so we'll understand it better scientifically and we'll be much more sophisticated in how we approach this. And I suspect that while today, when I say the field in its infancy, so point one, we're in infancy in terms of understanding the different mechanisms and how they come together and what they bring to the table when in infancy, in terms of treatment options that are actually available to patients in clinic today, we had injectables for some time. We now have some choices in oral therapy, but that's just route of administration. There are going to be other dual triple agonists that will be coming, that will be combination therapies that will be coming. And there are these other completely different mechanisms, whether they're amylins or activants or a number of others that are in development that I think will be fascinating to see what they add to potential value proposition in this space. And then of course, patients want different options for their needs, right? For some, it's really important what the run of administration is. For some, their goal for body weight may be different. For some, the comorbidity profile and how many complications they have and which complications have the biggest impact on their quality of life becomes super important. So I guess just to sum it up, I would say within the next five to 10 years, this field is going to be incredibly more vibrant. The treatment options will proliferate and the treatment of patients will become much more personalized and tailored.
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It's so important. It's going to be a real challenge for those of us out there in primary care and endocrinology to keep up with all of that change in information in order to be able to give patients what they want. I love the idea of personalized care. And it's not going to be one size fits all. Where do you see the big evidence gaps currently? Or let me even say, what are the challenges you see over the next five years in obesity medicine and research?
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Yeah, I would say, Neil, I would kind of separate the challenges. I mean, the evidence gaps I think we kind of talked about already. Right. They're all mechanisms and we obviously need to build a compelling evidence base to try to understand what they all do, how much value they bring. And frankly, just like in many other conditions, as I said before, expecting that One mechanism is going to solve all problems is not realistic. Right. So we need to understand how these different mechanisms come together to drive real value to clinicians and patients. And I would say the biggest. So aside from that, what are the biggest challenges? I would say challenge one is really scientific and clinical one, which is developing and building that compelling evidence base and really understand how it all comes together with different treatments, different mechanisms, different combinations. But I think combination therapies are going to be absolutely critical. And by the way, when I talk about combination therapies, I don't just talk about combinations of different mechanisms for weight loss. I'm talking about combination of different mechanisms for outcome, benefits and organ protection and combining weight loss related mechanisms with other foundational mechanisms that are important from a cardiometabolic health standpoint, like addressing things like LDL cholesterol and blood pressure and other things that continue to be very important. So that's kind of scientific and clinical challenge. Another challenge is if you think about a sheer number of people that have overweight and obesity and you think about, we're talking about this field being in infancy, where we are in a treatment of diseases of infancy, because globally a tiny fraction, much less than 10% of people with overweight and obesity are getting any kind of treatment or that chronic condition that we just said is the most important chronic disease. Right. A tiny fraction of people are getting treated. So what will it take to actually be able to treat all the people or even a fraction of the people, but bigger fractions than what we are dealing with today with effective treatments? It's gonna take a completely different approach to the way. What. Yeah, the way we've been kind of thinking about so far. Right. So I would say it will, you know, you frequently talk about, you know, many companies, for example, developing treatments and lots and lots of different treatment options. It will take a village to, to be able to deliver effective treatments to as many patients as will eventually need it. Because every one of these innovations that I've just talked about, every time they come to clinic, there will be tens, potentially tens of millions and sometimes hundreds of millions of people that all of a sudden will have access to treatments that previously did not. And of course, then you need to manufacture these treatments and actually get it to people all over the world that need it. So I think it's, it's a challenge from a scientific and clinical standpoint. We just talked about a challenge in terms of manufacturing, delivering it to people. But the other challenge, which I think you will relate to very well, is care delivery challenge. We do not have the capacity in the healthcare system right now to treat as many people as need to be treated the way that it needs to be done. It's not as simple as writing a prescription. These patients need support, they need care coordination. And how do you scale it to the point that it needs to be scaled for disease like overweight and obesity? I don't think we quite figured it out yet. The traditional healthcare systems are not capable of dealing with that kind of volume. And I think what you see currently in the consumer space is that a lot of the online companies are trying to fill that void, but there are challenges with that model of care as well. So I think that's something we still need to figure out.
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Those are such great points. I mean, it'll take a lot of will, political will and wisdom. It's very easy to say I have no choice but to treat this person who's coming into our ER with chest pain. Right? No one would turn that person away. It doesn't take a lot of wisdom to understand that needs to be treated. But it does take kind of what I think is an intellectual challenge to really understand the importance of treating obesity long before you have no choice but to treat, when you have those end organ consequences, whether it is coronary disease, heart failure, kidney failure, mash, et cetera. Mikael, I have so enjoyed this conversation and while I wish we had all day to continue talking, we're about out of time for our podcast. Any final thoughts for our listeners?
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Well, thank you, Neil, and it's always a pleasure to be with you. I would say my final thought would be that when all said and done, I'm convinced that perhaps when you and I are happily in retirement and we are reminiscing about the days of old, this story that we are talking about today, right? Recognition of obesity as a chronic disease, understanding its relationship with complications as a key driver and a root cause, and ultimately development of hopefully multiple efficacious treatments will go down in history as the biggest healthcare story of our lifetime. I certainly have never seen until I, you know, started both treating patients with these types of interventions and also doing clinical trials and science in this space. I've never seen anything so transformational and I think it will only become more so as the science move forward.
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I absolutely think you're right. It combines something where we make an important difference for outcomes and for patients personally. It's one of the few areas where we get regular thank yous. Right. Patients appreciate the care we're giving so much. Dr. Mikhail Kosabaran it has been an absolute pleasure once again talking to you. Thanks so much for joining us.
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Always great to see you in Yel. Thanks for having me.
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And to our listeners, thank you as always for joining us for this special edition of Diabetes Core Update and the changing landscape of obesity Care, research and management, sponsored by AstraZeneca for the American Diabetes Association. I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.
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Sam.