Future Therapies and Emerging Research

Welcome to this PureVoice activity. To access the entire activity including supporting material, go to w ww purevoice. com slash vac This activity is supported by an educational grant from AstraZeneca . AstraZeneca has had no involvement in the selection of the speakers, the development of the activity, the agenda, or the material s Thank you so much for coming and this really promises to be an incredible meeting. My name is Carl La Rue. I'm one of the clinician scientists at University College Dublin and I'm welcoming you to really talking about beyond BMI transforming modern health management, you know, for the heart, kidney and met,abolic health . And I'm being joined by a stellar faculty . And I really look forward to actually hearing from our faculty today, but also hearing from you as the experts in the room and we're going to ask you to actually fire as many questions at us as possible. But first of all, Bicam has been one of the leading cardiologists and again, I always just learn so much from listening to you and understanding what you way you approach this whole complicated situation. Dominica and myself have been around for a long time and shared lots of discussions. And actually I,' youve know, sort of grown up in Dominica's shadow and it's really always a pleasure to speak with Dominica and hear her view. And I've recently met Michael and I've been so impressed with what you bring and the discussions and the insights that you have. And I would really like us to infuse that into our discussion today. And of course, we also want to say thank you to Ast raZeneca that has supported this meeting with the unrestricted educational grant, etc . So let's go to our first present ation , which is all about what is the first step , identifying the risk burden . And if we are thinking about obesity as a chronic disease with multiple impacts. And you know, that's what I do for a living. So I treat obesity, I think about obesity all day long from a science point of view, thinking how we're going to implement it. But what we know now is that this is a chronic disease, but it's also multifactorial . And ultimately, whenever you see something as multifactorial, it also means that we as the so called specialists don't understand it that well. And I think that's something that we're going to learn together about obesity in the future. But you know that in many countries, including the US, this is a problem that affects many people . And of course, it remains a very key modifiable risk factor. We're going to hear from Bycom in a moment about thinking about this not only as a disease in its own right, but also a disease that drives complications, be it cardiovascular complications, kidney complications, metabolic complications such as diabetes, and of course many cancers. And obesity is therefore central in this cardio kidney metabolic syndrome and byken, that's something I've learned from you actually thinking about the CKM space and how we can actually use obesity and treat obesity to disrupt the C KM syndrome . So but we need durable long term obesity management. And I think one of the things I would like you to leave here today and again challenge us on that is that I would like to suggest to you that obesity isn't more special or less special any of the other chronic diseases that you are already treating. And all you need to do is just put obesity in that same box that you put all the other chronic diseases. And I think if we can do that , we may be able to simplify, you know, what we are doing . So let me actually throw this open now. So how should we as clinicians recognize the cardio kidney metabolic clustering in patients with obesity and why is this important to address obesity as this common upstream driver? So maybe if I ask you to take it from here Carl set the stage really well and this is an era where we need to recogn ize that obesity is not a singular disease . So when a patient has if an individual has obesity , think cardio, kidney, metabolic liver disease . Why am I saying this ? are recognizing that obesity is one of the central drivers for the potaphysiology, the common potophysiology we are now recognizing for heart failure, especially with preserved EF , hypertension, atherosclerotic events such as myocardial infarction , stroke, obesity , abnormal adaposity is a driver . It also is a driver for chronic kidney disease , and hypertension , and hyperlipidemia , and liver disease , and diabetes, which you all know really well. The important thing to recognize is three decades ago we used to see individuals with one comorbidity or one disease . That no longer is the phenotype. We're seeing clustering . We used to say coronary artery disease attributable to risk factors of high lipid and family history. Now we don't say that anymore. We are saying the triple usually diabetes, obesity, hyperlipidemia and hypertension , the clustering is more prevalent than ever . And attribution to single disease is rarer . And therefore, and we're seeing this even in our younger populations 're. seeing We it in even in the younger populations. The other important thing is so it's a common cause of causing an organ damage , but also when it is involved in clustering , the kidney disease causes heart disease, heart disease causes kidney disease . Same thing with a collateral bidirectional causality when metabolic dis order is in place . When a patient has a metabolic disorder, the likelihood of having MASLD mash with F . So it actually works in a bidirectional manner . Kidney disease, people have more heart disease when they have the diabetes and or the obesity. So that bidirectional effect is there. And the final component is unfortunately the, outcomes become exponentially higher . When a patient has the clustering of these entities in the context of obesity , their mortality is high , which creates the urgency. We used to say , oh boy, you know, this is a body habitous difference. The difference right now is to recognize either the disease that's there that we are not seeing because we haven't screened it , or it's occult or subclinical and is in the process of developing. That's the terminology that is very critical for all of us, regardless of the specialty is screen for the diseases that you see here and most likely they're there . And it's an opportunity that is lost if we don't recognize the burden of risk , i. e. the cl ustering of diseases and the urgency of treatment to prevent very much unfortunate outcomes that are cardiovascular mortality CKD, very advanced CKD , mathyline mash , cirrhosis and the burden that it has overall in the overall population. So this unfortunate trend is seen in most developing countries and all around the world. And I think overall we are aware of this as a community, but we have not implemented the screening strateg ies and working across all of the disciplines in this plural manner. So let's start with a patient. Meet our patient, Sarah. She's forty nine years old, but her story started years earlier. In her early forties, Sarah's BMI rose to the obesity range. She was advised to eat less and exercise more, but obesity was never diagnosed or treated as a chronic disease. At forty six she developed hypertension. At forty seven, early signs of kidney disease appeared. At forty eight, her HBA one C reached six point two percent. Considered pre diabetic and labelled borderline, the warning signs were there, but her care didn't change. Now at forty nine, Sarah lives with obesity, hypertension, kidney disease, and metabolic dysfunction. Multiple specialists treated the complications, but no one addressed the chronic disease driving them. Biologically, her body resists weight loss. Psychologically she blames herself. Her care is focused on complications , not the root cause. So Dominika, let me ask you, you know, how has your own practice changed, you know, thinking from what we did ten years ago to what we do now and how within this context, you know, you see this complicated patients. What's your go to thinking at the moment? Well, I think how things have changed is that originally we didn't really have any therapies for obesity, right ? In the old days . And so we did try to optimize, you know, we were treating p diabetes before we technically were supposed to be treating prediabetes, getting people treated for that, optimizing their blood pressure, and doing what you could. But the medicines we had at the time, like fentamine could exacerbate some of this stuff. Now we actually have medicine that actually does exactly what we were talking about is by treating the obesity, we get a decrease in inflammation, we get improvement in the liver, we get improvement in blood pressure. We can still treat individually , but we don't have so much fragmented care. care. I mean, I am definitely try to treat everything all at once and I drive my patients completely crazy . So I try to say, okay, we're going to do this and we're going to do this, but I really try to stay on top of everything as soon as we get a change. Sometimes there's reluctance, especially with sleep apnea, right? That's very difficult to get patients . But badger the heck out of people. And I recently had a patient of mine five years after I'm hassling her. She's using CPAP, and guess what? She feels better. So you have to persist, though, in treating all of these complications, but now we have much better medications that we can do. But Michael, maybe if I can bring this to you . you Are one of those patients that's being driven driven demented by, you know, people like Duminica, you know, where there's just so many things that's being, you know, thrown on you or do you find that it's a more of a systematic way? I mean, you've you've also experienced this over time. So maybe give your perspective. What's happening now, what's happened in the past? So I feel like Sarah's story is my story, right? My BMI was a lot higher. It was fifty five, but along the way , I kept going up and seeing other specialists, but no one along the way actually ever talked to me about obesity as a disease, right? So all I got was depressed in my thoughts and feeling like a failure, which didn't want me didn't allow me to engage in care. And that's what I see in Sarah is she's probably just constantly hearing about how she's doing poorly and not understanding that part of that is not her fault. It is not purely diet and exercise. And that's what I see, and that has changed somewhat , but not completely. Yeah, it's still there. I mean, I have I hear that from so many patients when they finally come to me . And you know, it is reinforced by insurance companies as well, right? Have someone had six months of lifestyle and behavior, etc . You should always say yes no matter what , okay ? Because patients and individuals who suffer from obesity are always trying to make changes. I think that's a really stigmatizing thing that we somehow assume no one is working at it. I'm sure Michael, you are working at it all the time. All the time. Yeah . And so I think you have to believe the patient when they come in and they say that they're working on it. And really now we have tools that even if you're treating the individual things by treating obesity , you're actually helping everything at once. I mean, I think you have to realize there's a dynamic aspect to this physiology. So as soon as you're kind of working to decrease inflammation and you get some weight loss, that affects all of the organ systems and as those organ systems get better, other organ systems get better. Everything is dynamic. It's not linear, we're not compartmentalized. Now, I want to just go back to Michael you said something and I want to pick up on that because you know it's also what missed opportunities since Sarah's care would be should we have triggered earlier. And this idea and you use the words a moment ago , saying to somebody who have this disease , this disease is not your fault, but it is your responsibility and my responsibility as a provider to find this a treatment for you. Do you find that empowering? Does that give you agency ? Or does that actually say now I can just eat as many hamburgers as I want? You know? Oh, it completely is empowering. I think the nine most empowering words are obesity is a disease. It is not your fault. I'm going to out myself here, but I didn't hear those words ever from a physician . I heard those words on TikTok and how sad is that I didn't hear it from a physician. I had to hear it on social media . Yeah. And let me ask you back and from that point of view because you have been in the midst of treating cardiovascular disease . And our view , you know, twenty years ago was like people's cholesterol was too high because they ate too many eggs and we need to make them eat less eggs, right? And now then we understood that it was a liver disease and HMG CoASynthase , you know, but how is that? What can we learn from the cardio kidney metabolic space because you've successfully treated disease, you've reduced cardiovascular death? What can we learn from that and apply that in obesity space. Absolutely. The magnitude of risk that is conferred by both the risk factors and the clustering is so much that the urg ency by which we need to address to reduce the event rates right now also creates the obligation for us to help the patient along with lifestyle modification. We've known in randomiz ed studies that the magnitude of risk reduction is very modest and takes ages . We lose patients to heart attack, stroke, heart failure within that time frame This is a cause of adverse outcomes. The problem in Sarah's case, who everybody watched she had the hypertension, she had the abnormal UICR , the proximate cause , the pathophysiology was not addressed . We tend to address hypertension. Everybody now knows how to treat hypertension, but in the context of obesity , it becomes refractory, resistant hypertension . When accompanied with the appropriate treatment strategies, we now are recognizing when we treat the obesity, the hyperlipidemia treatment , MI treatment, stroke treatment, hypertension treatment, masoleine mash treatment suddenly becomes facilitated and much easier than this sketchy and sporadic treatment. And I think overall , the urgency is being recognized both with the endpoints and thus this cannot be left for decades because her story is a reflection. It was over than ten years time of a neglected disease treatment that resulted in progression of the chronic kidney disease as well as the hypertension as well as what else did we miss? I mean, she may have other diseases . If we were to ask about symptoms, most of these individuals will have dysmnea, shortness of breath, right? Limited functional capacity, which are the two potagn ic symptoms for heart failure with preserve and when checked when checked, it's usually there . And these individuals will have very high cardiovascular adverse outcomes. So let me ask you now, so how would and should we actually assess Sarah beyond BMI? So maybe you want to talk to us about that by . Absolutely. And because of this reason, American Heart Association has now come up with the p aradigm of cardio kidney metabolic and add the liver to that. Now this is a cardiology centric perspective. I want you to focus on the far right which, is what we consider stage four of the CKM risk is individuals with cardiovascular disease. So these are the individuals who had heart attack, stroke heart failure. And this is stage four because we know that these individuals are at high risk of death . But let's now look back , right? Look back. And stage one is excess adaposity . That is what we term as stage one. Stage two is a deposity with diabetes as well as CKD , okay? Stage three for us is subclinical disease . It could be when you do the imaging in with echo, you see some features of a structural functional cardiac abnormality. Or you have plaques, or ascerotic plaques , but the patient hasn't developed the disease in terms of symptoms and or events yet . Now, how would we know whether somebody has stage two or three without screening . In Sarah's case , if nobody screens her for diabetes with hemoglobin A one C, and if nobody screens her for CKD either with EGFR or UACR, she may never get those diagnoses and heart failure, if not thought about , would be attributed to obesity. The symptoms would be obese attributed or blamed the obesity, whereas heart failure with preserve may have been there. So this is definitely opportunity lost. These stages are right now shared across the community, not only among st cardiologists, for us to emphasize screening and thinking about the clustering of disease states There are other societies coming up with new frameworks , KDGO heat map , which now combines , which I know that is being used in a variety of trials , the EGFR in the vertical axis and the U ACR. Uran albumin creatine a ratio in the horizontal axis. The thing I want you to focus over here is yellow is moderate and the pink to red or dark pink is high risk . Who is not at moderate or high risk? Is that green or blue ? Only if small percentage of our patients are without risk . Majority of our patients will have an EGFR less than sixty . That's when the CKD moderk starts. And UACR , exceeding that authority is moderate, exceeding that of three hundred is high risk. So what was Sarah's risk ? What was Sarah's risk? If we just stay on the obesity lane, we miss all of the clustering of the disease states and the adverse outcomes . Sarah's risk was quite high, looking at the Kiga heat map, she had abnormal UACR and looking at the cardiovascular okay , CKD KM stages , she is minimum stage two. Nobody has screened her for three and four. She may be four for all we know. If a patient has heart failure with preserved EF , what's their risk of dying from heart failure? The risk is equal to heart failure with reduced EF once they're hospitalized . So this is a deadly disease and is associated with very adverse outcomes and should not be missed. In her case, we don't know whether she even had that. We know she has CKV. We know she has hypertension. I will be very suspicious that she likely has stage three or four CKM disease states . So overall, I think this is the framework of how should be thinking across disease stages and be aware be aware to screen for other diseases beyond obesity. Obesity should not be thought in isolation . Can I say so? So you need to identify it, but you need act to, all right? So part of the problem that I see in patients coming back, and perhaps this Michael will resonate with your experience is that the patients will say , My doctor didn't treat any of this or everything was bord erline, right? And then they show up with an A one C of six point seven or something like that . But the doctor is saying, look, it's your weight . So you need to exercise, you need to push back from the table, you need exactly what we see in the video for Sarah . So I'm saying you guys need to act. I'm not saying you don't act, but I'm saying if you don't, you should. All right. We not only need to diagnose and follow up undiagnos ing, but we need to act on behalf of the patient and not blame the patient because it still happens a lot. All right, you know, we're in our own little cluster Let's go to this this concept now and maybe first of all I can let's talk a little bit about that. And again, Bicam, I would like to get your view. So Sarah's case illustrates how obesity related cardiovascular kidney metabolic risks often evolve together . You made that point. But in the real world practice clinicians may prioritize different entry points, you know, wherever you come from, what your specialty is. So how do each of us decide where to begin ? And what helps us to move from a single organ focus to this multidisciplinary focus? And is it necessary ? Because just because everybody talks about multidisciplinary care . That doesn't mean many of us cannot deliver it because we're not in those situations, right? So how do you see this, Viking ? I think the field has evolved the recognition of cardio kidney metabolic . What does that mean is we now across societies with all the trials emphasizing when you have the metabolic profile, a patient with obesity , we should all of us screen for diabetes , should screen for CKD , should screen for heart failure . And when and if symptoms the risk concept reaches a certain threshold , also for a teroscerotic heart disease . American Heart and American College of Cardiology are coming up with cardio kidney metabolic guidelines in this multidisciplinary realm and the concepts that I have verbalized is shared across ADA , nephrology societies, cardiology societies, hepatology societies. What does this mean for all of us? For example , HACC has risk calculators. I know you all hear about these risk calculators. We used to talk about heart attack risk and it was very lipid based, right? Age, lipid hypertension and smoking. That was it in the past . That framework has changed. AHACC is now focusing on prevent risk score or entities that include, what does the prevent risk score includes? That didn't use to be included. It does have the age, the sex , smoking , diabetes, but it now also has definitely the UICR as a component that is added over there as well as the BMI over there. Why did we do this? Because there's no ample evidence of telling us what that ten year risk is . And the risk is not only looking at atherosclerotic events anymore, it's also looking at the heart failure risk. So the prevents risk calculator now says anything over three percent risk may need intervention, anything over five percent risk of events for heart failure or cardiovascular disease needs intervention. I showed the KDO heat map. In the darker colors it says refer, you need to treat yellow , pink , orange , needs treatment. Why is that important ? We now have treatment strategies, right ? And the first question is the things that we need to think about is look at the risk burden for Sarah or any of your patient and then find the treatment strategy that checks off most of these indications . And I think that is the strategy by which we're going to start treating these . In my practice in cardiology , I'm telling my trainees now we need to screen for kidney, which we didn't used to do in cardiology. Yes, we will need to do UACR and EGFR and follow that and call that out to our patient . It's a definite we have been checking hemoglimina one case, but we had not been doing the kidney. We are totally ignorant about liver fib force scores and learning this. My practice , I need to learn it because now I'm recognizing my HefP atients have Masly and Mash . Did I speak to them about this? The answer is I did not in the past, now I'm starting to. So the concept is all of us need to talk CKML, cardiochid metabolic liver and be able to communicate this . We all fear that the patients when they hear this are going to be very disheartened , but I sometimes use the analogy of prevention, like how cancer did it? Precancer, that no longer has a stigma. You may have mild disease or you may have pre disease . You may have mild chronic kidney disease, but we're going to prevent that by using these terminologies is how I would approach it. But Michael follow up on that, you know, so that in what advice can you give us, you know, within a medical profession? Because you are that expert patient and as you said, you've identified with Sarah's story. So it's all good and well. We talk about multidisciplinary care, but does that mean you have to go from pillar to post , you know , or do you would you prefer the primary care physician to be that person that takes care of you and interact with others? How would you, what's the best for you? In a perfect world, I would love to do my primary care physician. But I've spoken to thousands of patients at this point . And I will tell you that very, very, very few of them on their care team, on their multi disciplinary team find multiple doctors who see it that way. So I don't care if it's my cardiologist or my obesity medicine specialist or my primary care doctor. I just want someone to see me as a person and to treat me holistically. And I just need one person to engage and I don't care what that specialist is. I just need them to see me. And Dominica, what shift in your own practice did you have when you shifted from being just an endocrinologist interested in the glands, you know, to actually make the hole . You know, I think it's evolved just as Bikram has said , that we do look at all these system diseases. Sometimes we were waiting for other people to sort of get involved. So like in the beginning of Fib four score, right? We would do one. We would see where they had to go, but I didn't have any fibroscans anywhere near me in terms of my sight, right ? And so what has happened over the years is now I have like a collective of cardiologists I trust that I know that they'll treat my patients well with obesity because I am loath to send a patient to someone who then turns around and says, you know, hey man, why couldn't you get your act together or diet lifestyle? What's the deal? So the cardiologists have come around a lot, right? Now with all the evidence with incritins and GLP one. So in terms of multi system management, I have accrued these different people . It turns out now we have a hospital near us that does hepatology work and they do fibros and they have their own like research protocols of just following people chronically . So now I can refer them there. I have neprologists that I know are going to be kind to my patients. I mean, honestly, that's been my biggest struggle is how do I assemble my team, but I know that my patient will feel safe when they go there. And do you actually proactively speak to the team and say to them, listen, you know, just like person first language or how do we think about the disease now? Do you actually or do you just hope and pray that they'll be ? No, I kind of check it out indirectly from patients who go there and then I've known them for a long time. But would you actually still go and say I would say and I have and then it depends on how receptive they are. And if they're not receptive, I don't refer anymore. I mean, I have had to cut that off. I mean , and sometimes like especially for my female patients , you have to be very careful. No offense to anyone here. I didn't see it come up. But with gynecologist s because women are extremely sensitive, which they should be , but there's a lot of judgment . And I'd say to doctors out there , even if you've struggled with weight or you have lost weight, whatever works for you doesn't work for the patient . And I think you have to be really careful. And Michael, you can comment on that, but I mean, I think you want to empathize, but you don't want to tell your own story to your patient nor do, you want to apply that kind of stuff? So anyway, multi system disease, I've assembled a team, I've got them on my cell phone, I know the text, I call them in advance . I let them know who's coming so the patient feels welcome. And I know they're in good hands. Because Michael also , each chain is only as strong as its weakest link, right? Yeah, you could be in this multidisciplinary team, but you know, if you see you see a doctor that actually that is just stigmatizing, you know, that's a negative experience right there, right? I mean, I see one all the time . And I will just say that it took me a year and a half to really find the sort of quarterback on my team who would only send me to doctors understood the disease of obesity. So it was a good year and a half of me struggling to find a care team that worked. But it was full time work and I am not a low information person. I am married to a physician, right? Imagine your average patient. It's a very different situation. Okay, actually, that's a really good point. Well, let's sort of take this part, you know, and the key takeaway mess ages for me would certainly be identify risk early , act on the current risk that you are seeing, and then match the treatment to that risk profile and use a multidisciplinary and a multi system approach, you know, to address the problem . So let's now see if we know go to the next step. So what should be prioritized when it comes to balancing weight , risk and organ health, etc . So Dominika, maybe I can ask you that question, you know, so how do you move from treating an individual , you know such, as, you know, with BMI, blood pressure, hemoglobin C, albuminuria to treating obesity as the underlying cardio kidney metabolic disease driver of patients' risk. So Dominika, maybe you can take this. All right . I mean, I have a certain advantage, I would say because I primarily do obesity. I have some other endocrine patients, but because I do research, I also have a clinic. So patients are coming to me, but what I think ends up happening is they're coming to me for weight loss , but what they really do like is we spend a fair amount of time, which apparently they're physicians are not doing is doing exactly this . So I end up spending a lot of time taking it from sort of fragmented care and depending on what information they've received where they're just supposed to lose weight , where I end up not only treating their obesity, but optimizing their blood pressure, depending on the treatment we use for obesity , maybe optimizing their blood sugar, especially if they have diabetes. So I end up treating all of these diseases . And then you end up really trying to focus on assessing are they at greater risk in some way that hasn't otherwise been identified, right? And so hence , the people that get referred to cardiology or patients might get referred for liver, although a lot of times when they go to the hepatologist, the hepatologist said, well, you're treating them with a GLP one anyway, so they send them back to me. But I think it's important to have that first bit because I have to say in the last two years, I've had two people with type two diabetes get diagnosed with cirrhosis when I pass them along to hepatology. And I think that's one of the things that we don't recognize as much. And I'm hoping that we recognize it more. And the other is right sided heart failure. You know, dyspnea and fatigue not ignored. Look, honestly, as a physician, I hate when people come in and say they're tired because it's like an incredible Venn diagram of all the things you have to go through. However, we can't just attribute the dyspnea to the weight alone in a structured way. They really do need to be assessed and we're seeing more of that in the clinic and I've had patients who even ended up having to switch cardiologists to actually get recognized that they really did have right side of heart failure. And they kept seeing one cardiologist who kept saying, look, you gotta lose more weight. And I kept saying to the patient, look, you already lost forty pounds. There's something wrong with your shortness of breath that has persisted . So I think it's really recognizing that the patient that's in front of you may actually have fragmented care. Someone may not be looking at all of these things. And I think patients like hearing to some extent as long as you're not blaming, but you're explaining . And I actually think that's the difference. If you explain how these different systems affect each other and you take the blame away from the patient and you explain how obesity is a disease and the regulation around weight management is huge between the brain and the feedback from all of these organs systems , then I think I don't have to convince people to treat their obesity . But it's very meaningful when we start focusing on, look, you can make all of these changes and improve your cardiovascular risk, slow the kidney disease, and improve your metabolic health. And that really resonates because that's what the patients want. They want to feel better. They want to feel healthier, that's what their families want. So that's kind of how I look at it . Hopefully that's helpful. People can ask questions if it's not. And this really just is repeating what Bicram showed you is that we have to focus also on weight without blame in an effort to disrupt this vicious cycle and understanding that as we disrupt that cycle, all these other things that get better , we improve insulin sensitivity, we improve blood sugar, we improve the impact on the kidney . Just that alone feeds back to those systems and improves that as well, right? And we see a decrease infl in ammation, which that decrease inflammation affects all of those organ systems. So the benefit of this is we're getting a really one, two, four punch or whatever we're doing. I think L uo Aonri likes to talk about some other gambling thing. But in reality , we get a very triggered across improvement. So you have multiple system improvement. So I think we go on to the next video Let's come back to our patient Sarah. She's now forty nine and the full picture is clear. Her BMI is now thirty six, her blood pressure remains elevated, placing her at cardiovascular risk. risk. Algainuria and reduced EGFRs signal chronic kidney disease. Metabolically she's in the pre diabetes range suggesting further progression is likely. Multiple risks evolving around cardiovascular, renal, and metabolic systems . Because in real world practice we often have to decide what do we treat first? Do we focus on weight, cardiovascular risk, kidney protection or diabetes prevention, or the underlying chronic disease driving it all . How do we match treatment to risk? Maybe ask, you know , if I go to you, Michael from that point, you know, how long do you think it has taken for this concept to have emerged, you know, for in Sarah's case, that people have really understood that we can treat the disease of obesity, not only for the weight loss, beyond the BMI , really to disrupt this cardio kidney metabolic disease. Do you think that idea has really taken hold or are we still in the early stages of that? So I don't think my primary care physician has figured that out yet. To be very honest with you . I think we're still at a very early stage for so many physicians to understand obesity as a disease that affects so many multiple systems. I mean , when I finally was my medications were coming really kicking in, I will tell you the best part of it wasn't the scale. The best part of it was looking at my blood work and watching it all go into the green, all go into the green at the same time, right? It wasn't like it solved a problem, then it solved another problem, then it solved another problem. It was like six months in, it was like the most exciting time you could imagine. And frankly, the best day on this entire thing wasn't a number on the scale, it was the day I was told I was up blood pressure meds, which I assumed I'd be on for the rest of my life. Yeah. And isn't it interesting that we think and I think maybe please, Michael, tell us what your view here , but my experience is most patients come to us because there's nothing wrong with it, but people want to be thin and happy , right? And it turns out that the two things we cannot do even with these great treatments is we cannot make people thin or happy . But what we can do is we can make them healthier and more functional. And ultimately, even when people lose twenty, twenty five percent of their weight, we see that fifty percent of people stop the medication, right ? But if we shift that focus to the health gains, right? Michael, I bet you you would fight people with sticks if they want to take your medications away now because of the health gains, right? Absolutely . There's no question. My life has changed dramatically and I would pay whatever I needed to pay to stay on these medications. Yeah . So Litton Baiten made me ask you this. So in a patient like Sarah, you know, with obesity and evolving cardiovascular kidney metabolic risk, how do you decide whether to prioritize obesity treatment, cardiovascular protection, kidney protection, heart failure prevention . And how has recent outcome evidence influenced you? You work in a super specialist center. You are leading this, but you know, even you are human, right? You know, so we can't, you know, how do you approach it? Maybe if you tell us your view? So the paradigm shift is looking at the whole health as you're alluded to and being able to communicate the benefit for cardio kidney metabolic benefit, which I'm going to show the data for , that is in line with the risk burden because I need to see it beyond BMI , and we need to recognize a disease beyond in addition to the obesity, beyond BMI, it's there. When we look for it, the cardiac metabolic disease is there . When somebody has the disease then the urgency definitely is there for further progression of that disease as well as the death . So my urg ency is recognizing the burden of disease . And let's look at the evidence because that's what we need to communicate. The therapy is not solely targeting BMI anymore. The therapy is not solely for obesity treatment anymore The select trial was in individuals with overweight or obesity with cardiovas cular disease. Who were these individuals? Individuals who had history of MI , stroke other cardiovascular disease established cardiovascular disease . And these individuals when treated with GLP one RA had twenty percent risk reduction in the cardiovascular composite endpoint, which was a three point mace, cardiovascular death or stroke or heart attack . Very strong risk reduction . So right now , we are looking at this as a cardiovascular medication. It's not just a weight loss drug. It's in essence a secondary prevention for cardiovascular disease . So you now suddenly recognize the urgency of treatment . And the heart failure also signaled was very favorable . Cardiovascular death and heart failure events were reduced too with the GLP one RA . Let's look at another patient phenotype . This one was pati ents with diabetes with C . And in this trial, flow trial GLP one RA resulted in prevention of progression of kidney disease , as well as prevention of cardiovascular death and combine cardiovascular events again, stroke, heart attack and cardiovascular death. The magnitude of risk reduction was very comparable to what we saw in select very robust . Actually, cardiovascular death reduction by itself was almost twenty nine percent . The combined three point mace was about eighteen percent. We're talking about individuals with diabetes and CKD, which is a large number of patients that we see and giving an agent that then reduces their cardiovascular death, heart attack, stroke , and progression of kidney disease. So we're not talking about solely weight loss. We're talking about disease prevention for existing disease and also prevention of new disease and death, cardiovascular death. All cause mortality in both of the trials were significantly reduced too. So a very interesting paradigm shift of what we're going to communicate. I believe we're beyond BMI and I believe we're beyond the weight loss concept. And by the way, Bost i studies , amongst individuals with even less than five percent weight loss , there was benefit for cardiovascular risk reduction. The Mace endpoints were reduced, even those individuals who lost less than five percent of their body weight. So the paradigm is very rapidly shifting to cardio kidney , metabolic disease management and risk. And of course , we now have data from heart failure trials . This is showing the data from Step F PF , which were individuals with heart failure with preserved EF and obesity . When treated with GLP one RA , they were able to lose significant weight , have improve ment in their health status , quality of life , which is shown on the left side , along with improve in six minute walk distance , and inflammatory mediator CRP levels were reduced too. Very interesting. And filling pressures biomarker and TPNP was reduced. This was a paradigm change for us in Heartfay with Preserved EF and a second trial, this time with GLP one and GIP Agonism, Therzipatite, demonstrating combined clinical endpoint benefit, cardiovascular death as well as heart failure events , as well as quality of life and health status changes, six minute walk distance as well as NTRBMP. So in now heart failure with PreserDF, these individuals have had history of heart fail with PreserDF. We're seeing these agents as agents that help weight loss, but also improve quality of life , functional capacity in heart failure patients . And also we now have data demonstrating very favorable effects on MassLD and even MASH . And this portfolio should tell us that it is beyond BMI . We're treating the whole cluster of risk and disease . And your question to me, how should we do this? We should be able to communicate this . We can say you are at high risk for this or you are pre or you look like you have this disease, but don't worry. We can in a collaborative manner treat . And we have agents that is targeting all of these and these agents will actually help us either reduce the risk for this in some cases eliminate . You may treat a patient in a pre diabetic state and if they lose weight and you may prevent diabetes. And these are the concepts that now we're looking at whether we could move the needle from stage four of everything coming after they've had all these events to the pre. So I think that's the paradigm shift and we need to take it beyond just weight loss and BMI . Let me throw that now to Dominica. So how do you prioritize obesity treatment in a real world practice when the evidence access, tolerability and long term adherence to all of this needs to be considered, right? So now we have these treatments, but you know, we have these challenges. So how do you address that? Well, I'm going to show this next slide, but I mean obviously you're individualizing treatment and we do recognize that patients have different insurance concerns, right? So that's probably the biggest stress for most of you out there. It's one of the stresses for me doing all the prior authoriz ations, and also finding sometimes even if somebody has the indication , the insurance company's going to refuse , right? So I think we have to kind of coexist on several different levels when we're choosing obesity treatments, all right? So we can look at what the guidelines are from the ADA and the standards of care are going to be presented wait is today Sunday, no tomorrow Sunday . I've lost track of time in this hotel convention world. Okay, anyway, you can see that. But there are guidelines now of what we do. And then I'm going to go through that, and then I'm going to temper that a little bit with my sort of my own experience. But in terms of the guidelines, really, you want to have regular follow up with your patients , right? And I know some of you, depending on your institutions, you may not be able to follow up as frequently. I tend to see my patients once a month if I can because I often need to work with side effects, keep 'em on track, see what's going on , reinforce things, reinforce expectations, right? Because there's a lot of impact of expectations that probably are inappropriate just from social media and TikTok and Instagram and all that kind of stuff. So but the recommendation is to follow up at least every three months . I think from a behavioral counseling , nutritional standpoint, with some of these new medications, I can say that my dietary approach has really changed. I think historically, sometimes patients would get quite frustrated because I think that's a place where there's a fair amount of judgment where people would expect that they weren't having good healthy nutrition. But with some of these new Incrotin based therapies, actually our dietary approach is really helping people optimize their fuel. Again, it's the same thing we're talking about. We're really talking about health gains , okay? How can we help people make sure they get good nutrition? And if the incrotin therapy inhibits their appetite quite a bit, we need to optimize and make sure they're actually getting good fuel and they're not getting micronutrient deficiencies . And people are all different . So some people are doing great with fuel and some people are not. We do want to recommend regular activity just in the terms of strengthening , improving mood, et cetera. Not activity too. You've got to run more to lose weight, all right? The drugs are actually quite effective at helping with that, and you also need substrates so you, need fuel to exercise . However , it's from a basic conditioning standpoint to improve. Now you may have patients who really need many of my patients go to physical therapy. My average BMI is probably about forty three, but I have people with a BMI of sixty when they come into the clinic. And so we just really try to optimize their strength , help them feel better . Many of our patients are afraid that if they go for a walk, they'll fall and they won't be able to get back up. So sometimes the therapy is really working with that. We need to identify pain . We need to identify fear that they're going to have a heart attack . Okay. So I've sent people to cardiac rehab, and I mean, we've done a lot of different things. So that's important , but it's not just saying, Hey, go walk every day for thirty minutes or whatever. And understand that sometimes that's an evolution. Sometimes people have to just start where they are. And as they're able to lose weight, maybe they can add some activity, etc . And you always want to look at their medical history and look, are they on any medicine that actually is inhibiting weight loss , et cetera. So we do all the same things we always did , but now we have the benefit with these medications . So we do know from clinical evidence and this is what this chart is that these different dise ase states that we have been talking about that are aggravated by obesity, such as type two diabetes, hypertension, cardiovascular disease , the drugs in these categories with A have basic good, supportive clinical evidence from clinical trials that they are effective . So in an ideal world if you have somebody with Hef puff and you're not worried about insurance and payers and all that kind of stuff , you look in that box and you'll know the best evidences for samaglatide . And so you would give Samaglatide. However, you know that in a payer situation, if they will cover Terzepetide, you give them terzapetide because there's some evidence and certainly supportive. Same with sleep apnea, opposite, right? There is an indication and there's good evidence of tears appetite, impacting sleep apnea, etc . So this is just a nice chart to see what evidence is there as I select that medication. And then obviously you're going to look at tolerability because one of our big issues is efficacy and tolerability . And efficacy and sustained treatment depends on does someone tolerate it . Clinically we go very slowly with dose escalation. We don't try to go fast. The way I look at it is it's taken a long time for people to get here. The brain is very sensitive, and we just go with that initial dose or maybe a dose in very slowly and let that medicine support these other things and make those improvements. And there's tons of evidence to show some people are very sensitive to low doses. There is no goal to get to the dose unless the dose is not working and you gradually increase. But allow people to have that. And I know Carl and I have talked about this quite a bit. You can have very little side effect if you approach this appropriately , there is no time that you've got to get to the target dose. And let's just first sort of bring this together. So first of all, saying obesity remains the central driver of it. But so let's do this yeah, so obesity remains a central driver , you know, but we need effective care that requires a medication select selection, balancing, efficacy , tolerability, as we heard, goal is risk needs to be aligned and to integrate treatment and ultimately treatment should reflect the risk severity and the trajectory. So can I add ? I think the interesting framework that's rapidly evolving is cardiovascular guidelines, nephrology guidelines , diabetes guidelines , prevention guidelines, which has the obesity are now starting to look very similar . So when we say obesity based and or multiple even if it's the cardiology centric, let's say for secondary prevention treatment, we're going to be seeing very similar recommendations. So I think the thing to recognize it regardless of your specialty , that our momentarium of which agents we're going to prioritize and treat with are going to look very similar across the societies and guidelines. And I think that's important for us to recognize and maybe we're going to call them for different indications , whether you know in my field, it's going to be for the indication of obesity versus cardio kidney metabolic or cardiovascular not matter because most of them are actually rapidly enhancing the evidence to potentially find or get the indications in the package inserts as the ADA guidelines represented the level of evidence, but I think the field is so rapidly advancing, we're going to be seeing similarities across specialties. Good, well, let's now go and talk about who when and how in coordinating this multidisciplinary care. So this sort of tells us about this current multidisciplinary approach . You know, the primary care approach, the specialist list approach and also the shared care approach. So I want to go to our next video to really illustrate where we are in all of this. So let's go to the next video if you wouldn't mind moving on for it. Over time, our patient Sarah has seen multiple specialists, each treating a single complication in isolation. Her blood pressure, kidney function, and cardiovascular risk were managed separately , but no one addressed a chronic disease connecting them all. As her risks evolved around multiple systems, her care remained fragmented, reactive, and even siloed. And this is where the real gap lies, because when risk is multi system , care must be multisystem too . So let's now go to our next slide which really sort of shows us mult i system care and what that looks like . But Dominica, maybe I can ask you first, whenever I see something like that, it could be a bit scary . I would say it's very scary. Yeah , actually You know, I think that not every person is going to need all of this first of all, right? So you just need to identify what's going on with the person and if you are the person electing obesity therapy , which is the ideal situation, you start with that, and then you figure it out. Like all of my patients don't need to go to physical therapy, but I was talking about people who might need some physical therapy to get started , etc . So you can't look at it like, Oh my god, how can I treat a patient with obesity because I can't do all this? Like how much paperwork is that? I think you just need to focus on the individual in front of you, figure out what they need and come up with a plan. I do think it helps if you have people you know that you can trust with those referrals . But Backham, I really liked what you said earlier, which is also for all of us as doctors, you know, to take that personal responsibility to recognize what you said. Look, you know, I'm working in one of the top centers. I'm one of the top cardiologists, but it turns out I'm not measuring album inuria, right? So I need to educate myself or you made the comments say, listen, this whole liver thing, this is a big thing in my patients and I don't know enough about it. So how about this also us taking some responsibility . Though this concept is being recognized within specialties, cardiologists are now aware that liver and kidney are definitely cardiovascular risk factors for us, how to incorpor ate that in the implementation is lagging. I think the concept is how to work with the health systems, the payers for coverage. For example, we do have it in our guidelines, in the heart failure guidelines, to screen for heart failure when patients are at risk who are those individuals patients with diabetes, hypertension, obesity, hyperlipidemia, coronary artery disease, screen for heart failure with naturic peptides, which is a class two A recommendation. But the payers may not be covering it . So we are also advocating when suspected use it as a diagnostic measure. The systems of care will need to catch up with the evidence . And I think we need to facilitate it. And therefore now in our cardiology guidelines, we're putting UACR is card ai ovascular risk marker so that the payers will allow for that to be checked in my clinic because they may say why are you checking UACR? So I think the paradigm is shifting and the concepts are now going as classes of certain recommendations . ADA is spearheading a variety of these initiatives . HACC is owned the same and hepatology is owned the same. So what we will need to be aware is be cognizant of these things that are changing for screening , incorporate , raise our hands to our hospitals saying, well, we're supposed to be checking this , and we're supposed to be doing this . And I know there's a burden on the clinicians to having to do much more. Therefore, I'm actually also communicating with the health systems to incorporate it in EHR. If the HR says your patient appears to have the following indication and no counterindication for the following one, two, three, four indications . Dan, we know that the magnitude of burden of risk is there even without the prevent risk calculator. So things could be facilitated with the new modalities of care and algorithms and AI and others. I think we're getting there. And I also think it's not going to be only the special ists. I mean, we have community health workers. We have I'm always thinking of how the cancer model did this in terms of the screening and turning it to the pre level for intervention. And I think we're going to be part nering. All of us, specialists will need to be able to allow us to become consultants on the chart without delaying the care . And we are now coming up with yes, you can diagnose heart failure . And yes, you can initiate the therapy for heart failure and refer when sicker or have the following features. KDO did the same thing for refer when EGFR is below a certain level. CKD two is in all our lane . So we're all I am treating CKD two. You all are treating CKD two , three B even. So I think we need to be comfortable with these diagnoses and cross treat and know when to refer when they're advanced . And Michael, maybe last word to you, you know, is that scary and how what advice would you give us, how to communicate you know this to a patient, you know, because this could be incredibly daunting, you know , I came in with one problem and now suddenly I'm facing this plethora of you know, challenges. Yeah, I think if you've been living with the disease of obesity for your entire life, you're used to the fact that there's been building disease states, right? This is just the way it's been for me my entire life. But when I see that chart, what I see is way too many days off of work seeing too many specialists My immediate reaction is is there a way to like for me to see a limited number of people to take care of my care because I just don't have time to treat all of that, right? I think realistically, though, someone does have to take responsibility. Whoever you are as the physician or the provider seeing the patient , some of this is very easy in the sense of asking the right questions and looking at the blood work. And that you just have to pay attention to it. And I think if each of us does that , then patients get recognized and treated. So let's go to our take home messages here . And this is all about care models must reflect risk complexity . And the fragmented care leads to missed opportunities. So I think that's what we can all agree. It's when it's fragmented, that's the worst option. Multidisciplinary approaches should be early and proactive, but again it needs to be available to you and of course this coordination is critical to translating treatment into better pati ent outcomes. And that's why I certainly am promoting that obesity needs to be a primary care disease . And I need to be referred to twenty percent of patients that don't respond or may have some additional problems So we need to be able to empower our primary care physicians . So let's now move to our next question. So that's really all about targeting obesity to protect the heart, kidney and beyond Dominica maybe you can talk to us about , you know , what we see. We're going to run through some with the step step one extension because I know we're running out of time. All right, so this is the data. You may be familiar with these data from the step one trial with samaglatide. And in the first panel, what you see is in the gray, you see the weight loss with placebo , which is basically just lifestyle. And in the blue, you see lifestyle plus samaglitide with an average weight loss of about sixteen percent . And what they did is they followed patients a year stopping treatment . And what you see is Placebo group went back up to baseline and samagglatide group went back up, but not everybody went returned to basel ine . Basically, the message from this is it should not be a surprise given the physiology around obesity and the protection of weight and the very complex neuroendocrine regulation around it that when you stop the therapy people regain weight . And I still get this question all the time, obesity is not an infection. We're not giving antibiotics and everything's better , all right? And it's not a surprise that we need to treat and we now have treatments, but you need to talk about it with your patients. I find that patients accept chronic treatment much more readily than my colleagues. I don't know why that's the case, but probably because they've been suffering so long from it. So it is a chronic treatment. We're learning about maintenance. We don't know why some of these folks didn't go all the way back, but there were a lot of main tenance trials now, and we will understand more of what is going on with maintenance. Some of the things to understand and what you're going to see about the future, and I'm going to give you kind of a very brief thing on this is why do we need other treatments? Well, first of all , all of us know from treating our patients , not everybody is sensitive to our current therapies , right? Probably every single, I know every one of us, but every one of you guys probably has had someone sitting there very frustrated because their aunt or their sister or their brother responded to these drugs tremendously and they're having no response . All right . It's complex . Not everybody is responding to incritin therapy. So we need alternative approaches . Not everybody loses the weight that their sister and brother and everybody else in the world lost . So we know there's a heterogeneity and response, right? We see a bell curve for everyone. And I know no one wants to believe this, but go back to the papers there are some people that gain weight on these trials , all right? And that's the physiology and it's very hard for you if you have that patient sitting in front of you and they're actually gaining weight on obesity medications. So we're going to need additional therapies. Some people don't lose enough. We're going to need combination therapies. It's also something that we're looking at and thinking about is what happens when there is a dietary restriction. Well, you may lose bone mass . And so you're going to see new developments trying to figure out how do we protect bone mass? And that's with every calorie deprivation situation. It's not just with incritins. And we're looking at that data. How do we preserve muscle? There's a lot of discussion about fatigue, and are people losing strength or not, or are the muscles becoming functioning better because we're getting rid of myosteatosis, which is fat deposition in the muscle . So you're going to see now more and more trials looking at muscle, not just in terms of quantity and loss, but also function . Because at the end of the day, how are your patients functioning? We see this all the time. The patients at all the trials report that they're functioning better. They're doing better . And we have papers showing that people with the poorest of physical functioning are actually functioning quite a bit better. All right. So these are the considerations. You're going to see a lot of different modalities. We're going to be looking at monthly dosing. We're going to be looking at oral medications . People do have injection fatigue. There are people who want to switch just to switch because they want to try a new therapy. So there's a lot going on in the future and you will see more and more options for our patients to individualize therapy. So there's a lot of different mechanisms. We're not going to go through it at length, but I think it's important to understand what is going on. A lot of most of you guys are very familiar with GLP Ones because we've used them for diabetes as well as obesity, all right ? But there are other molecules that have been identified, other GI peptides that actually also participate in signaling to the brain . And so we're all aware of the dual agonist GLP one with GIP . And it's the whole idea of dual agonism is combining physiologic effects to optimize efficacy in terms of weight loss and also certain or gan targets and disease states, but at the same time hopefully improve tolerability . And I think many of you know that some of the early work with GLP one and GIP has shown that there's less nausea . We do see more weight loss on the average . There is thought to be some increase in lipolysis and some fat targeting and we're going to see how that happens. We did have our one question about gl ucagon. I'm not sure why that was isolated, but anyway, so you're going to be seeing and if you heard Red A Trutide today, right, a triagonist including glucagon and the question of, you know, are we going to see increased energy expenditure perhaps because of lipolysis? A lot of the glue we saw tremendous weight loss today . Surgery level weight loss that we have never ever seen with it. We saw improvement with A one C, but the weight loss was tremendous. And these were in patients with a BMI greater than thirty five . All right . So besides the weight loss though, the gluc on entities and you're going to see more research coming out is going to be focused on improvement of what we've been talking about the liver, hepatic stiatosis, changes in fibrosis , as Bikram showed you. So watch this space. Now we also have amylin, right? And there have been a lot of talks today about or not today, well, this whole time. As I said, I'm losing track of where I am. But anyway , an amylin monotherapy and adding amylon. Amylin works at different parts of the brain, and again, it has actions . And so the idea is can it be complementary to GLP one ? We also think that at least some of the targeting amalin may improve bone . Because that is a question that we see. So will some people respond who don't respond to GLP ones and various GLP combinations? Will they respond toalin A?m We're going to be learning a lot from the new studies that are coming . Next generation therapies, you're going to see, well, we have oral GLP ones now to improve convenience for patients , but you're going to see more oral forms of these drugs. You're going to see a huge opening up of amalin based therapies and there's a lot of information coming in a lot of drugs in development. And you're going to see all various combinations with this idea of how do we get better weight loss and durable weight loss. People need to keep taking it . How do we have certain medicines for certain targets of systems and individualizing approaches . Thankfully for all of you, I'm not going through each one of these , but this is just showing you how many different therapies are under investigation at Phase two , phase three trials , both for GLP one, oral therapy, amaline based therapies at variety of stages , combination approaches, GLP, glucagon, GIP, and all stages . I'm now going to maybe start with Biker. Maybe if you wrap up, what have you learned from our discussion at this point? What do you think we have really taken from this? Please wrap it up. Think beyond BMI , screen for the cardiocidney metabolic liver , message the benefit beyond weight los for risk reduction in the whole cardio kidney metabolic liver realm. That messaging, especially with the burden of disease, is critical , especially individuals who have the diseases or the cluster of diseases. So it's critical for us to do this in a collaborative manner and as I mentioned before, do not miss the opportunity to diagnose all these other diseases. The diagnoses are not very tough or complex . It just requires simple screening. And we're trying to make it simpler at a scale, at a large level. And I think we'll need to be able to message this. And I know it could be potentially disheartening for the patient, but we want to also move it to the prevention role. We're screening you for this. Even if we were to diagnose it, it will be at early stage rather than in a hospitalization with a very adverse event. And thus , even if we find, let's say a teroscotic disease and or heart failure will be able to prevent progression. That's going to be the message that I would love to convey. And Dominika, what do you want the audience to do differently on Monday ? Well, I would agree with what she said. I think just listen to your patient, recognize and respect your patient . And the future is bright , remind them that it's not their fault and empathy Empathize with their situation. I can say, you know, the future's bright. We've got so many exciting molecules coming , so many different drugs . And if you have patients who can't respond to things, find research strategies, find programs, find them other options to help them medically , besides everything Beakrim said. And Michael, if you walk into a clinic on Monday from any of these good doctors that are joining us tonight, you know, what would you like to experience differently to what you have done so far? I would want to walk in and hopefully one of the things you've walked away with is the fact that anyone who's been dealing with the disease of obesity has decades of medical trauma behind them . And if you walk in and see them as a person not to go right through your differential, but to see them as a person immediately , ask the questions and then treat their disease and tell them it's not their fault. You will be their hero and you may save their lives. That's wonderful. Thank you . But ultimately, I really want to thank you in the audience for participating in this. I certainly have learned from your responses. So thank you very much for that. But I also want to thank the panel, you know, for your generous time and really the insights that you've given us. Again, thank you very much also, you know, to the organizers and of course the support that we have receives from AstraZeneca. So I hope you enjoyed the rest of the meeting. I hope you enjoyed tonight and thank you so much for your time . This has been an activity published by Peer Voice.