Hello everyone. Welcome to the first joint session of European Association for the Study of Obesity and the American Association of Clinical Endocrinology. I want to thank ACE and ESO for organizing this session. Please post your questions for speakers, which will be addressed at the end of the session. Dr. Dicker and I will be moderating the session. He is the head of internal medicine and obesity clinic at Tel Aviv and is the co-chair of the Obesity Management Task Force ESO. We have the pleasure of having four internationally renowned obesity experts for today's session. I will introduce the ACE speakers and he'll be introducing the ESO speakers. Dr. Garvey is the Butterworth Professor of Medicine in the Department of Nutrition Sciences at University of Alabama in Birmingham. He has achieved international recognition for his research in type 2 diabetes and obesity. The research has furthered the understanding of obesity as a chronic disease. As ACE board member and chair of ACE Obesity Scientific Committee, he has been a leading contributor and author to several obesity ACE initiatives. These include the position statement and proposition affirming obesity as a disease, the ACE evidence-based management guidelines for obesity, and a cardiometabolic disease staging system. Dr. McKenick is the professor at School of Medicine at Mount Sinai. He is the Medical Director of Center for Cardiovascular Health at Mount Sinai Heart and Director, Metabolic Support, Division of Endocrinology, Diabetes, and Bone Disease at Mount Sinai. He currently serves as chair of the Board of Visitors for the College of Computer Mathematics and National Sciences at the University of Maryland. He's the past president of American College of Endocrinology, American Association of Clinical Endocrinology, American Board of Physician Nutrition Specialists, and currently chairs the Physician Engagement Committee at ASPEN. He has more than 370 publications, 80 chapters, and 10 books. Thank you, Monica. We are honored and privileged to take part in this joint session. So I want to present Professor Gemma Furtberg. She is the Co-Director of the Obesity Area at the Clinica Universitat de Navarra in Pamplona, Spain. And she is also co-chair of the Scientific Advisory Board for the European Association for Study of Obesity. And also Professor Luca Busetto. He is Associate Professor of Internal Medicine, Department of Medicine, University of Padova, and is also a co-chair of the Obesity Management Task Force for the European Association for Study of Obesity. And very recently, he is the president of the Italian Obesity Society. So I'm looking forward to this session. And what I'm going to do is provide an introduction to this new framework of obesity, which we term adiposity-based chronic disease. And here is the outline. You saw my disclosures. Here's the outline. First, we'll talk about the problem. And then we're going to move on to the different models of chronic care model, adiposity-based chronic disease, provide some context for dysglycemia-based chronic disease, and of course, cardiometabolic-based chronic disease. We'll begin with the ACE obesity care model. And in this model to the left panel, you can see that we begin in our patient encounters really not just with a medicine or with lifestyle, but activating the patient for change. This is the behavioral component. And also you can see to the right that the ACE model begins with an anthropometric component, which is really centered on BMI, and then a clinical component, which is centered on an inventory of obesity-related complications. With that, then there's staging of the disease, selecting or mapping to a particular level of prevention. And then that prevention can be fleshed out into certain interventions, which can be lifestyle, judicious pharmacotherapy or procedures. But what happened was we realized that just focusing on BMI as the anthropocentric component felt short. It generated some paradoxes and controversies. So we reasoned that, and particularly taking into account different populations around the world and different phenotypes or expression of obesity, that there were components of adipocyte distribution and also function. And together, this would be contextualized by the environment and behavior, physical environment and non-physical environment, which is culture, to produce an obesity phenotype characterized by the burden of disease or complications. And in fact, you're going to hear a little bit later by our other speakers on the European Association for the Study of Obesity and their incorporation of ABCD in their position statements. Here you can see using photonics, this is from a chapter in our Lifestyle Medicine book by Dimna Gallagher, looking at three individuals all with roughly the same BMIs, but look how there's a difference in the distribution of body fat, particularly with age. And you can see with those differences in distribution, android versus gynoid, that the android distribution with more visceral adipose tissue was associated with different hormonal changes, particularly insulin resistance, but also changes in lipids that follow. And moreover, besides just the distribution, you can see through high throughput analysis and molecular analysis that in fact, the genome and the epigenome are different depending on the type of body fat. You can see in the top right panel that with the android distribution, you can see increased inflammatory markers, whether it's IL-6 or monocyte chemoattractin peptide one. And there's a correlation of the android versus gynoid habitus and deposition of visceral versus subcutaneous fat on the way we see other metabolic syndrome traits evolve like hypertension and lipids, triglycerides and cardiovascular risk. Now, here's a paper that Tim was part of, it was a paper using the VemSols registry in Venezuela. And looking at the far left, you can see that the pie distribution of the various stages for obesity, overweight, normal weight using just BMI in that dark gray, relatively under detects patients at risk compared to B the obesity complication centric model of ACE or C looking at body composition and how much body fat or D looking even specifically just at the waist circumference, like you might see in South Asians. So clearly we need better metrics for early detection and therefore early and sustainable prevention. Now, what's the context of this ABCD model? You can see to the far left, it feeds into insulin resistance and then propagates a whole spectrum of dysglycemia. So rather than looking at pre-diabetes or diabetes in isolation, we aggregate insulin resistance, then a beta cell defect early pre-diabetes, late type two diabetes, and then further on vascular complications, macrovascular from insulin resistance, microvascular from hyperglycemia. And with different ethnicities and races, this may change for instance, in South Asians, you'll see the insulin resistance and the beta cell defect occurred together very early on. Whereas in other populations, you have insulin resistance and then beta cell defects. Here's another way to look at it. You could have adiposity based chronic disease and have an insulin sensitive phenotype where you still have biomechanical complications. The patients are not overall healthy. They may be quote, metabolically healthy. And then you can have an insulin resistant phenotype with the full force of that dysglycemia based chronic disease. Now, how does the adiposity actually start that dysglycemia and cardiometabolic chain of events? Well, one avenue is going to be via macrophages. So in beige, brown adipose tissue, more healthy adipose tissue, you can have M2 macrophages, but in white adipose tissue, inflammatory adipose tissue, you can have transformation to M1 or pro-inflammatory macrophages. And then on the right panel, you can see that involvement of insulin resistance, not only of adipocytes, but also in muscle and in liver, you can have a global whole body insulin resistant state. How does this happen molecularly? Well, there are lots of theories how increased or abnormal adiposity can cause a beta cell defect. But in one popular theory, this is a murine model. You can see that macrophages are the dominant immune cell in obesity associated islet inflammation. And in fact, in that top panel with all the colors, you can see that in red with the staining, the macrophages are engulfing the yellow insulin containing beta cells. So you could have apoptosis, but you can also have the cellular destruction of beta cells, decreased beta cell reserve, and then the hyperglycemia. So you can see this all fits together in one narrative. Now, ABCD can actually go toward cardiovascular disease. Epidemiologically, you can see with increased BMI, you have more cardiovascular risk, morbidity, and mortality. In fact, there may even be a little bit of a paradox and some reverse causality because patients with increased years of cardiovascular disease will have a higher BMI, not what you would think, but maybe that higher BMI gets them to medical attention a lot sooner. And then you can intervene earlier to prevent or at least mitigate the progression of that cardiovascular disease. Now we pull it all together in cardiometabolic-based chronic disease. At the top, the adiposity component, the dysglycemia component intersecting with insulin resistance, and then cardiovascular disease, atrial fibrillation, heart failure, accelerated atherosclerosis, coronary artery disease, coronary heart disease. And in my final schematic, COVID. Of course, we need to talk about this. This was a paper that we wrote in Jack in the midst of that first wave here at Mount Sinai. And we put this together and you can see where adiposity-based chronic disease plays a role. To conclude, ABCD pertains to increased adipose amount, distribution, and function. Cardiometabolic-based chronic disease is the context for ABCD. Lifestyle medicine is a cornerstone of therapy. Nutritional medicine is the core component of lifestyle medicine. And then there are novel pharmacotherapies, not only commercially available, but coming down the pipeline, which you'll hear about. What are the next steps? Better body imaging, molecular testing. We need validation studies of the ABCD model and better education and guideline directed management. Thanks so much. Thank you, Professor Mocznik. So now we want to move to the second talk. So I want to invite Professor Gemma Fodbeck. She is the past president of IASL and now she is acting as the co-chair of the scientific committee of IASL. And she also a co-director of the obesity area of the Clinical University de Navarra. Professor Fodbeck, please. So thank you very much. First of all, I would like to thank the organizers for inviting me to present in this joint session with our American colleagues. It's really a great honor and pleasure. This is my conflict of interest slide. I'm based at the Clinical University de Navarra in Pamplona, Spain, and I'm co-chair of the scientific advisory board of IASL. When I talk about obesity, I really put the slide of NASA's space shuttle and I always say that obesity is not rocket science, that it's really much more complicated. However, in the area of personalized medicine, obesity diagnosis and management seem to be frozen in time. And we know that precision medicine really requires a different approach, focused more on individual characteristics, which we know are going to determine the response to treatment. So when I started as president of IASL in 2012, one of my main objectives was really to change the international classification of disease definition of obesity and also to set up a beyond BMI working group. John Blandel, the chair of the scientific advisory board, then really led this working group and we just released this statement, Beyond BMI, where we really identified the need to do much more detailed phenotyping, but we also identified that we need to talk more about obesity instead of obesity in singular. We also just released the need for a paradigm shift in adult overweight and obesity management and our obesity management task force really was very active and still is, and they're really fantastic in updating and producing clinical guidelines for our healthcare professionals and also for the patients. Our Canadian colleagues had already set a hallmark with the Edmonton Obesity Staging System and I very much like this because they really focus on how healthy the patient is based on medical, mental and functional impact of obesity instead of focusing only on a number or a BMI. They just set the framework where they looked at the mechanical and also metabolic alterations, but also incorporated the psychosocial and economic ones, which we know are very important drivers for obesity and also barriers to treatment. In this case, they really identified that in stage 0 there are no apparent risk factors, in stage 1 you have already preclinical risk factors, stage 2 established comorbidity, stage 3 end organ damage and stage 4 is the highest degree. And then we were able to show that this staging system predicted mortality and it did much better so than the BMI, where you see on the left panel how the different BMI categories really overlap, but when you use the Edmonton Staging System, they very nicely separate in black those individuals with no risk factors, just having a low mortality and mortality increasing as you progress within the staging system. So in 2017, our American colleagues really released this position statement on the ABCD concept that Professor McCannick so nicely outlined before me. And we also released our proposal to improve the ICD-11 diagnostic criteria for obesity based on a three-dimensional approach, where we looked at etiology, the degree of adiposity and also the health risk. We also made our contribution to the ABCD concept of obesity, focusing, as was mentioned before, on the importance of looking at the amount, but also the function and distribution of fat, because we know that it's going to entail what we call the fat mass disease, which is mainly based on altered pathological mechanical forces, but also the sick fat disease, which relates to deranged endocrine and immune responses that Professor McCannick highlighted before. Moreover, this needs to be put into a physical and cultural context, because we know that the impact on health of a person is going to be determined, obviously, by gender and also age, but obviously also by how many years this individual has been exposed to obesity. This is going to affect the predictive signature of risk, taking into account potential protective effects and even more so the detrimental influences. And this really sets the basis for an adiposity-based complication and disease staging system. We need to be aware that there is a continuous spectrum between a healthy and unhealthy profile, and we really need to focus much more on identifying what's the contribution of adipose tissue metabolism, obviously about fat cell dynamics, the different characteristics of the muscles, gene expression analysis, and also the effects of exercise training. And we need to bear in mind that obesity really exerts multisystemic effects, and it's important that we incorporate those in the need for a patient-centered approach. So, setting new criteria to define a healthy weight based on pathophysiology, we really should pay attention, obviously, to body composition, obviously, as was said before, to visceral adiposity, but more so, we also need to focus our attention on the pancreatic reserve, what's the situation of the liver fat, the intramyocellular fat, obviously, cardiometabolic risk factors and endothelial dysfunction, and other alterations like sleep apnea. When we have a patient in front of us, the clinical features that we identify obviously depend on the genetic background, and we now, we do have much more sophisticated tools to really identify what's the situation in our patients. We really need a much more detailed assessment of comorbidities, and not only of all comorbidities, but also the functional degree, because when we have a patient with normal glycemia, in 30% of the cases, if we challenge this patient with an OGDT, we may see that it has already impaired glucose tolerance or it even has overt type two diabetes. So it's important that we really address that in a more functional way. We also need to pay attention to the stress axis. Obviously, we need to take into account the environmental influences where climate change, global warming, endocrine disruptors, but also urban planning determines the development and also how the patient may deal with the obesity problem. We also can have into account epigenetic changes. And one of the important aspects is the syndemic one, which incorporates the psychosocial, economical, cultural network that we are looking forward to determine in a more precise way. Therefore, in the future, we should be really looking forward to studying all these different layers or networks that really determined obesity development, the metabolic one, the disease one, and the comorbidity ones, but also the socio-economical ones. And I started with a picture of NASA. This, I will just end also with a picture of NASA. This is more recent. It's a couple of months ago, showing just the parachute deployed during the descent of the Mars Perseverance rover. And we were told that there was a hidden message within this irregular pattern of red and white stripes. And it said, dare mighty things. And I'm really looking forward to just achieve great things for our huge community together and in collaboration with our colleagues. So I will leave it here. Thank you very much for your attention. So- Thank you, Professor Furberg. I will- Yeah, Gamma, you want to say something, Gamma? No, thank you. That's fine with me. I will be happy to take questions at the end. Great. So thank you. And now we have to take this, all this concept of the ABCD into the clinical field. And for this task, I want to ask my good friend, Professor Luca Busetto, who is Associate Professor in the University of Padua. And he's also the new president of the Italian Obesity Society and my co-chair of the Obesity Management Taskforce in IASO. Professor Busetto, please. Thank you, Adrian. And I am really very pleased to be here with this very nice panel of colleagues and friends. And I think that it's very important where this kind of collaboration across the Atlantic Ocean, because we are working together. We need to work together more than in the past. So the title of my presentation will be the clinical, the application of the ABCD context in the clinical practice. So we learned from our previous speaker, the complexity of the new concept of ABC, the importance, not only of the amount of fat, but only, but also the importance of fat distribution and the importance of the function of adipose tissue. So how we can translate this new concept in our clinical practice, because our clinical practice is still based on old concepts. And we still continue to work based on the old concept of BMI-based disease. For doing that, I decided to go through an overview of the clinical guidelines, because clinical guidelines are the means in which we try to translate our knowledge into the clinical practice. So they are very important in understanding where we are now and where we want to go in the future. So I will start with the current European obesity management guidelines for adults that we published more than six years before. And I will start from here for three reasons. First, because I belong to HIESO and this is my guidelines. The second one is that I was part of the group that wrote the guidelines. And therefore, this is the third question, I am also free to be critics about these guidelines without the fear of offending other people around the world. So what are my critics now regarding these guidelines? First, these guidelines are very prudent. So we decided to enforce or increase the intensity of our treatment according to the presence of complication of obesity. And this is strange because of course, we should be more active and intensify our treatment before the occurrence of complications, at least in patients with high risk of having complication. The second point is that we are very not prescriptive. So we put all the three branches, lifestyles, drug and surgery, pretty at the same level. We prescribe when we can do anti-obesity medication, we can use anti-obesity medication, when we can use surgery, but we don't say when we should use or we should recommend anti-obesity medication or bariatric surgery. And in my opinion, this is a way to enforce therapeutic inertia. So we can have patients with very high BMI, complicated obesity, still staying on lifestyle modification for a year before having a more intensive treatment. And third, we are still too much based on BMI. So we still remain with the BMI as the most important driver of the therapeutic decision. Now I will move to the guidelines produced by our colleagues in the United States, the American Association of Clinical Endocrinologists Clinical Practice Guidelines. And indeed we move a bit forward. For first, on the anthropometric basis, we decided to consider BMI in a more critical way. They reinforce the importance of measuring fat distribution. And also they claim for a clinical interpretation of BMI eventually with the use of body composition techniques in those cases in which the BMI level can be misleading because not representing the real body composition of the patients. And more importantly, they couple the anthropometric component of the diagnosis with the clinical components. So a very profound, precise evaluation of the complex clinical state of the patients. And on the basis of these two components, they decided to move toward a staging of obesity. And I believe that staging is a very important point because in most of the chronic diseases I know, decision about therapy is based on stage of the disease, not on BMI or other parameter, not on glycemia, but on stage of the disease. So it is very important to introduce this concept and to decide what therapy to use according to stage. One possible critic here is that in my opinion, the staging is too much concentrated on the medical or metabolic complication. And in these guidelines, yes, we have depression here at the bottom, but we know that mental complications and in particular, physical complication are very important in determining the staging of obesity and the burden of the disease in our patients. So I think that we need to incorporate more the mental evaluation and the physical function. And this has been done by our Canadian colleagues. Gemma already talked about the Edmonton Obesity Staging Systems that try to incorporate these three domains in the clinical evaluation of the patients, the medical, the mental, and the functional. I don't go through the description of the Edmonton Obesity Staging System because I believe that you are aware about that. And Gemma explained the significance of the system. And this system has been incorporated in the Canadian guidelines as a means to staging the situation of the individual patients and to decide the intensiveness of the therapy according to the stage, more than according only to the severity of obesity, BMI, and so on. The importance of the Edmonton Obesity Staging System is the demonstration already shown by Gemma that it can be more predictive of survival or mortality than BMI classes. It's independent from BMI. So you can be in every stage according to Edmonton, whatever your BMI is. Of course, there is a tendency to associate because people with higher BMI tend to have higher Edmonton score, but you can have a significant amount of patients with high Edmonton score, even at lower BMI. And these patients need to be treated as intensive as patients with higher BMI with the same staging, in my opinion. One problem with the Edmonton is that most of the patients tend to concentrate in stage two because most of the staging is guided by the medical component. With our groups in Padova, we try to improve our ability to describe the physical component by introducing in the evaluation of the patients, the real truth of the patients are derived by the cardiopulmonary exercise testing. This is a paper that is accepted in the International Journal of Obesity. We revised it last week. So I hope that it will be published very soon. And in this way, we were able to reclassify patients according to this new Edmonton score and we increase the importance of the physical component in the staging system, because we believe that the more strict evaluation of the physical component of obesity is as important as the medical or metabolic component is. Of course, this is only a proposal and only one study and we need to work more on this field. So I will move to my closing messages in order to leave space for good discussion at the end. I believe that the complexity of obesity requires diagnostic and staging processes that should integrate anthropometric and clinical data, medical, functional and mental domains. And we already did something in this field. The decision to treat or what treatment to use should be made more on clinical staging than simply on anthropometry. And I believe that we need to more prescriptive in this field as many other guidelines for the treatment of chronic diseases do. And finally, the construction of a common and shared diagnostic and therapeutic framework is highly advisable. And this is the reason we are very happy to organize a meeting and to work with other society around the world. So thank you again for your attention and I leave the floor to the last speaker. Grazie. I'm going to now invite Dr. Garvey to do it for his presentation to share his clinical insights. And I would like to remind the attendees to post their questions for the panel, which we'll discuss after this talk. Well, thank you very much. I'd really like to thank Dr. Garvey and thank the organizers of the meetings and my colleagues on this session. The title of my talk is Medical Management and Newer Therapies for Obesity. And this is within the context of the diagnostic term adiposity-based chronic disease that's been embraced by ACE and ASO. It tells us not only what we're treating, abnormalities in adipose tissue mass distribution and function, but why we are treating it, namely that it's a lifelong disease with complications that impair health. And this is all consistent with... I'm having trouble advancing my slides here. Can you pull it on full screen, Tim? Yeah, I can't see that component in my... Okay, here I see it. Yeah, great. That's... And we put this in the context of the ACE obesity guidelines with its complication-centric principles for treating ABCD, which namely we treat obesity to improve the health of the patient. And that's the prevention and treatment of obesity complications, whether they be cardiometabolic, biomechanical, or quality of life issues that were mentioned by Luca. And it's the prevention and treatment of these complications that's a goal and endpoint of therapy, not the loss of the given amount of kilograms per se. And when you look at how much weight loss it requires, and this is all evidence-based, to address the various obesity complications, you see it here. 10% weight loss is maximally effective for preventing progression to diabetes. But in treating diabetes, we know from Luca had, the more weight loss, the better, including greater than 15% for lowering blood pressure, improving dyslipidemia, and improving hemoglobin A1C. For NASH, you need 10 to 30% to address fibrosis and inflammation. And really 10% weight loss in sleep apnea to get predictably improved scores on the apnea hypopnea index. And you see some of the other complications there. And when you look at this, you realize we really need 10% weight loss or more if we're gonna effectively improve the health of patients by preventing or treating these complications. And this is where we are now. You see this range of categorical weight loss and the efficacy of current therapies. We know we can get two to 7% loss of body weight through lifestyle. If we use diabetes medicines associated with modest decrease in body weight, we can get a two to 6% decrease in body weight. We can do better with obesity medicines, four to 10% loss of body weight, but we're still not approaching the degrees of weight loss we can achieve through bariatric surgery, whether lap band or particularly by a gastric bypass or gastric sleeve. So we need better medicines and more effective medicines, but help is on the way. This is a partial list of emerging pharmacotherapy, medications that target gut hormones, act on the CNS, nutrient sensors, anorectics, drugs that increase energy metabolism and other mechanisms. And I'd just like to address a couple, just a few of these by way of example. And we've all heard the good news this meeting about somaglutide. This slide just shows the structural alterations of the basic GLP-1 peptide, which make it a longer lived molecule, allowing for once a week subcutaneous injection. And we've all read the four phase three clinical trials in the STEP program of somaglutide, step one, two, three, and four, all published this year in JAMA, JAMA Lancet and New England Journal, all showing very nice effectiveness. And I'll just show step one here. We see on the left base body weight change, weight loss over 68 weeks. At the top in the gray curve, you see placebo plus lifestyle, 2.4% decrease in body weight. On drug, whether in trial data, analogous to intention to treat 14.9% loss. On treatment, I guess analogous to completers analysis, 16.9% weight loss. And the categorical weight loss on the right is really impressive. Over half of patients lost 15% body weight or more, and a third lost 20% body weight or more. When you look across these step trials on treatment data, step one, three, and four, weight loss of 16.9% to 18.2%. Step two in patients with diabetes, less weight loss, 10.6% compared to 3.1% of placebo. We often see this in interventions in diabetes where they're a little less effective with respect to weight loss. What about other targets? Well, there's amylin. We know this is a peptide secreted with insulin from pancreatic beta cells. It activates the calcitonin receptor, inhibits gastric emptying, suppresses glucagon. It also inhibits appetite by binding the calcitonin receptors on POMC cells in the arcuate nucleus and in the area of post-tremo. It's rapidly degraded, so modifications are needed to make it a longer lived drug-able compound. And this has been done. This is a long-acting amylin by Novo Nordisk. This is a early study that just shows dose ranging for amylin alone. You can see that the highest dose, there's a minus 10.8% weight loss after only 26 weeks, and the weight is still decreasing. What if we combine this long-acting amylin with somaglutide 2.4 milligrams? Well, this is what we see in this phase one study, a weight loss on maximal doses of these medicines of 17.1% after only 20 weeks, and it's still decreasing. And this includes 16 weeks of drug escalation. So very promising drug targets here. We're very hopeful about these compounds. Of course, many companies have looked at what we call unimolecular multihormonal agonist single peptides that incorporate active components of GLP1 and our glucagon and our GIP, either by chimera or peptide fusion technologies. GLP1 of course makes sense because it produces weight loss via CNS effects and also augments insulin secretory responses for glycemic control. Glucagon may be a little counterintuitive since it raises glucose and increases hepatic glucose output. However, it is thermogenic and lipolytic. GIP also, there's arguments for either agonism or antagonism being justified. It can amplify effects of GLP1, but GLP1, I mean, GIP rather, and GIP receptor knockout in rodents is protective against obesity. Nevertheless, a large number of companies are working with these bifunctional, trifunctional proteins, whether it's GLP1 glucagon, GLP1 GIP, GLP1 glucagon GIP. And this is not a complete list. Amgen, for example, is working with GLP1 agonist and a GIP antagonist rather than agonist. So I think there's going to be a little bit of luck involved. There's going to be these different combinations, put them in humans and see which one works out the best. And of course we have seen this published phase two data with terzopatide from Eli Lilly, GLP1 and GIP agonist in patients with type two diabetes. On the left, you see very nice decrements in hemoglobin A1c, 2.4% units decrease after 28 weeks at the maximal dose. On the right, a decrease in body weight of 11.3% in these diabetic patients. So again, a very promising area for drug development. And one final target, maybe earlier in development, but I think fascinating is active in type two receptor antagonists. Now active in type two receptors negatively regulates skeletal muscle growth like myostatin. And in humans, an antibody that blocks active in two receptors by Magruvab has been shown to augment lean mass in patients with sarcopenia, for example. And here's a trial that was published administering by Magruvab to insulin resistant individuals. On the lower left, you can see the increase in lean body mass following I think a single injection of this antibody over 24 weeks. And you can see a dramatic increase in total body lean mass. On the top, you see it also decreases fat mass pretty dramatically. And all of this was accompanied by a 20% increase in insulin sensitivity by clamp studies. We also have a recently published a month or two ago, a phase two study in patients with type two diabetes and obesity. You see a total body fat mass in this graph, placebo on top. You can see that this drug led to a decrease of about eight kilograms of fat mass over 48 weeks. In fact, 96% of subjects lost 5% or greater body fat by Magruvab versus 21% on placebo. And this was associated with an increase in lean mass of 1.7 kilograms. So when you have a drug with these characteristics, you can't measure your response by BMI or even body weight. You have to look at body composition because lean mass is increasing and look particularly at loss of fat mass. So very exciting. So as I started out with, this is where we are now, but with the advent of these new medications, achieving 15 to 20% loss of body weight, I think at this point, when hopefully they become available to patients, weight loss becomes the primary therapeutic goal in patients with type two diabetes, including glycemic control. And this is sufficient to address many of other weight related complications to improve the health of patients. And I think leads us to a new way of thinking about how we treat obesity. And that's mainly treating the disease to target. We treat other chronic diseases to target type two diabetes, hypertension, and atherosclerosis. We use biomarkers, hemoglobin A1C, blood pressure, LDL cholesterol, not that we care so much about these particular biomarkers, but it's the reason we pay attention to them because we know if we control them, we can prevent complications, which is the reason for treatment in the first place. And these complications are listed here. Why should obesity now be any different with these more effective medications? Yes, we follow BMI, but we really are treating the BMI in essence to prevent or treat complications, which is the end goal of therapy. And those, some of these complications are listed here. So these are kind of the range of weight loss that we need to address various complications. The orange color is cardiometabolic. The light blue is biomechanical. You can see these ranges of weight loss that we need based on data. And with these new medications, again, we're losing 15 to 20% loss of body weight, which covers all of the, essentially all of these complications. So we can now think about individualizing care, treating weight loss to target in order to prevent the complications that any individual patient might have. So thank you very much. Thank you to all our presenters on this very informative topic. We will now go ahead and open the floor for Q&A. Please type your questions in the chat. I'll start with the first question from Megan. And the question is for, I'll ask that to Dr. Garvey, that there is, what are your thoughts about using the word obesity in our medical records since patients have access to them? And there is an emphasis on patient first language. We often use obesity. So what would you say to our providers? Well, this is an important consideration. Patients tend to not like the term obesity. When approaching patients, we also, we usually say we want to discuss your weight or your weight problem and how that's affecting your health. And you're right. Now, patients have access to their electronic medical records and there's potential for exacerbating stigmatization and defeatism on the part of patients and low self-esteem. I think if we've explained the implications of excess adiposity on health and use the term adiposity based chronic disease, that can be helpful. Although that's a medical diagnostic term for clinicians at this point. I don't think it's universally or widely embraced by patients, but it's important to use it in the context of person first language. I mean, these aren't obese patients. They're patients with obesity. They have a disease. It's not part of who they are. It's not their fault. And so that is important in kind of minimizing these effects, even in the electronic medical record. Yeah. I also want to add, Tim, I absolutely agree, but we know that most of the electronic health record does not put obesity as a diagnosis. And we also know that putting the diagnosis is double the chance to treat those patients. So putting the diagnosis of obesity is crucial for the treatment of people with obesity. And we have to really urge all the system to change from obesity to people with obesity, but this is manageable. It's very important to put obesity in the diagnosis list. Okay. So next question, are there algorithms or questionnaires or scoring systems which can help determine staging of obesity in a busy clinical practice? Jeff? Well, yeah, thanks so much. Well, you mentioned, Hema mentioned in her talk on the Edmonton and Tim Garvey has his own cardiometabolic scoring system. These are validated scoring systems. And so we have scoring systems that are used to not only predict risk, but also to guide treatment. I think what we're trying to do is have specificity and sensitivity for these scoring systems. But they're fraught with some problems. I mean, you can consider the ASCVD scoring system and the way in which we incorporate lipids, for instance, into management for cardiometabolic-based chronic disease. But the answer is yes, we do have these validated systems as our knowledge, our basic understanding of diabetes improves, the theoretical constructs improve. We recognize the pragmatic difficulties in the management of patients with obesity, getting reimbursement for behavioral medicine, reimbursement for sleep hygiene, for nutrition, for exercise, for stress reduction, for tobacco cessation, for all the modifiable cardiovascular risk factors. We need to have a more granular, more detailed way of characterizing this chronic disease. And again, I would go back to some of the papers that Tim's wrote on coding and trying to leverage this at the socioeconomics level and with social determinants of health and disease. But yes, we do have scoring systems in place. Can I add to that? Yes. I think EASO and ACE, I really think have been leaders in advancing a complication-centric approach to care and staging the disease on that basis. And I think if we're going to be coding disease, which codes are used, like ICD codes are used differently in different societies. Some people use them epidemiologically to study disease prevalence. In the U.S., it's largely a billing platform. But if we're going to make a difference here, we need to have a more sophisticated coding system that registers how sick the patient is, the severity of the disease in terms of the presence of complications, as well as what we've called aggravating factors, which are social determinants of health and the psychological overlay of the disease. If you don't take those into account in your therapeutic plan, you could be destined for failure and inefficacy in terms of your patient's outcomes. Yes, I absolutely agree again, Tim. I think it's a very important issue in the bariatric or metabolic surgery world because the option to have bariatric or metabolic surgery is only by BMI, which is no, you know, there is no basis for this. And most of the country does not allow people with type 2 diabetes that are in the end of the way or above any treatment, and they have BMI of 32 to have a metabolic surgery. So I think the basis of BMI as a criteria for surgery is obsolete. And we have to really look on the complication and all the indices that you mentioned. So we have to do a really joint effort to change this perspective. If I may add on that, I can only fully agree on what has been said before, but not only for metabolic surgery or bariatric surgery, I would extend that even to pharmacotherapy and even also to health management of our patients, because we may have people with BMI within the normal range. And if we look at the adiposity, it should be classified as people with an excess adiposity and therefore being able to to be treated and to benefit from that treatment and decreasing their cardiometabolic risk factors. So I think that this is a very important question. I completely agree with this point. The problem that we have here is that most of the evidence that we have so far, they are based on BMI. So many of the bariatric surgery studies are based on BMI. All the trials in the pharmacologic drug for anti-obesity medication, the inclusion criteria are based on BMI. So we are a bit in a circle and we need to to make a cut in order to go up forward. That's why you have to have a very, very good tool to measure adiposity. So when you will have a measure to when we have a tool to measure a fat sick disease, so then you could plan a study. But until the time that we will have, you will have a problem. What will be the cut line? I would say that we have improved. So in the last years, because some groups like yours and ours have been focusing also on the changes in adiposity following bariatric surgery. And we have established different trajectories, not only based on BMI, there is really a separation between the decrease in BMI and what we see is happening on the adipose tissue level. So in that sense, I believe it's important that we continue in that line. But probably you have had paradoxical examples where some patients have had to gain weight to be able to be operated upon, which is really such a weird situation. And we really do not want to continue with this situation. But again, you are expert in the field. What do you recommend for us as a tool for discriminate patients for operation or not? Okay, patient sits in front of me and I have to decide if to operate or not to operate, if to approve the surgery or not. What will be the tool? Obviously, I would follow Professor Mechanic's advice. So I would try to follow their algorithm because I believe this is one of the very nicely outlining the risk factors, what's the situation. And I will focus on comorbidity. So the weight for me, the BMI is not really the variable that I'm interested in. We are all interested in health. And when you speak to the patients, they don't want to be looked upon like a number on a scale. They want to know what's their health. And for that, really, we have more interesting variables. I would, if possible, try to identify the adiposity, not only the amount, what's your body composition. And there are obviously not everybody has access to the very sophisticated techniques. Not everybody has a blood pot like we do or the underwater weighing or even a DEXA scan. But you can implement, you can use bioimpedance, which is going to provide a reasonable, a very reasonable and a result of the adiposity of that patient. I always tend to just say to my colleagues, if you have a body composition analysis tool, use it, whatever it is, because it's going to provide an additional and a complementary information. And bioimpedance is really, it's cheap. So it's something that you can really afford. And if you don't have that, there are some algorithms with or a body adiposity equations, which we have developed, and that can, again, are freely available for everybody. And you can use them too. And they are really free of charge. Okay. Okay. You're muted, Monica. Monica, you're muted. Sorry. There are several questions in the chat, but I'll try to bring up two questions. One of them is by Dr. Tranz. Could you address behavioral medicine's role if you believe there is any supportive data in the treatment approach to weight management? Luca? Yes, we have data about the role of behavioral medicine. And behavioral medicine is one of the components of anti-obesity management. The problem is that in some cases, behavioral medicine and lifestyle modification, they are not enough for reaching the therapeutic target that these particular patients need to have. So if you want to have a weight loss or sufficient to change some comorbidities, usually or frequently, this weight loss is not achievable only by behavioral therapy. This does not mean that we don't, we forget behavioral therapy in these patients. Behavioral therapy is a part of the treatment of the patients, but these patients need more than behavioral therapy alone. This is my opinion. And I think that we have a lot of evidence about that. This is also a way to respond to one question in the chat. When I ask for more intensive, more prescriptive approach, it's exactly for this reason. So we know that for people with low BMI range, good fat distribution, no metabolic complication, probably there is no reason to search for weight loss at all. We need only to improve lifestyle of the patients in order to prevent future complication. But in other patients with more advanced disease, we cannot stay on lifestyle modification for year and year. We need to be more aggressive. And there are a lot of evidence showing that some therapy is superior to lifestyle modification at all. Thank you, Luca. I see we reached the time that we have to end this excellent session. I really congratulate all the speakers and thank them and congratulate the ASO and ASE for this mutual session. I hope it's, and I believe this is a beginning of a wonderful cooperation. And I think we have to unite all forces to battle obesity disease. So thank you. Stay safe and stay healthy. Have a good day. Thank you. Bye bye. Cheers.

obesity management

adiposity-based chronic disease

ABCD

complications

individualized approach

lifestyle modifications

behavioral therapy

pharmacological interventions

emerging therapies

weight management