Good morning, everyone. Thanks for being here. Thank you to all of you who are attending virtually. My name is Oscar Morivargas. I am an endocrinologist at Cleveland Clinic. It is my pleasure to chair this symposium together with Dr. Ana Espinosa, a distinguished endocrinologist and professor of medicine from Panama. The title of this symposium is Weight Maintenance After Weight Loss. This is a very important topic for us and for our patients. Today, we are lucky to have three renowned experts in the field of obesity medicine and weight management who are going to present the lectures. I am sure that we are all going to learn a lot and that there will be very interesting questions at the end of the session. We are going to have the Q&A session at the end of the symposium. And please remember to scan to be able to write your questions. Our first speaker is Dr. Jamie Almendoz. He is the medical director of the University of Texas Southwestern Medical Center's Weight Wellness Program and an associate professor in the Department of Internal Medicine. Dr. Almendoz is an endocrinologist and a diplomat of the American Board of Obesity. He will talk about the role of weight loss medications during weight maintenance. Thank you, Dr. Almendoz. Good morning, everyone. Thank you so much for the kind introduction, Oscar and Anna, and thanks to the Endocrine Society and the Program Committee for the invitation to speak today on the important topic of weight maintenance after weight loss. It's my pleasure to talk about the role of anti-obesity medications to facilitate weight maintenance. These are my disclosures, and if you'd like to put questions into the chat, please scan the QR code or you can go through the online website in order to do that. So the objectives this morning are going to be to review the challenges for weight maintenance after weight loss. I'm going to do a very brief introduction because Dr. Srivastava is going to go into that next. Discuss the mechanisms and effectiveness of anti-obesity medications, and then outline the role of anti-obesity medications for treating obesity as a chronic disease, which it is. We know from numerous well-designed studies that the response to numerous interventions, including lifestyle pharmacotherapy and surgery, is highly variable. In the left part of the figure, you can see the excess weight loss in response to bariatric surgery and almost universal weight regain. This occurs more so after lifestyle intervention, and these are data from the Lookahead trial showing that with recurrence in body weight, you can also see a recurrence in hyperglycemia. However, what's important to note is that they don't always track together, and the recurrence of cardiometabolic complications associated with obesity can occur independent to weight regain, and therefore, we need to look at the whole picture. If we look at groups who lose large magnitudes of weight, such as those in the Lookahead, data suggests that increases in physical activity from baseline are better predictors of weight maintenance than calorie restriction. However, when we look at people who lose more average, let's say, amounts of weight through lifestyle and other interventions, and we look at what's helpful for weight maintenance, the data are less convincing for activity and would suggest that calorie restriction, meal replacements, and anti-obesity medications may be the most effective way for us to help people to maintain the weight that they lose. The challenge is the body weight regulation is incredibly complicated. We try to oversimplify things as calories in, calories out. We tell patients to eat less, move more, but this really isn't helping to either treat or prevent the obesity epidemic we're facing. There are certainly homeostatic mechanisms that will promote weight regain, but beyond that, there's high variability with respect to hedonic or non-homeostatic mechanisms that can contribute to weight regain after weight loss. When we look at kind of trying to distill down, well, how can we categorize factors that contribute to weight regain, we can see that there are decreases in calorie expenditure and improvements in muscle efficiency that contribute to decreased energy expenditure. With regards to intake, there are changes in satiation perceptions of food, increased responsiveness to food in terms of consumption, and decreased restraint. From an endocrine perspective, there are changes in the sympathetic and parasympathetic nervous system that promote an energy balance for weight regain, and changes within thyroid, leptin, and other factors, which can also impact metabolic health beyond that. If we look at this study that models weight reduction and changes in calorie intake and energy expenditure after weight reduction from lifestyle modification in men, we can see that with the reductions in body fat and body weight and the plateau in weight, there are changes in or decreases in energy expenditure and then increases in calorie intake, which converge to promote this kind of somewhat flat line of weight maintenance. However, what the right panel shows is the modeling of the increase in appetite that occurs in response to weight reduction, and they've modeled out that for every kilogram of weight lost in the studies, the men experienced about 95 kilocalories increase in appetite. Therefore, for that 10 kilogram weight reduction, they were experiencing about a thousand kilocalories more per day of appetite. And even though this is not the whole picture, the reason I highlight this is that the mechanism of action of the majority of anti-obesity medications we have is to help people to manage their energy intake and consumption of calories. Anti-obesity medications are approved for use in those with a BMI greater than 30, or in those with a BMI of 27 with one related comorbidity. There are lots of ways or constructs in which we can propose how and when to prescribe medications. I like this one from a paper we did recently, which points out that you should start by excluding contraindications as to why someone may not be a candidate for a specific agent or therapy, looking at their comorbidities. So, for example, selecting a GLP-1 receptor agonist in someone with type 2 diabetes or maybe cardiovascular disease cues what challenges is the patient having with respect to their weight management and regulation, considering combinations of medications, because like people, medications work better together often. And then the real challenge is cost and coverage, and I think this is a sticking point for many people, and I'll touch on that later. With all of this together, anti-obesity medications are prescribed in less than 2% of the eligible population, and I think we need to do a better job of promoting medications for treating obesity as a chronic disease. And what I'd like to highlight is to use the analogy of hypertension for treating obesity, because we treat obesity very different than we do other cardiometabolic conditions, which have something of a genetic underpinning that are influenced by everything, including diet, lifestyle, physical activity, et cetera. If we had a patient in the clinic with hypertension and we started Losartan, we wouldn't then stop it six months later to see had they learned how to manage their blood pressure without the use of medication, nor would we be surprised if the blood pressure increased when we stopped it. If the Losartan was not helpful for the blood pressure, we wouldn't tell the patient that they had failed therapy or that they must not be exercising or still eating too much salt and stop the treatment. We would add something else in, and that's not the way in which we're approaching anti-obesity medications or treatments, and patients are consistently confused and frustrated when treatments are stopped that may have been helping them along the way. When we look at broad classifications of anti-obesity medications and treatment, Orlistat is an old but not very well tolerated pancreatic lipase inhibitor. There's Gelesis 100, which is a cellulose citric acid hydrogel which occupies about a quarter of the volume of the stomach when taken before meals. Phentermine is a sympathomimetic agent, which increases dopamine and norepinephrine, and it's also approved for chronic use in combination with extended release to Pyramid for weight reduction and is one of the most potent anti-obesity oral combinations that we currently have. Bupropion naltrexone is something that was borrowed from the world of addiction psychiatry where it's used successfully for alcohol use disorder, smoking cessation, and some other factors, and we tend to use it more in our patients who are struggling with hedonic or reward-based eating challenges, and the GLP-1 agents have really kind of come to the fore as some of the most effective ways in which we can help people to manage not just their obesity but their cardiometabolic disease as well. But with challenges with coverage, there's a lot of off-label medication use, and when we look at the data from many studies, much of the data is reporting the use of metformin to Pyramid, bupropion by itself, and other factors which aren't technically approved for obesity management, but we need to provide treatment to patients regardless of coverage that they can afford. Now, we've been beaten over the head by this Surmount-1 data several times through in the meeting, but once more onto the breach. So what this study shows is that combinations of receptor agonists along the incretin family, and this is a combination of a GLP-1 receptor and GIP agonist, are highly effective for weight management in people without a history of diabetes. We can see an average weight reduction at 72 weeks of about 21%, with close to 57% of people achieving a 20% body weight reduction. So this is incredibly effective and incredibly exciting that we now have medications that can consistently help people to achieve a meaningful weight reduction from the point of view of cardiometabolic health. In the wings and along the theme of multiple agonists, the addition of cagrelentide to once-weekly semaglutide is something which is we're very much looking forward to, as we can see that at 20 weeks of intervention, weight reduction exceeds 20%, and we can anticipate something similar to what trizepatide, or perhaps superior to it. And what we see then is that if we look at over the last several years, oral medications at best have helped patients to lose about 5% to 10% of their body weight. With the addition of incretins, and especially highly potent incretins such as semaglutide, trizepatide, and cagrelentide with semaglutide, we can see that what we're doing is we're bridging this treatment gap between lifestyle, which has a non-durable weight reduction of somewhere between 3% to 7%, and bariatric surgery, which has a weight reduction of about 20% to 35%, with these more potent and more effective anti-obesity treatments. But how durable are they? So if we look at phase three clinical trial data, typically they only go out to about two or three years, and so these are data demonstrating the effectiveness of naltrexone bupropion out to two years, with about four to five kilograms of maintained weight reduction. The sequel study looked at the combination of extended release phentermin to pyramid out to two years as well, and we can see weight reductions in the order of eight to ten percent, which are sustained at two years. The scale obesity trial of loraglutide three milligrams looked out to three years, and what people like to point out with this study is that once treatment is discontinued out here at 160 weeks, over the 12-week post-treatment follow-up period, that there is an increase in body weight in response to cessation of pharmacotherapy, and that's very important. When they were doing the step trials, they had the foresight to look at what does this look like with this continuation of treatment. So this is semaglutide 2.4 milligrams after a 20-week run-in period and approximately a 10% body weight reduction, and what they did was they then switched to either placebo or continued therapy with a 2.4 milligram dose, and we can see a recurrence in body weight in those who were changed to placebo, but then a continuation of weight loss in those who had continued in the active treatment arm. But these are people who have not yet achieved their plateau or their nadir in terms of weight reduction. If we look at the data from lorcasarin, which is unfortunately no longer on the market, once patients achieve a weight nadir about kind of six to 12, excuse me, 12 months out, and they're then switched to placebo, you can see that their weight reduction then tracks along with the placebo arm following some weight recurrence. So these medications do work in a durable way. Continuation of therapy is important for weight loss maintenance, but that's really not something that we're doing. I apologize for the formatting change here. And there are several factors that go into the challenges of anti-obesity medication prescribing and why they are prescribed in so few people. This is a popular, well-circulated New York Times article from several weeks ago highlighting the doctor prescribed an obesity drug. Her insurer called it vanity, but there's much complexity that goes into the American insurance coverage system that's well beyond this. And it may be that employers are not selecting anti-obesity treatments for their beneficiaries or their employees rather than insurance companies making these decisions. And I think kind of a lack of understanding often leads to confusion and frustration on the patient end where just because something is approved by the FDA does not mean that it is covered by their insurance. And I think this is problematic when Medicare does not cover any branded anti-obesity medications. With respect to commercial insurance, one-third exclude anti-obesity treatments and one-third have very heavy restrictions on their prescribing. Anti-obesity medications, especially the neuroincretin-based therapies, can be quite expensive. Less than 1% of doctors are trained in obesity medicine. And many consider obesity to be a lifestyle disease and have a misbelief that anti-obesity medications are both ineffective and dangerous. So much of this practice is informed, unfortunately, by weight bias and stigma. And we need to shift that in order to acknowledge and to treat obesity as the chronic disease that it is. When we look at a quarter of a million Americans who are prescribed an anti-obesity medication treatment and then we follow them out to 3, 6, and 12 months, the proportion of people in green who remain on active therapy is perishingly small compared to the baseline. The mean treatment was about 81 days. And if we look at some of the trial data that I presented before, this would have been prior to when a patient would achieve maximum benefit from an anti-obesity medication treatment. And I can guarantee that at 81 days, these people were not cured of their obesity. And so it's problematic when we do not continue prescriptions that may be working or helping people to maintain the weight that they lose. Data from Weill Cornell show that at two years out, you can achieve and maintain about 10% body weight reduction primarily by combining therapies together. And those who were on two or three medications were more likely to achieve and maintain a 5% body weight reduction. But again, if we look at the medications that are used, the most common are metformin, phentermine, bupropion, and topiramate. And so these aren't terribly expensive medications, but when used in combination can be effective. Dr. Weintraub presented their five-year data in an oral abstract at this meeting. And this is definitely a preserved and well-seen thing. If you continue multiple agents, you can help people to maintain a 10% weight reduction. When we look at the treatment of weight recurrence after bariatric surgery, the data are even less, or I should say they're more problematic in terms of their scientific rigor. So much of these are retrospective reviews looking at a single center or a few centers' experiences with weight reduction. This is from Fatima Cody-Stanford and her group, which shows that when people achieve or experience weight recurrence after bariatric surgery, the addition of medications can help them both to achieve a more significant weight loss and to maintain it over time. Topiramate appeared to be one of the most effective agents, but this was a study or the period that they looked at was prior to the approval of or general use of loraglitide. If we look at patients who've undergone Rune-Weigastric bypass, and this is a retrospective view, who were then prescribed phentermine, topiramate, or a combination of the two, when you model out weight regain, people who are on treatment are less likely to regain weight after gastric bypass. However, people who were prescribed phentermine, topiramate, or the combination were less likely to achieve as much weight loss as those who didn't. So there are a lot of factors that go into how we look at the data that are important. Our group at UT Southwestern looked at the combination therapies that included GLP-1 agents versus not, and what it showed was that those who received combination therapies that included GLP-1 agents were more likely to lose significant amounts of weight than those that did not have GLP-1. And one of our fellows who's in the audience, Nadia, is about to publish a great review looking at the difference between loraglitide and semaglitide for treating post-bariatric weight recurrence. What's important to note when we talk about recurrence is that combination or multi-modality therapy is often more effective and has additive effects. When we look at people who lose about 13 kilograms through lifestyle intervention and then randomize them to either placebo, exercise, loraglitide, or exercise plus loraglitide, you can see that there is an additive benefit to exercise from the drug and that at best exercise helps people to maintain their weight for some period before breakthrough. And so what we need to do is look at how can we help people not just receive evidence based pharmacotherapy but also programs which help them to achieve meaningful weight reduction. So to bring this all home as endocrinologists, you know, excluding hormonal medication and other behavioral problems that may contribute to weight recurrence is the important first step. Looking at an integrated weight and comorbidity management program where you focus the patient's activities on choosing one or two nutrition activity and behavioral goals to help promote healthy weight are important. And when that is not helpful, and it seldom is, looking at pharmacotherapies to reinforce some of these changes or to facilitate these changes. For people who are not experiencing clinically significant weight reduction or weight maintenance, considering bariatric procedures either traditional or endobariatric surgery as part of a combined program but also acknowledging that pharmacotherapy can be a very effective tool to help people to maintain meaningful weight loss after bariatric surgery given that many of the comorbidities, cancer risk reduction, et cetera, benefits that we see from bariatric surgery are dose dependent according to weight reduction. So in summary, weight recurrence after weight loss is common, multifactorial, and difficult to treat. Obesity is not treated as a chronic disease with evidence based therapies for durable weight reduction, and this needs to change. Anti-obesity medications are effective for weight maintenance and are more effective when used in combination and as part of an integrated plan. So with that, I'll say thank you very much. Thank you to my weight wellness team who helps to manage all of our patients with obesity. If you'd like to ask some questions, please feel free to scan the QR code. And if any of you are interested in a career in obesity medicine, we are hiring. We're booked out more than a year. Thank you so much for letting me do that shameless plug. Thank you, Dr. Almandos, for that excellent lecture. Our second speaker is Dr. Jitanjali Srivastava. She is an Associate Professor of Medicine, Pediatrics, and Surgery in the Division of Diabetes, Endocrinology, and Metabolism at Vanderbilt University School of Medicine. She is the Director of Clinical Obesity Medicine and Program Director of the Obesity Medicine Fellowship, as well as Co-Director of the Vanderbilt Weight Loss Center. Dr. Srivastava will explain to us why it is difficult to maintain weight after weight loss. Thank you so much for that introduction. It's a pleasure to be here, and thank you so much for that fantastic talk, Dr. Almandos. And so the question is, why is it difficult to maintain weight after weight loss, and how do you translate some of the science and some of the evidence that you just learned about in the previous talk to our patients, and also convey that in a layman terminology that patients can understand? These are my disclosures. Well, let's start with a question. When a patient comes and says, Doctor, why can't I lose weight? In order to address that question, you need to communicate effectively without bias and stigma, and that's going to permeate through obesity education of the providers, which is you as a team and the patient, and embedded in that is the knowledge of obesity science and pathophysiology, and then further translates, obesity is a disease in common language. So what is obesity? Before we even dive into, we could say that it is excessive fat accumulation, which it is, that presents a risk to health, and it can be measured by a variety of factors like the body composition analysis, and it can be estimated by biomarkers such as body mask index and weight circumference, but it really should not define obesity, right? When we think about diabetes, we can, if I were to ask you that question, what exactly is diabetes? All of you would not say, oh, it's hypoglycemia. It's low blood sugar. Well, that's the symptom, but what exactly is diabetes? What is the pathophysiology? So when we take a look at these trends over time, and this is from the World Health Organization, the deeper shades of green is the more higher prevalence of obesity. This is the world map in 1975, 1985, 1995, 2005, 2016. And here we are with the most deepest shades of the color with the United States, Alaska, and the Middle East. And United States likes to be the top of everything. So here we are in the world map, number one, and our obesity rates approaching well over 40%. And every country makes it to the map, including Japan and Korea. This was an article that was published in the New England Journal of Medicine a couple years ago that looked at the health effects of overweight and obesity in 195 countries over 25 years. Obesity does not spare any country, and this is irrespective of socioeconomic status. It does not matter if you are a Western part of the world or if you are a third world country. It actually affects us all globally. When we look at early obesity, it's associated with later disability and receipt of a pension. So this was a study that was published recently in 2019 looking at an end of well over a million. And when you take a look at the right over here, the x-axis is the age in years, and the y-axis is the cumulative index. So if you have adolescents and children that start with disability and complications and severe obesity, that will translate in adulthood to, for sure, for a disability pension. And think about that for a moment. What does that mean for our economics, for our tax burden, for dollars, and hospitalizations later in life? So going back to the scenario, why is it difficult to maintain weight after weight loss? And you may be wondering, why do I have these obesity science analogies? Why do I have a paper cut and footprints and a thermostat? And these are very common analogies that I use daily when communicating and having the conversation with my patients. And I spend a lot of time on obesity education in that initial visit so we can help the patient understand what needs to be done in terms of having a durable treatment option. So obesity is a disease. We know that obesity is inflammatory. And we'll circle back around to this paper cut. But it's a major contributor to disease. And it actually affects over, actually now well over, to 300 medical comorbidities affecting every single organ system and specialty. Oops, I'm going backwards here. My slides are stuck. Give me a moment. Here we go. So obesity, this is how obesity causes disease. We know that there's increased expression of hormones and suppression of others. And we know this is how we can get atherosclerosis, cancer, endometriosis, dyslipidemia, hypertension, and the list is endless. We used to think that the adipose tissue is a dynamic organ system. And it was inert and sitting there. We know that that is not true. There is all of these efferent and afferent signals that are being emitted from the adipose tissue itself. And there's also different types of adipose tissue. We have white adipose tissue. And we have brown adipose tissue. Now we have beige. Maybe in a couple of years, there'll be different colors. But when we take a look at brown adipose tissue, it's very thermogenic. They're very thermogenic. And this is from the line of the skeletal muscle. The brown adipose tissue is rich in mitochondria. It's densely vascular. And it expresses uncoupling protein 1 and is stimulated by the cold. When we look at white adipose tissue, it actually stores energy. And there's large lipid droplets. And this secretes adipokinins such as leptin and adiponectin. And it does increase with age. When we look at adipose distribution in metabolic health, we know that there is variation. When we have normal, we have adiposity. But then there's different types of adiposity. There is subcutaneous adiposity, which is typically underneath the skin and not so much around the organ systems. And these patients typically have a normal metabolic profile. On the parallel, we have visceral obesity or visceral adiposity, where the deposition of the fat is actually around the organs affecting liver and kidneys and liver, kidneys, heart. And these patients have an altered metabolic profile and the presence of metabolic syndrome clinical criteria most of these patients meet. So obesity is inflammatory. And what do I do? How do we explain that to our patients? So I have a paper cut. So this is how I explain to my patients that imagine if you have a paper cut in your thumb, what does it look like? It becomes very beefy and red. And that's what your body starts to look like when you start to become pre-obesity and certainly in the obesity state. Now imagine paper cut number two. Like if it's a wide, gaping, open cut, and what's going to go on? Is there a difference between paper cut number two versus paper cut number one? So like in paper cut number one, we might treat it by putting Neosporin, because we want to expedite the healing process. We want to get better, like anti-obesity medications. But at the same time, we want to put Band-Aid around it, because it actually helps us and we feel better, like intensive lifestyle modification. But if you throw red pepper on it, what's going to happen? It's going to sizzle. Your body's not going to get better over time. In the second scenario, we have paper cut two. Is the treatment going to defer for paper cut number two versus one? We might need to go in and suture and cut it out. You might place Neosporin or Band-Aid around it, but it may not be sufficient. We have to escalate treatment. So in this scenario over here, just like a paper cut, the body becomes beefy, red, irritated, at a body mass index of 27 or higher. After it's more severe obesity, it becomes more inflamed, like paper cut number two. And definitely asking your patients, is the treatment going to defer for these two analogies? And if you throw red pepper on it, what's going to happen? And that typically gets most of the patient's attentions, because you're actually translating that obesity science into common terms that patients are able to understand. And in the mind, in the patient's mind, the patient now understands that obesity is very inflammatory. And therefore, we need to do something and act upon it. When we take a look at, in terms of body mass index, the less intensive disease responds more favorably to lifestyle and behavioral changes, whereas more intensive disease responds favorably to escalated treatment, such as medications and bariatric surgery. And when we look at the criteria for pharmacotherapy and bariatric surgery, most of you are aware of that. We don't need to go into that. But certainly, a body mass index of greater than 27 with a weight-related medical condition, and a greater than 30, the patient meets pharmacological criteria. So if you pause for a moment, how many of you think that's more than 90% of your patients in clinical practice that we see? Now, going back to the second analogy, the body weight is regulated, and weight is not volitionally controlled. So how does this thermostat analogy interlay? And how can you translate this to patients and in a manner that we can understand, that patients can understand? So imagine that you have a house, and you have a thermostat that's very functional. And you have the sun that is actually emitting heat on the house. What's going to happen? There's going to be outside temperature is 90 degrees, and there's going to be a different sensor that senses 90 degrees, right? Then there's going to be a signal that is sent to the central AC heating unit in a thermostat that's functional. And what is the functional thermostat going to do? It's going to emit a cooling signal, right? And then the house is going to get cooler, and the temperature is going to fall to 66 degrees. But now let's take a look at another scenario. Suppose that you have the same, like maybe a twin house next door or next to it. But in that house, the thermostat is now non-functional, and it's not working. So in the same scenario, you have a sun that's going to actually emit heat onto the house. But what's going to happen? There's going to be a signal, a different sensor, that's going to sense 90 degrees, and it's going to send a signal. But that is not functional. The cooling signal does not get emitted. And so the temperature may maintain 86 to 90 degrees. You might open the windows. You might do other things to actually alleviate that temperature increase. But what is going to happen chronically over time is the house gets hotter over time, unless someone calls the AC guy to fix the central system or plays cooling fluid. And we're getting into escalated treatment over here. So in the same way, in the arcuate nucleus of the hypothalamus, we have a yin-yang relationship between two neuron clusters, a neuropeptide Y and the POMC neurons. So when you have cumulative activation, and I'm going to put my pointer here, cumulative activation of this neuropeptide Y-axis, you're going to have orexogenic signaling. And there's all these efferent and efferent signals that are emitted. But with the cumulative activation of the neuropeptide Y-axis, you're going to have an orexogenic signaling, which is going to increase in food intake and decrease in satiety, further causing your body to gain weight. But if you have cumulative activation of these POMC whoops, cumulative activation of these POMC cart neurons over here, it's going to be anorexogenic signaling. You're going to have an increase in satiety, decrease in food intake, further leading to increase in energy expenditure or weight loss. And added to this complicated system, why is it complicated to treat obesity? Because we have these biological influences. We have early life events. We have imprinting. We have epigenetics. But then we have the modern microenvironment. And those are things that we cannot change, such as food production, social structure and cues, television and technology, and endocrine disruptors. And then we have modern microenvironment. And those are things that we may have volitional control over, such as nutrition, exercise, sleep, stress, or circadian rhythm. So for instance, if it's raining outside, you do not have control over that environment. That's the macroenvironment. But you do have a choice if you pick up that umbrella and walk outside. And that's your personal microenvironment. Those are things that we actually have control over. So 70% of our weight is decided at birth and genetically determined. And this is an intricate feedback regulation of energy metabolism. And there is an interplay between this cognitive brain and the GI tract, the adipose tissue, the muscle, the liver. This is all intricately related. So your next question is, if body weight is so intricately regulated, why is weight regain prevalent? And why is it difficult to maintain this weight, even after I've lost weight? So this goes into a study that was published many years ago in the New England Journal of Medicine that brought a lot of attention. And when you go to obesity conferences, the study is often pulled up because there is very important lessons that we need to teach and that we can learn from. So in 2009, there were 50 men and women that were partaking in a study. And they were subjected to extremely low calorie diet. And they reported feeling hungry and preoccupied with food before the weight loss. And so what the study did is what was interesting about the study is that they continued to study these patients after the intervention. And what happened to these patients? The body continues to fight weight. So there were sustained changes in peripheral signals up to one year following weight loss. The appetite stimulating hormones were higher. And the appetite suppressing hormones were lower. The body remembers. And you may be wondering, oh, my goodness. Do I have a chance, fighting chance? The body continues to fight. The body has memory. The body has remembers. And this is even after a short period of dietary restriction. So the question is, why does the body do that? Why does the body defend the fat mass? The body needs to defend a fat mass set point to shed the excess calories consumed daily and to recover appropriately from acute illness or injury. So for instance, evolutionary, when you take a look at human evolution, we are not designed to be in an obesogenic environment. And when we look at evolution, we are designed to fight against famine and hunger and stressors in times of critical illness. So the body defends its fat mass set point, even if it is abnormally high as in obesity. And when we take a look at the defense of a body fat storage or the set point, we see this intricate relationship over here. So let's say that if you have a lean body mass index of 25 and you gain weight, the body is going to try everything in its power to actually increase its energy expenditure and decrease this energy intake in order to get back and pull back towards the norm. When you actually end up losing weight, the pull of these forces are even more strong. And you have the body is going to actually try to increase its energy intake and sort of decrease its energy expenditure and pull back towards the norm. And we refer to this as metabolic adaptation. And where have we seen metabolic adaptation? And where have you heard about that? And where have we experimented at? All of you may be familiar with the Biggest Loser study. And this is the follow-up. The fat regain correlates with metabolic adaptation. So in this Biggest Loser follow-up study, what they did is they went back and they looked at the patients and followed them several years later. And what happened to all of them? They had all regained weight. And when you look at the resting metabolic rate changes, it's significantly lower. And all of these lines are going down with the exception of one patient. Do you all know what happened to that one patient? Why the resting metabolic rate or the metabolic adaptation was not there in that one patient? Anyone? So that one patient actually underwent treatment, and he underwent bariatric surgery. So obesity results from a failure of normal weight and regulatory mechanisms that leads to an elevated defended body fat mass set point. And when we look at the obesity and scarce, the battle forces that influence the fat mass set point. Over years, you may have abnormal dietary constituents, unhealthy muscles, sleep deprivation, stress, disrupted circadian rhythms, and weight-inducing medications. But over time, through years of chronic exposure, this is going to increase your body fat set point further. And when we take a look at that, what are the things that we can do to mitigate the body fat mass set point? When we think about lifestyle modifications, think about the pathophysiology and scientifically, how is it changing our body? And how is it changing our microenvironment on sort of a cellular level that your body is starting to respond? And your body may be responsive to a healthy diet. Or maybe some patients may have regular physical activity, more or better sleep. There could be stress reduction, stable eating patterns, or weight-stabilizing alternatives. When we look at anti-obesity medications, they reduce the body fat mass set point significantly. And in terms of bariatric surgery, it's more intensive. These are how these treatments work. And as you've heard in the previous talk, these anti-obesity medications reduce the fat mass set point. So here we have lorcastrin. That's actually off the market right now. But it's a 5-HTC agonist. We have fentermine working on the locus coeruleus. It's a sympathomimetic amine with norepinephrine, topiramide, and the gabonergic receptors. And bupropion and naltrexone are kind of interesting, too, because when they're all affecting the CNS pathways. And in here, in one of these pathways over here, we have what we call the POMC auto-inhibitory loop. So remember that I stated that the POMC activation of the POMC cart neurons is going to cause anorexogenic signaling, meaning that it's going to increase in satiety and decrease in food intake. So if you have an inhibitor of that pathway, we would expect the inverse. But what happens when you have an inhibitor of an auto-inhibitory pathway? Two negatives make a positive. This is going back to sort of our algebra over here. But two negatives make a positive, and you have indirect stimulation of these neurons. And then we have GLP-1 agonists, and now the combinations, GIP and GLP-1 agonists. And then added to that is set-melanotide, which is for a rare genetic obesity indication. It's an MC4R agonist. When we take a look at restrictive dieting versus bariatric surgery, there are changes in physiology after bariatric surgery that lower the set point. So this is an article that we had just published recently taking a look at diet versus bariatric surgery. So in the diet and in patients who undergo dietary modification, there is going to be, over time, increases in ghrelin. Ghrelin is the hunger hormone. That's going to go up. But your satiety hormones, like PYY and GLP-1, and there's also gut microbiome, all of these other factors that are involved, all of those are going to increase or decrease respectively, decreasing satiety overall. And these are homeostatic mechanisms to defend the higher body weight. But when you look at bariatric surgery patients, and there's data to support this when we take a look at gut hormones and peptide pre- and post-op bariatric surgery, all of a sudden, the patient's ghrelin levels are down. But the satiety hormones are up, and there is a resetting of that body set point to lower the weight, explaining the durability and sustenance of weight maintenance after weight loss. And you've just seen this in terms of, you know, you've heard this over and over, and first-generation anti-obesity medications versus bariatric surgery and the treatment gaps that are there. And when we take a look at first-generation anti-obesity medications, previously, we used to think, OK, 5% weight loss is good. We can actually have an influence on PCOS and fertility, maybe depression and urinary incontinence, and in diabetes prevention. But when you look at bariatric surgery, look at what we are able to accomplish in terms of the improvement of the health consequences. There's better glycemic control, hyperlipidemia. We can maybe actually treat obstructive sleep apnea, osteoarthritis, fatty liver. In order to get improvement in fatty liver, you want to at least achieve 10% to 15% or more. And so now this is great, because now weight loss of greater than 10% provides a clinical benefit. And we have these armature. And you've had these slides before, and you've seen this. And now with terceptide as well, we're getting into these game-changer medications, like especially with Sema 2.4 that was FDA-approved last year with minus 12.5% total body weight, and terceptide that you've heard about that is able to achieve unprecedented weight loss of greater than 20%. And back to this slide that was just shown a little bit earlier, this is from the Step 4 trial that the weight regain occurs when it's discontinued in participants on Step 4. So there's a discontinuation of a steady drug over here, and the patients regain weight. This is physiology at its best. So if you understand physiology, you understand what is going on. And the patients in the placebo increase had a 6.9% increase in body weight from weeks 20 to 68. And the patients that continued the treatment had a minus 7.9 reduction in body weight from weeks 20 to 68. So back to this analogy, let me circle back around to this thermostat analogy. And how do we translate that? And how do I explain to my patients so they understand why these treatments need to be long-term and durable? We have a weight set point that regulates our body weight similar to a thermostat regulating temperature in a house. If your thermostat reads high, temperature is going to be high no matter what. If your weight set point is high, your body weight will regain weight back to that set point. It's not your fault you developed obesity. There are treatments that lower that set point so you do not have to struggle when you are engaging in healthy behaviors. And back to now to my final analogy. And you may be wondering, why do I have footprints on a sand? And how does that translate to? Well, there's biological early life events, epigenetics, influences of environments, and behaviors that all affect our weight set point, even if those culprit causes may no longer be present. So this complicated and regulated system gives rise to very heterogeneous disease, right? There is environmental and lifestyle factors. And then there is the central factors, which we term the cognitive or emotional brain. We have peripheral signals. And added to that is genetics and all of those factors that contribute to ideology. So there are many different types of obesities. And when I'm teaching my fellows, I ask them when they're presenting a patient, what type of obesity is your patient presenting with? It's not just the patient that you have severe obesity. I want to know what type of severe obesity or which one of the severe obesities is this patient presenting with. So back to the footprints in the sand, when we walk on the sand, we make imprints on the sand, right? But we're no longer there, but we can actually see those imprints on the sand. And it's different. In the same way as patients go through life, they may have new onset of disease processes. They may be exposed to a culprit weight gain promoting medication. And that culprit medication may no longer be present, but your metabolism is changed. There are these cellular footprints that are placed there. And there could be examples of antipsychotic medications that patients are exposed to. All of these are just example. But the way that we explain, or the way that I explain in clinical practice, is your cellular metabolism is now different and changed. However, we can recognize it and treat it accordingly. I have an eraser. I have a metabolic eraser that I can go in and erase those footprints. And those erasers may be anti-obesity medications, or they may be bariatric surgery. And let's go ahead and treat that obesity. So to conclude, we learned that body weight is intricately regulated in the brain. Obesity results from pathophysiological dysregulation of the weight set point. There's biological, genetic, early life, epigenetic, environmental, nutritional, and behavioral influences that all affect the weight set point. Let me see if I can, there we go. And then weight regain after dietary-induced weight loss is expected. It's physiological and attributed to metabolic adaptation. It's important that we understand that. And when we begin to understand that, we can appropriately translate to our patients and explain to them what's going on inside their bodies and why is it after these years there's a lot of yo-yo cycling that has been going on. Increases in hunger and cravings are the result of physiological up-regulation of hunger hormones and down-regulation of satiety hormones. Anti-obesity medications and bariatric surgery are effective treatments for obesity and weight regain in patients who meet clinical criteria. And these work by addressing the dysregulation of energy balance that occurs in obesity. With that, I want to conclude and toss the baton over to our colleagues here. Thank you so much. Thank you for that wonderful overview. Our third speaker is Dr. Reyna Villarreal. Dr. Villarreal is a physician scientist and professor of medicine at Baylor College of Medicine, Houston, Texas. She's an endocrinologist with research interest in obesity. It is my pleasure to present Dr. Villarreal. She will talk about weight maintenance recommendations for the elderly population. So, I have nothing to disclose. By the way, good morning, everybody. Sorry. So, before we go into approaches in weight maintenance in the elderly, we have to realize that this subgroup of the population actually behaves not like the other older adults, you know, the younger older adults. So, we have to go over, of course, what happens to these patients. So, there's an increasing number of elderly obese, as you can see from this slide. The most recent estimates shows that men and women in their 60s, there's about 40-some percent of them who are obese. So, there's a difference in, you know, as you grow older, you know, aging is associated with increasing body weight because of the decrease in energy expenditure accounted for a decrease in resting metabolic rate, decrease in physical activity, and also in the thermal effect of food. In addition to that, there's an age-related decline in hormones, such as menopause in women, underpause in men, and, of course, there's an overall decrease in IGF-1 as one ages. So, this is a study from the NHANES showing that with aging, usually the fat-free mass, you know, peaks at around 45 to 55 years old. There are different racial groups here, Mexican, these are the B are the blacks, the W are the whites. So, essentially, everyone at around the age of 55 had a decrease in fat-free mass whether males or females, resulting into the elderly population being at risk for sarcopenia. So, is weight loss recommended for the elderly? Let's examine the effect of BMI on mortality. On the lower end of the panel, this is, by the way, a group of 12,700 patients from multiple racial groups followed for about seven years. So, there are different lines here. The open circles is the one where analysis is adjusted for baseline comorbidity. The closed circles where analysis was unadjusted. And the closed triangles where smokers and those who died within the first year of follow-up were excluded. All of these patients are 65 years old. So, notice that for the general population, the best BMI is actually between 27 to less than 30 when it comes to mortality. After which, there is a gradual increase in mortality. But notice on the lower end of the spectrum in the elderly population, notice that, in fact, there was a greater risk for mortality for those with lower body weight. However, if you exclude smokers and those who died within the first year, it's not much a greater increase in mortality with increasing BMI. But what is not good, you know, with increasing BMI, there is a greater risk for disability. So, it's not unusual to see an elderly patient using a walker or even a wheelchair. So, in 2004, Dennis Villarreal reported that 96% of older adults who are obese are actually frail, defined as a physical performance test scores of less than 32. There was also a study who corroborated that finding, showing that there's an odds of being frail by about 3.5 for those obese who are elderly. So, it's not surprising why there's an increase in the admission of obese older adults in the nursing home. So, is weight loss indicated for the elderly? And would it help the elderly? The weight loss in the elderly is controversial given the fact that the relative risk or relative health risk decreases with increasing BMI in the elderly. And also, there's a thinking that this patient have already a lifestyle that was been there for many, many years, so it's very difficult for these people to change lifestyle. But the most important concern is the fact that there would be a weight loss induced loss of bone and muscle mass, which could aggravate the age-related decline in bone and muscle mass aggravating sarcopenia and osteopenia. So, but these patients are physically disabled or have physical limitation and also have poor quality of life. So, between 2010, 2006 and 2010, our group randomized a group of 107 older adults to either, these older adults were all obese and they have also frailty, again, for a physical performance test score of less than 32. The perfect score for the physical performance test is 36, I'm sorry. They're randomized to control, diet, exercise, and diet plus exercise. Notice that at six months, I'm sorry, it's advancing. Notice that our goal here, the first six months is the intensive lifestyle period. The last six months is the maintenance period. Notice that at six months, we were able to achieve our goal of making them lose weight for about 10%. That was the target weight. And we're able to maintain them at the end of the study. Notice also that those randomized to control and exercise by design did not lose weight. So, this is what happens to their physical performance. Those randomized to diet alone and exercise alone have increases in physical performance test scores, but more so for those patients randomized to diet plus exercise. There was also improvement in cardiometabolic fitness shown by increase in peak oxygen consumption for those randomized to exercise alone, diet alone, but more so for patients randomized to diet plus exercise. Now, there's also improvement in body composition. This is the same patient at baseline and at the end of the study. This is an MRI of the thigh. This patient lost about 20 kilograms, 15 kilograms of fat, and five kilograms of bleed. This is by DEXA. By MRI, this patient lost about 30% of fat and 10% of muscle mass on the thigh, but notice there was improvement in frailty score from 30 to 35. So, this patient went from being frail to non-frail. This is another patient where exercise was added to diet. So, this is the baseline MRI on the other side and after the study. This patient lost about nine kilograms of body weight, eight kilograms from fat, and eight kilograms and one kilogram from bleed, but the thigh MRI shows that, in fact, the patient gained muscle mass by about 4%. This patient went from a PPT score of 35, moderately frail, to non-frail at the end of the study. So, in this study, we were able to produce similar weight loss for those randomized to diet and diet plus exercise, similar degree of fat mass loss. However, notice that in the diet alone group, there was a decrease in fat-free mass, which is greater for the rest of the group, and also those randomized where exercise was added to diet. In fact, there was a decrease in fat-free mass, which is attenuated. However, if you look at the strength, the increase in strength in those on the diet plus exercise is similar to those randomized to exercise alone. I'm sorry, keep on flipping. I have to go back. Okay. Randomized to exercise alone, and for those randomized to diet alone, there was no change in strength, despite the decrease in fat-free mass. This is a study by Dennis Villareal and colleague. Looking at the effect of exercise and diet on the muscles, these patients undergo 12 weeks of exercise and diet with a loss of 7% of body weight in the diet group. Basal biopsies were done at baseline and at the end of the study, showing that, indeed, there was a decrease in inflammatory markers, but more so, significantly so, in the exercise group than the diet group. There was also an increase in mechanogrowth factor in the exercise group. This is a spliced variant of the IGF-1, which stimulates muscle growth. So this may account for the improvement in strength in those randomized to exercise. Then what about the bone? There were significant drop in bone density on the patients randomized to diet, and this is the hip bone density, which was prevented in patients where exercise was added in the diet exercise group. But, in fact, there was an increase in bone density at the total hip for those randomized to exercise alone. So this is reflected by changes in bone turnover. For those randomized to diet alone, which is the orange circles, there were increases in markers of bone resorption, CTX, markers of bone formation, osteocalcin, and P1NP. This increase in bone turnover markers is prevented by the addition of exercise to the diet. There was decreases in markers of bone turnover in those randomized to exercise alone. So what about improvement in cardiometabolic function? This slide shows the improvement in insulin sensitivity among those patients randomized to diet plus exercise as shown in this slide. Those randomized to diet, the improvement in insulin sensitivity stabilized at the end of six months, whereas it continues for those randomized to diet with addition of exercise. As you can imagine, there's a lot of patients with metabolic syndrome. In the diet alone group, there was a reduction in the number of patients with metabolic syndrome from 73% to 58% at the end of the study, whereas the diet plus exercise, there was reduction from 79% to 39% at the end of the study. There were also improvement in quality of life. This is one of our outcomes. So the improvement is actually greater in the overall quality of life here. It's actually much greater for those diet and exercise group. So in summary, our studies show that lifestyle intervention in older adults or diet improves body weight, reduction in body weight, improves physical function, reduces fat mass. However, there's a tendency to decrease in fat-free mass and bone density, although quality of life improves and cardiovascular risk is improved. Exercise, there's improvement in physical function, reduction in fat mass. However, there's an increase in fat-free mass, which is good, and bone density, increase in bone density. A quality of life also improves and cardiovascular risk improves. What about the combination? Yes, there's additive effects for physical function, fat mass, and quality of life and cardiovascular risk. Now, our next project was looking at which distinct type of physical exercise is best to combine with diet-induced weight loss. So in the next study, this study, we are trying to tease out which is the best exercise for the elderly. So in this study, we randomized 160 older adults who are obese and also frail, randomized to control diet plus aerobic, diet plus resistance, and diet plus aerobic and resistance. This is only a six-month study. We were able to achieve weight loss of 9% at the end of six months in these patients. There were similar improvements in peak oxygen consumption or cardiovascular fitness for those randomized to aerobic and randomized to a combination of aerobic and resistance. Similar improvement in strength also for those randomized to resistance and the combination of resistance and aerobic, but notice the improvement in physical function. It was additive for those randomized to both aerobic and resistance. There were improvements in the aerobic and resistance, each aerobic and resistance, but the effect is additive if you combine both exercises. So what about the changes in the lean mass? There was reduction in lean mass in the aerobic group which is way greater than the reduction in the lean mass, in the resistance, and the combination. There was also reduction in the aerobic group which was way more than the resistance and the combination. So now, so there were similar patterns in the changes in the femoral neck. There were also increases in bone turnover markers in the aerobic, increasing resorption, increasing formation, which was prevented by resistance and aerobic plus resistance. So in summary, our results show that in obese older adults, weight loss by lifestyle intervention improves physical function, metabolic profile, and quality of life. A combination of aerobic and resistance exercise seems to be the best exercise to improve physical function. Some degree of bone and lean mass loss remain a concern. So I would like to highlight the look-ahead study. This is the eight-year follow-up, the look-ahead study. If you think that these older adults cannot maintain their, you know, their, a good lifestyle, you know, because they're old and their, the habits are probably in there for a long time. But notice that in this study, though, look at the result of the eight-year follow-up. So they lost about the same amount of weight at the end of one year. But look at the end of six years. These people were actually, have better maintenance of their, of course, they had some weight regain. So does the rest of the group. But their weight regain is much less compared to the younger groups. And this is another study that I would like to highlight. This is from Wake Forest. So this is a different form of, you know, activity that they're trying to promote. So everybody was randomized to diet, but physical activity was different. They called it the sit-less exercise, or sit-less activity, where patients are told to perform day-long movement, reduce sustained sitting, do frequent bouts of activity with a step goal of 10,000 steps per day. And the aerobic exercise is moderate-intensity treadmill walking four to five days a week with progression to a maximum of 200 minutes per week. So in this study, there are three groups. So weight loss plus exercise, weight loss plus sit-less, and weight loss plus sit-less plus exercise. At the end of the study, the first six months is the intensive lifestyle period. The last 12 months is the maintenance period. Notice that there were similar weight reduction in all the groups. However, as expected, they have weight regain at the end of the study, or the maintenance period. But the weight regain was much less in the sit-less group. There was a statistically significant difference between the sit-less and the exercise group, such that the authors concluded that pairing dietary weight loss with recommendations to accumulate physical activity contributed to similar weight loss and less regain than traditional aerobic exercise. Then this is a study conducted also from the Wake Forest Group. This study utilizes the personnel from the YMCA to produce weight loss by dietary therapy, weight loss plus aerobic, and weight loss plus resistance. In the first six months, that is the intensive lifestyle intervention. The last 12 months was maintenance. And again, these people were able to enforce this one. This is like a community-based lifestyle intervention. So now, but what about our group? We did a follow-up on those who finished the 12-month study. And then we asked them to come back after 18 months. Assuming that they have implemented the weight loss, like behavioral therapy, the diet, and exercise interventions that we taught them. So at the end of the 18-month being in the community, we called them back. Of course, there was weight regain. But notice that the weight regain was only 2%. So they went from 10% at 12 months to 8% at 30 months. But notice that with the increase in weight, there was a reduction in physical function, which mirrors the reduction in weight. But what is more concerning, that despite the increase in weight, these patients continue to have bone loss at the total hip. So this brings us to the next project that we are doing right now. This is also funded by the NIH. So this is looking at the effect of whether this decline in bone density by DEXA would be reflected by bone quality. So we're having follow-up measurements on patients doing lifestyle intervention. This is for one-year intervention. So looking at effect on microarchitecture using high-resolution peripheral QCT. Then using finite element analysis as a surrogate for bone strength. And checking on the effect of lifestyle intervention on bone tissue material properties using microagmentation. So now going to the practical approaches to management of weight maintenance in the elderly. So weight loss in obese persons of any age can improve obesity-related complications. However, in the elderly, the most important thing for long-term goal is improvement in physical function and quality of life. Could be the most important goal of therapy. Of course, you have several tools for weight loss. We will review one by one. So in an elderly, I'm not a genetician, by the way, but it's just like what our experience is in our center. So we have a patient who desires to lose weight. So we have to evaluate the willingness to lose weight, facilitate setting of goals, involve the family and care providers, and also personalize weight loss. Something that they can maintain the rest of their lifespan. So what about weight loss therapy? So we generally recommend a combination of energy deficit diet, increased physical activity, and obviously, importantly, is behavioral therapy. That causes moderate weight loss, but lower risk of treatment-induced complications. Also, the weight management therapy that minimizes muscle and bone loss is recommended for these obese older adults. So exercise therapy. To improve physical function and help maintain muscle and bone mass, it should be individualized with consideration of diseases and disability. Also, start at a low speed, then you gradually intensify over time. So the goals here is increased flexibility, endurance, strength, which can be maintained for a long period of time. This, what we generally recommend is a multi-component exercise of stretching aerobic activity and strength exercise. As you have seen earlier, accumulating physical activity may help in weight management. Diet therapy, the realistic goal for these patients is five to 10% reduction in body weight for six months. I know the younger ones, you may aim for high body, for high, you know, weight loss, but may not be a good idea in this group. So we recommend a calorie-reduced diet, balanced diet, with one gram per kilogram high-quality protein diet. Of course, multivitamin and mineral supplements should be given to prevent bone loss. And also, recommend referral to a registered dietician, not only for nutritional education, but for counseling and behavioral modification. So we have several drugs in the market approved, we know that, okay? So how is it, what's our experience in the early? The problem is very, very few patients who are elderly are included in these studies, as you can see from this. This information was actually, I took this information from the package insert. So, but regardless, there were no report, to my knowledge, there was no reported differences in safety and efficacy between younger and older adults. So with regards to pharmacotherapy at this point, we cannot make any specific recommendation, because there's insufficient data to determine the efficacy and safety in this population, largely because they're excluded from the clinical trials. But probably a dose that you use for diabetes will be okay. So it can add additional burden, because this patient's a polypharmacy. There are potential side effects that may be more serious. Also, a thorough review of medications is necessary, you know, so many medications, drug-drug interaction. There's a bigger problem here, because there are no long-term data in older adults that we know of. So what about bariatric surgery? Effectiveness and safety data are limited, considering selected, select individuals with disabling obesity, who can be ameliorated with weight loss, and who meet, of course, the criteria for surgery. Need care for evaluation by a multidisciplinary team, pre-op and post-op monitoring is needed. So this is a meta-analysis of the bariatric surgery performed in patients 60 years old and over. This consisted of 26 papers. Overall, they found, the authors found, a complication rate of 14.7%, which is considered acceptable. There's an excess weight loss of about 54%, and resolution of diabetes in 54%, and hypertension in 43%. This is a follow-up study on patients who have sleeve gastrectomy, and they categorized patients as to more than 60 and less than 60, or 60 and less than 60. Notice that there was a greater weight loss for those patients, the younger, near the blue line, at the end of one year, which is about 31%, compared to the older group, which is only about 26%. However, at the end of five years, there seems to be a great weight, a higher weight regain in the younger age group, such that their weight loss was down to 25%, which is similar to the older age group. So the older age groups were about, were able to maintain the weight loss. The problem with all these studies, there was no studies on physical function, there was no studies on bone density and lean mass, whether this patient lost a lot of lean mass and bone density, which I assume. So in summary, in the elderly, it is particularly important to consider weight loss therapy in older adults to improve physical function and metabolic complications associated with obesity. Probably not so much with improvement in mortality, because probably that doesn't exist. Treatment options include comprehensive lifestyle interventions, such as dietary therapy to promote weight loss, behavioral modification, and exercise therapy. In choosing therapeutic options, healthcare professionals must consider the potential and desirable effects of weight loss and muscle and bone mass. And finally, few studies on long-term weight maintenance in the elderly suggest continued behavioral diet therapy and increased physical activity are likely to sustain weight loss. Further long-term studies, weight loss studies, most especially probably using drugs, are needed in older adults with obesity. I would like to acknowledge that people have made these studies possible, and also the funding sources. Thank you very much. Thank you. Thank you for that very interesting lecture. I'd like to invite you. Thank you very much. Now we're gonna start the Q&A part of the symposium, so if all the speakers could come. And if anyone in the audience would like to ask a question, please come to the mic, because this session is being recorded. And we also have, right now, 180 people watching us online with questions in the online system. Thank you for a great symposium. My name is Manasisha. I'm from Virginia. I have a couple of questions, I guess, to anyone. One is, I saw the semaglutide 2.4 study, the one that had weight regain and weight loss, continued, was going up to about 68 weeks. So I wonder if the other drugs have similar length of time, and there is anything longer than that. And if there is sustained weight loss on the medications, because I wonder if patients could be developing tolerance to those medications. So if there is any data on that. So I can start. The longest kind of trial data we have is the three years scale obesity of loraglutide 3 milligrams, and kind of showed sustained weight loss with that. And so the challenge is that it's very expensive to continue patients in drug therapies, and would likely kind of escalate the costs already of drug trials. And so we're very limited in terms of long-term data for maintenance. But it shows that these are effective. Thank you. And the second, just in practice, I've seen, and I'm sure you have too, that the efficacy of GRP1 agonist in losing weight is tremendously good, except in some patients where they tend to not lose any weight, or maybe even gain weight. Are there any predictors before we start someone on a medication that could help us understand who would and who wouldn't respond? In that small population, who doesn't? No, that's a great question. You're pointing to the heterogeneity of response where we see a variation. And you're picking up on the fact that not all patients are going to be responders to medications. And we see that in intensive lifestyle modification. We see that in anti-obesity medications. And we sometimes see that also in, often now, in this bell-shaped distribution. We can see that in bariatric surgery. And this is where we get into being astute diagnosticians and trying to figure out what is the phenotype of the patient that is presenting with. So, for instance, that if you have patients that maybe have more of the hedonic drive, and that addictive behaviors, and things like that, they might gravitate towards certain anti-obesity medications, like the bupropion naltrexone combination, where that may be actually more effective in that phenotype compared to someone who's presenting with increase in hunger all the time, where maybe, and maybe some stress eating, emotional eating, where a combination of mentamine and topiramate may be effective. But in those patients, I don't think that we have yet discovered predictors and biomarkers that would translate to the therapeutic option for that patient. We are getting into a lot of novel research, but as I point out to my patients, and I tell them that I wish that there was a blood test that we could do, blood test or DNA test that we could do, that would spit out exactly what is the ABCD of treatment. But right now, based on our current evidence and knowledge, it is a clinical art combining your clinical experiences, your astute clinical decision-making skills, the phenotype of the patient, and also some of the minor details of these pharmacotherapies and treatment options that you can apply that knowledge together towards treating the patient. Thank you. Thank you for a wonderful presentation. I'm Agopin, I'm a clinical endocrinologist from near Chicago. So I see a bunch of patients who come, who has this complaint that I don't eat anything and I'm gaining weight. And I am thinking in my mind, if you're not eating anything, you should be dead by now. But I don't tell her that. So any of these studies, do they take a baseline calorie count before they enroll patients? Or can we guess a response very similar to what the previous question was asking? Can we anticipate a response to weight loss medication based on their baseline calorie intake? Because many of these patients actually eat less than 1,000 calories a day and they're still gaining weight. So is there any medication that can increase the calorie expenditure? I know that there's nothing, but except for a glucagon receptor agonist I just saw, and I'm pretty excited about it. So I just want to ask your comments on that. How do you counsel that patient? Sure, do you want to take the floor? Yeah. You can share. You can share. We can share. I'm sure that we both have comments. Maybe Dr. Ghida actually might want to answer, because I think your talk was... Sure, sure. And we can both comment on that. So first of all, when patients come in and they are not eating anything, we refer that to as metabolic starvation. And I have a strict conversation, a long conversation with my patients that's probably not the best thing to do to lose weight. In fact, you're actually causing your body more harm and you're causing your body to gain weight. And we get in the conversation about metabolic starvation and you're stressing out your body and the body goes into sort of an energy conservation mode where it becomes increasingly difficult to lose weight. And I do have a multidisciplinary team, including a behavioral health specialist who can work with the psychological aspect of that piece of metabolic starvation, and also experienced dieticians who really help our patient increase the caloric intake. So there's a lot of education and explanation that we have to do on that front to revert restrictive dieting or severe restrictive dieting, which is not the beneficial thing. So you would not put a medication right at that point? You want to change that diet first and then put the medication? So there's a finite. So it's a case-by-case basis. Oftentimes, it's a little bit complicated, right? Because a lot of these patients may have BMIs of 42, 45. They may not have class three severe obesity. I've seen some BMIs in the hundreds range as well. So I typically, and maybe my colleagues can comment on exactly what they like to do, but every patient is very different, and I don't withhold treatment at the same time, but it is a multidisciplinary team intervention, and I have that conversation. And when I do some reassessments, sometimes we do catch patients that we've started, let's say a pharmacotherapy, and the patient is losing weight, but the patient is also secretly restrictive dieting. They'll come to me and they'll give me a different story, but my dieticians and my behavioral health team are actually getting a completely different history, and we have the conversation that, hey, you really do need intensive cognitive therapy. We need to work around this. We're not going to be, and it ends up being sort of an ethical discussion about how is the best care of this patient. But in general, if patients do come in with restrictive dieting, oftentimes education, and trying to explain to them, they'll revert, and what we'll see is that they'll increase their caloric intake and start to lose weight, and they feel healthier, and they feel more energetic and happier. And so it does take a multidisciplinary team. Thank you. I'll just add briefly to that. This is a common complaint that patients will come in and say, but I'm not eating anything, and I think if we look at the prevalence of obesity in society, and if they're looking in relative to what those around them are consuming, they may not be eating as much, but that may be relative metabolic overfeeding for that patient to at least not achieve significant weight reduction consistently. How we often frame this clinically for our patients is, I'm hearing you identify that really you're not eating in a way that reflects your weight, but there may be a lot of variability in terms of what we do, and we kind of work in self-disclosure and other things to help patients understand that human behavior is highly variable, and that there are things that can help to manage that, and be that stimulus control, or other pharmacotherapies that can work on impulsivity or cravings, or GLP or GIP combinations that may work on decreasing gastric emptying and reducing early satiety. These can help to reduce some of that variability, but trying to avoid the kind of bias-informed healthcare, well, you're not being honest with yourself, and me and I can't help you, I think is one of the most important pieces of how we can help people more consistently. Thank you so much. Thank you very much. Before going to the next question, I'm just gonna do a couple from the online audience. So, for Dr. Villarreal, mainly, what is the role of the dexa body composition in the management and evaluation of obesity? And the other one is, more practically, about weight loss drugs in the elderly population, fentermin, topiramate, and GLP-1. So, yeah, okay, so let's go for the first question. I think we should measure body composition in people doing weight loss. The only thing is, I don't think it's paid at this point, but there's a diagnosis now, sarcopenias, a diagnosis code, you can use that, and the patient get paid. So, because body composition is very important. Probably you don't worry much about the young people, but what about the elderly? As they are, they are losing, they have age-related loss of muscle mass, and you would compound that by making them lose weight. So, the bone density is easily get paid, but not the body composition, but you use the diagnosis, the sarcopenia would be better. Now, for the use of the medications, as a contrary. Yeah, I mean, it's a tricky thing. I think you can use them in these patients. Honestly, I think you can use them, but you have to see the drug-drug interactions, because they are a polypharmacy. So, to me, though, I think the safest one is this GLP-1 receptor agonist, because you can just make them, you can probably, I mean, of course, the diabetes dose was also associated with weight loss, but it's not as much, see what I mean? Because you don't want them to lose the 20% or the 30% weight loss that we aim for the younger people. Okay, thank you, thank you very much. So, regarding the exercise, when you see a new patient obese, obese diabetic, the question is, what exercise do you not mind doing? Because we know if they do mind it, they're not gonna do it, okay? So, that's important to have the exercise that is proper for that individual, particularly if they have any severe arthritis or some other limiting factor. The question I always ask them, well, so what do you do now? And they say, all the time, oh, I take my dog for a walk three times a day. Okay, well, we know how dogs walk, slowly. They stop every two seconds to sniff around. So, I ask them the fundamental question, what do you sweat when you take the dog out for a walk? And it's never, it's always no. And I explain, that's fatty acid oxidation in your visceral fat and your burning fat. And that's what we want you to do. And sweat is the biomarker. And so, we have to get you to that point. And we work on, obviously, the schedule often with a rehab physician who can then work with the patient given their limitations. That's really critically important if you want to get them to burn calories and burn fat. So, what are your thoughts on that? So, essentially, I think, let me take, you know, remember there's the study, the sit-less study? I mean, the sit-less where these patients are just encouraged to do a lot of physical activity at home, you know, it counts, you know, that you are not sitting all the time, it counts. You know, where you probably would like to cook your own food, you're standing up, you know, and doing a lot of stuff, that counts from the study from the Wake Forest group. Actually, it does. And also, you know, we know that exercise alone will not produce weight loss, okay? But they have to have, you know, dietary restriction. And even with medicines, a lot of patients override the effect of medicines and still gain weight. I have that in my practice. They gain weight. Yeah, that story, I'm not eating anything, why am I gaining weight? But if you sit down and the patient, he's not eating any meal, but actually he's eating a ton of snacks. So that's another thing, but as I've said, you know, other form of exercises that, you know, if they cannot walk because they have arthritis, you know, resistance exercises like upper body, you know, they can do that as well. So great talks on the symposium. My comment question is for the last speaker. When you presented the data on the improvement of frailty with exercise, I guess the biggest challenge we have when we treat sarcopenia of the elderly is knowing how many fibers have that particular elder patient kept over the last part of his or her life, right? Because it depends on how long had that patient been really sedentary to know exactly how the exercise is going to work. And unfortunately, DEXA is not going to help you on that. Yes. Also, depending on the type of fibers that they have, they would respond better to aerobic exercise or strength exercise. Regardless of whatever we want to do, I guess the most effective thing that we can do as physicians is to try to prevent sarcopenia by recommending exercise, you know, at all ages. In particular, if you're nearing 60 years of age, you should continue to do exercise, at least a little bit every day, if there's no other condition that prevents you from doing it. I wholly agree on that. The reason why exercise improves physical function, or whatever, weight loss therapy, is that, you know, I mean, especially in the obese people, you know there are intermuscular and intramuscular fat, okay? So once you remove, I mean, there's more fat loss than lean mass loss, as you know that. So once you remove that fat, you know, so you have a muscle of good quality. Even if you don't have a muscle of massive quantity, meaning the quantity may not be improved, but the quality is improved. So that's why the strength will improve, physical function improves. But you know, you're right, you're right. The study that you did showed differences between the groups over 75 years old and the groups below 75 years old. We haven't examined that. I think we should, I think that's a good idea. I think we should. Yeah, we have a lot of those, actually. The question was if there was any difference between the groups above 75 and less than 75. Yeah, we have that. This will be the last question. So thank you. One of the unifying messages I heard from all the speakers is that there's a large unmet medical need, not only for weight loss, but for weight maintenance. And I guess it seems a little bit of a paradox to me because as far as I know, the obesity medications are not approved for weight maintenance. They're approved for weight loss. And there's actually no regulatory path to approval for weight maintenance. So I wanted to get your thoughts on that, and if that's something needed, what can be done to try to fix that apparent paradox? Sure. I guess we can probably both comment from those perspectives. I think that's a great question that you brought up. I think some of the novel therapies are probably going to undergo indication for both weight loss and weight maintenance. Those are two different things physiologically. But when we've had the FDA approval, when you take a look at the FDA labeling, these are FDA approved for chronic weight, chronic obesity or chronic weight management. So these medications are intended to be long term. And if you look at other disease states, such as high blood pressure and diabetes, and when you look at the FDA labeling for those medications, I don't think any of those medications have an indication for hypertension maintenance or high blood pressure. They're just indicated for high blood pressure. And when you look at diabetes medications, I don't think any of those are indicated for diabetes maintenance long term. So it's that concept of stigma bias that we still need to permeate and kind of evade from that perspective. But as we get novel therapies approved, hopefully some of those indications will come up. I just want to add on to that. Some medications may not result in weight loss, but they may be very good at weight maintenance. So that's kind of a problematic definition for the, you know, it's problematic to get your foot in the door with the FDA in that. Yeah, absolutely. And that's where we get into combination medications and therapies, where the more armature that we have, so we have basically, you know, really novel, powerful anti-obesity medications in terms of weight loss, but maybe some of the other medications can come in a little bit later for weight maintenance, and that's where we get into combinations. Okay, and we got to the end of our session, so thank you very much to our speakers for a great, wonderful, and very practical talks. And to all of you for being here and for our online audience. If anyone else has any other questions, you can approach these speakers.

weight maintenance

weight loss

anti-obesity medications

inflammatory nature of obesity

regulation of body weight

underlying causes of obesity

weight set point

genetics and behaviors

heterogeneity of obesity

personalized treatment plans

bariatric surgery

treatment options

obesity