At this time, we're going to welcome Dr. Penning. He's the chair and associate professor of family medicine. He's board certified in family medicine and obesity medicine. He's recognized as a fellow of the Obesity Medicine Association and a fellow of the American College of Osteopathic Family Physicians. Dr. Penning's moved from private practice into academic medicine, joining the faculty of the Campbell University School of Osteopathic Medicine in 2013. In addition to his role as family medicine chair, he also serves as the director of the Campbell University Health Center. Dr. Penning's contributes to continuing medical education for clinicians to practice through his role as the executive director of clinical education for the Obesity Medicine Association. His research interests focus on the disease of obesity. In particular, the relationship between indigenous insulin production and weight gain, as well as the impact of intensive lifestyle change on health improvement. Dr. Penning's also maintains a special interest in an obesity related condition called lipidemia. He's a graduate of the Philadelphia College of Osteopathic Medicine and completed his family medicine residency at Parkview Hospital in Philadelphia. At this time, we'd like to present the Murray Goldstein Commemorative Lecture in Public Health and General Preventive Medicine. This award, this is given each year to an honor of Rear Admiral Murray Goldstein, founding member of the College and Division of Public Health and General Preventive Medicine. Dr. Goldstein was designated a fellow in 1985 and served as president of the college in 1990. Rear Admiral Murray Goldstein is an osteopathic physician with postdoctoral clinical training in internal medicine and neurology and research training in epidemiology and clinical research. He was the first DO to reach flag rank serving as Assistant Surgeon General of the United States Public Health Service. At the National Institute of Health for 40 years, he served 11 years as the director for the National Institute of Neurological Diseases and Stroke, the federal government's focal point for brain research. In 1975, while at the National Institute of Neurological Disorders and Stroke, he organized the first NIH research symposium on the research status of spinal manipulative therapy. Following this in-depth analysis of what was known at that time about spinal manipulative therapy and the principles on which it was founded, recommendations were made about additional areas of research to targeted additional attention and priorities were established for research training opportunities in chiropractic and osteopathic professional schools. Thus a stage was set for further study of the broad area of manipulative manual therapy as an interdisciplinary and interprofessional collaborative research endeavor. Dr. Goldstein served as the medical director for the United Cerebral Palsy Research and Educational Foundation in Washington, D.C. He's a world-renowned authority in neurological disease. Recently, he retired from the American Osteopathic Board of Preventive Medicine on which he served for many years. Dr. Goldstein also serves on the National Center for Complementary and Alternative Medicine Education and Training Review Committee. Since 2007 to 2011, and the Advisory Board of the National Headache Foundation. This is a named lecture given at the Mid-Year Convention of the American Osteopathic College of Occupational and Preventive Medicine by someone who exemplifies service in the field of public health and preventive medicine. Congratulations. Thank you. Thank you. I'm honored. I wasn't expecting that. Isaac Newton said I see further because I stand on the shoulders of giants and certainly Dr. Goldstein is a giant that allows us all to see further and allows us all to practice better medicine and also really advanced osteopathic medicine which is excited for me to be a part of. I was a clinician in private practice for 22 years and then decided to go into academic medicine and started at the Campbell University School of Osteopathic Medicine. And it's been a wonderful experience working with our students. I was very excited. 40 of our students matched in family medicine this year which was really, really nice being able to contribute to the future of the profession. So, let's see. There we go. I'm gonna be talking about the role of, I call it, I refer to it as incretins and not just GLP-1s because it's really expanded beyond GLP-1. But what's the role of the GLP-1s have played in the treatment of diabetes and then how that's expanded into the treatment of obesity. We're gonna talk about some of the key studies that were involved in these medications and being able to be approved for the treatment of obesity and then talk about some of the risks, some of the benefits and some of the opportunities for future treatment. And I think it's really an exciting area to be in. I've been doing obesity medicine since 2008 and I became board certified in 2012. And it really is amazing how much this field has changed as we were talking a little bit earlier. It's amazing how long it took for it to become an overnight success. So, we begin with the Gila monster. This is a venomous lizard. And when I wrote and submitted this lecture, it was considered non-fatal, but I understand that a fellow that was in Colorado that had a Gila monster was bit by that Gila monster and died from it. So, it's now potentially a fatal. But the venom in this Gila monster contains peptides, a specific peptide, Xendin-4, which was identified and then modified in a synthetic format to make Xenotide. And that became the first GLP-1 agent and that was now sold as Biada. And so, that was approved in 2005. And so, this class of medication has been around for a while because one of the questions I get from patients is, is this something that's safe to use long-term? And now we have almost 20 years of time that this class of agents has been used. And really, I'm not seeing any kind of long-term consequences or harmful side effects of these agents. So, that was followed by loraglitide in 2010, a long-acting form of Xenotide. And then dulaglitide came on the market. In 2014, loraglitide was approved for weight loss. And that was a very exciting step, but it didn't really take off. In fact, around that time, a couple of agents were approved. A combination of bupropion and naltrexone sold as Contrave. Q-Semia was also approved, which is a combination of Phentermine and Topiramate. And it really didn't gain too much traction for the treatment of obesity. Subsequently, somaglitide came out, both in an injectable and subsequently in an oral form. And now, that has been approved for the treatment of obesity as of 2021. And 2022, terzapatide became available for diabetes and now is approved for the treatment of obesity. So, a lot has happened in a short period of time here. And one of the reasons why these have garnished so much attention is because they're very effective for the treatment of diabetes. You can see the lowering effect of somaglitide in being able to bring A1C down almost two points on average and being able to bring down fasting glucose. So, very potent for the treatment of type 2 diabetes. And one of the things that we've even seen is how it compares to insulin. Insulin was always sort of the go-to if somebody had uncontrolled diabetes, type 2 diabetes, that we needed to get under control quickly. This study looked at adding on somaglitide versus adding on insulin for being able to control A1C and bring down the blood sugars for diabetes and found that somaglitide actually performed better than insulin in lowering A1C and, at the same time, lowered weight, but also, very importantly, had a much lower incidence of hypoglycemia, which is always a very big concern for our patients, both because it's a terrible feeling, but also it has a dietary effect that people are constantly trying to avoid hypoglycemia. So, they start eating things and they start consuming, particularly, sweets and things like that, and that makes weight management and overall diabetes control much more difficult. So, there's real advantages of that. And so, what we're seeing is then a shift for those patients that have uncontrolled diabetes, that insulin is no longer just the only go-to option for that, that we now have these high-potency GLP-1 agonists, dulaglitide and somaglitide to be able to bring glucose under control, and then also terzapatide can be used in that same setting. So, those can be ways of being able to bring glucose under control. So, I think it's a big evolution in the treatment of diabetes. What I think is also important, these are the ADA guidelines and recommendations, is that the shift has moved away from a glucocentric model, which was just getting that A1C down as low as possible, to really looking at, you know, what are the underlying health conditions of the individual? Do they have arteriosclerotic cardiovascular disease? Do they have heart failure? Do they have chronic kidney disease? And these agents, along with the SGLT2 inhibitors, are very effective for each of those, and I expect GLP-1 to be in this heart failure category soon as well, and also plays a key role in chronic kidney disease in helping prevent the progression of kidney disease. And also, one of the things about the GLP-1 agonists is that they can be used at any stage of renal failure, even on dialysis, without dosage adjustment. So I think that's a pretty exciting opportunity. But probably most important, from what I'm talking about today, is looking at patients with diabetes and thinking about what's going to impact their weight. And when we're treating their diabetes and their weight is high, we really want to be treating with agents that are going to help lower that weight. Insulin sulfonylureas will typically increase weight, whereas other agents are either weight neutral, like the DPP-4 inhibitors, but the GLP-1's SGLT2 inhibitors promote weight loss. And weight loss is going to lower insulin resistance. And that's really the fundamental part of type 2 diabetes. We should be treating insulin resistance, not just treating glucose. And so when we're helping people lose weight, we're decreasing insulin resistance and improving insulin function. And so we can see that not only does it have great glucose control, but also has a big impact on weight. And semaglutide really stood out very strongly in comparison to the other agents for its impact on weight. And that led to its approval. And that was really kind of monumental, and I think really a big shift in the attention. Suddenly, we used to spend at the obesity conferences spending a lot of time talking about what's the right way to approach a patient to talk about their weight. You want to do it in an empathetic, patient-centered way, caring, and compassionate, and understanding that this is a big challenge. And we still do that, but now patients are coming in asking us about it rather than we having to bring up the topic. So that really makes the discussion a lot easier. But it's important we have this discussion because you can see the progression. This is data that was published in the New England Journal projected at what are the obesity rates, what's the trend been, where are we looking? State by state, where are we going by 2030? And unfortunately, the 2030 is blocked out. Is that? No, it's not. That's good. Yeah, we can support it. I think, was that? There we go. All right. Okay. And we're going to resume slide slow. There we go. Okay, now we can see it. Are we? Oh, it didn't go away. The issue for them is they can't see it either. I'm watching. Captioning. No, it's not. This is something else. You're in Zoom right now. So we don't want to go there. It's actually... That's what I was wondering. He's got it... Yeah, it's like, it's not up there. Let's do this. Are there slideshow under that? Is that working now? Okay, good, yeah, so it's not blocking out, great. All right, well, thank you for your help there. So we can see that the trends in obesity have been rather dramatic. We're really just looking at a 40-year timeline here, and you can see the prevalence in the upper right-hand corner there, and how it has gone, and really, if we go back to 85, most places in the country had 15% or less obesity rates, and now we see a steady progression over the decade by decade, to the point where in 2030, it's projected that some areas will have 60% obesity rates in the country, and with that come all those diseases that are associated with obesity, some 237 diseases that are caused by or made worse by obesity. And so it really becomes very important that we address this issue, and there are significant disparities in the population that that affects, that it's more likely to affect females than it is males, that we're gonna see it particularly in non-Hispanic black populations, but also in Hispanic population, and one of the things that really has been a big shift is that obesity used to be a disease of the wealthy, right? You could afford the food, you didn't have to labor as hard as others, and so that was really a sign of wealth and prominence, but now with the shift in how our food is priced, and our access to food has changed, that those in lower income categories are more likely to have obesity, and so those that are with less than 20,000, I think is the category, are much higher incidence of obesity. So some of the advice that has been typically given is eat less, exercise more, that's what you need to do, and that sounds like it makes a lot of sense, but it implies that it is a patient's decision that is driving all that, they're deciding how much to eat and when to eat, and to some degree we all do, but it's much more complicated than just calories in and calories out, that it is when we're hungry, it is our biology that is telling us that we're hungry, that certain hormonal agents are regulating our appetite, regulating our weight, and driving consumption of food, and these are some of the regulators, there's lots of them, but these are some of the key agents that are involved in appetite regulation, so we have ghrelin that's made in the stomach that creates hunger, and then we have different agents that create satiety, we actually have a lot more agents that create satiety, we have leptin that's made by the adipocytes, we have insulin, amylin, and I would add glucagon to this now, as another agent made by the pancreas that sends signals to the brain that creates a sense of satiety, a sense of fullness, helps you stop your meal, and then the GLP-1 and GIP agonists, or GLP-1 agents are key agents that send signals up to the hypothalamus of the brain and say you're full, CCK, PYY are other agents that are involved in satiety, but the GLP-1 and GIP is what we're gonna focus on today, but the key concept I want you to understand is that when we go into a negative energy balance, when we are on a diet, and when we are exercising, and we are burning more calories than we are consuming, the physiologic response of our body is for those hunger signals to go up, those fullness signals to go down, and we feel hungry, and so asking somebody to stay in that state is not easy, when you're in a constant negative calorie balance, it doesn't feel good, in fact, we have a term for it, right, we call it hangry, right, when we can't eat, and so it really does affect us that our appetite regulators are affected when we're trying to lose weight, so when we eat less and exercise more, these mechanisms kick in, and it's in part because that's how our body's designed, now when we overeat, we also don't wanna keep eating, we have these signals when we are in a positive energy balance, when we eat a big meal, we actually then are not hungry, so we're gonna decrease our calorie intake, and we're gonna increase our physical activity, and this is a natural response that we have, on the other hand though, when we're in a negative energy balance, those hunger hormones go up, those fullness hormones go down, and we also have metabolic adaptation that is changing our metabolic rate, one of the key components of metabolic rate is your weight, when you look at the Harris-Benedict or Mifflin-St. Georges equation for calculating resting metabolic rate, then one of those key components is weight, so if you lose 10 pounds, your body's gonna burn fewer calories, roughly about 100 fewer calories, and so as your weight is going down, that metabolism is going to down as well, and what this picture is meant to depict, is that it's not a fair fight, that our body's desire to eat is so much stronger than our body's desire not to eat when we are full, which is why you can have dessert at the end of your meal, you just had that little bit of calories, this pole is not as strong, and therein lies one of the key challenges, and this challenge is not a short-term challenge, this challenge is a long-term challenge, and this study is a beautiful study that really exemplifies this, and really a key study, landmark study in obesity medicine, and looked at people who, they looked at their fullness signals, their hunger signals, before they went on to an intense dietary program, and then they had them go through a 10-week intense dietary intervention, where they lost 14% of their body weight, and they looked at what were the levels of those hunger hormones, or those satiety hormones, at the end of 10 weeks, and they were higher, as you would expect when you're losing weight, it would be higher, but then they also looked at it again at 62 weeks, and so a year later, ghrelin levels were still higher, hunger hormone was still higher, satiety levels were still lower, leptin, PYY, GLP-1, CCK, were lower at the end, a year after they had lost their weight, and maintained their weight, and in fact, at the end of a year, perceived hunger was higher, and desire to eat was higher, this is why obesity is a chronic long-term disease, this is why it doesn't make sense to stop medication at the end of, once they lose their weight, because these drivers are still going, and they're gonna keep going, we don't know how long they go for, we don't know what that end point is, but this is why people regain weight, if they were to stop medication at the end of their weight loss, question? Yes, does the type of diet though, have any effect on these hormones? So the question is, does the type of diet have any effect on these hormones? And it does, so different types of foods are going to impact these levels differently, so refined carbohydrates don't have as big of an impact on these, where protein creates a greater sense of satiety, by lowering ghrelin levels, increasing leptin levels, so different foods, different macronutrient combinations are going to impact that, and that should be a part of any kind of dietary planning, when we talk about medications, and I'll talk about this a little bit towards the end, we need to think about nutrition, we need to think about physical activity, and we need to think about that in combination with medications, but the key thing I want you to take away is it's a long-term process, and this is why we consider obesity a chronic disease, so the GLP-1 agonists have come into being, and one of the things that's amazing about these medications, is they really affect various different parts of the body, it's not just limiting your appetite, and they seem to have some neuroprotective benefits, so on the heels of the great Alzheimer's lecture we just had, they seem to have a neuroprotective effect on the brain, and we see lower dementia rates in patients who are being treated for diabetes with agents that reduce insulin resistance, so we don't see a beneficial effect with like insulin or sulfonylureas, but we see a protective benefit with agents like the GLP-1s, the DPP-4s, metformin, all have some benefit, and I think that insulin resistance does play a role in dementia, not likely to be the sole explanation, and I don't know if type 3 diabetes is the right term either, but it is certainly a factor in what we see, we see it impacting the heart with increasing myocardial contractility and decreasing some stress related to ischemia, we see beta cell protection that it protects beta cells, and helps new beta cell formation, which can also be extremely beneficial in diabetes because beta cell failure is a key component of that, glucose uptake in muscles is a benefit, we see endothelial benefits, we see increased filtration of sodium in the kidney, fat cells are functioning better, breaking down fat, we see slowing of gastric emptying, which is a factor in some of the side effects with these, we see increased glycogen storage and less glycogen release, so there's a lot of different pleiotropic effects and benefits that we're seeing with these agents, so their GLP-1 is naturally produced in the small intestine, and it's more in the distal small intestine, which is also one of the reasons, one of the benefits of eating slower, and stopping before you feel full, one of the expressions is eat till you're 80% full, or eat till you're no longer, until you're not hungry rather than you're full, because by the time, it takes about 20 minutes for food to get really down to the small intestine where these agents are produced, and be able to create a satiety effect, so if you're eating faster, you tend to eat more, they're affected by carbohydrates in the diet, and they have a central satiety effect, so they go up to the hypothalamus, they accentuate glucose-dependent insulin release, so when you eat a meal, you tend to make more insulin, which is beneficial, because it's gonna clear that faster, and then it also decreases glucagon, because one of the challenges in diabetes is that glucagon isn't turned off, and that raises blood sugars afterwards, it's inactivated by DPP4, and so the other thing that happens is in conditions like diabetes, pre-diabetes, obesity, pre-diabetes, and type 2 diabetes, people are actually producing less of these GLP-1 agents, and the natural production is much less, and also, this is one of the benefits of gastric bypass, we often thought that gastric bariatric surgery was really intended to just create less room to eat, but it's much more than that, when we do a gastric sleeve, you take out a large portion of the stomach, your ghrelin levels drop immediately, hunger goes down immediately, because of its impact, and for the Roux-en-Y bypass, what you're doing is you're shorting that transit time, so food gets to that small intestine, and promotes the natural release of GLP-1 much faster, so you become full much more quickly, not just because you have a small stomach pouch, but because you're creating a metabolic response that increases a satiety effect, and so loraglutide and semaglutide are approved for the treatment of obesity, and we titrate those steadily, with loraglutide being a daily injection, versus semaglutide, which is a weekly injection, and one of the things that are endogenous GLP-1 is broken down very quickly by DPP-4, and so it doesn't last for a very long period of time, where these are very long acting, semaglutide will stay in the system for up to five weeks after you stop it, so it really has a prolonged effect, but there's a titration process, and the titration process is because you, they have significant side effects, but these side effects tend to subside the longer you're on the medication, and so the titration process allows you to get adjusted to those doses, to those higher doses on a gradual basis, so same for both semaglutide titrated on a four-week basis, now for obesity treatment, one of the things that you'll get in inquiries from the insurance company wanting to know how much a patient has lost at 12 weeks, right, well if you're on semaglutide after 12 weeks, you're just starting the 1.7 milligram dose, you want to make sure that they're assessing that patient at 12 weeks on their maximum dose, right, so that's the argument I give back to the insurance company if they don't want to cover it because they haven't lost the 5 percent minimum, which is what they require for that, but you want to make sure it's 5 percent at the maximum dose, and so what are some of the studies? Well, when semaglutide was first, when this was first published, this is what really garnished a lot of attention in the world of obesity treatment, a 15 percent weight loss. This was far greater than anything that we had seen and really felt to be a game changer in the treatment of obesity. And also the other way that we look at these is how many people lose 5%, how many people lose 10% because not everybody responds the same. You'll see that some people don't lose any weight on these agents. But when we look at these agents, we see pretty pronounced that 86% of people lost at least 5% of body weight. Well, that's a huge number. That's much greater than anything that we've seen. And that 5% is where you're gonna start to see health benefits around it, right? That's where you start to see improvement in glucose control. And so that is kind of the threshold that we've looked at. Five to 10% can help improve blood pressure, improve blood glucose, improve lipid profiles. But now we're seeing 32% of individuals had a 20% or greater weight loss. And that was really very impressive. And this kind of speaks to what I was talking about before. They did an extension trial and looked at what happens if you stop the medications. And well, patients gain weight when you stop the medications. The more weight they lost, the less they regained, which I think is important because some people think if you lose it fast, then you're more likely to gain it fast. And this goes against that concept. But the main point is that when you discontinue those treatments, then your hunger signals are gonna go up, your fullness signals are gonna go down, and you're going to eat more. And so that you're going to gain weight. And this speaks to the need to not just stop treatment once you get to your goal weight. That you want, it needs to be an ongoing therapy. Looking at two years, you'll start to see more of a plateauing, but a maintaining of significant weight loss. So this was looking at a two-year timeline. And again, those that are maintaining a 5%, 10%, 15, and 20% weight loss are quite high. And this is kind of breaking down the numbers as to its impact, its reducing weight circumference, which is really important because that reflects visceral adiposity, which is the adiposity that's associated with cardiovascular disease and associated with diabetes. It lowers blood pressure, it improves A1C and lipid profiles. But I'll call your attention to the number on the bottom there. When we look at the change in C-reactive protein, when the reduction was 56.7%, that's huge. And I think that speaks to one of the key components here is the anti-inflammatory effect that we see with these agents. And it's interesting, I treat a lot of different patients, but one of the things that patients will say, my knees feel better on this. I don't have as much knee pain. I'm thinking more clearly. Just different things that happen that are additional effects beyond. And I think inflammation plays a key role. And I think it played a key role in this study, which was really also a landmark in obesity medicine, looking at cardiovascular risk reduction when treating obesity. We know that the GLP-1 agonist showed cardiovascular risk reduction in the treatment of diabetes, but this is looking at patients with obesity without diabetes and found a 20% reduction in major adverse cardiac events at four years. And you can see that the lines separate very quickly, right? And to me, that implies that that anti-inflammatory role, which we know plays a very important role in cardiovascular disease was a key, I think plays a key role in that. But this is also really the first study that has been done that has shown that treating obesity reduces a health risk and specifically reducing cardiovascular risk. Question. Maybe you're talking about the mechanism of action that causes the reduction in inflammation. So the question is, what is the mechanism of action that causes a reduction in inflammation? And I think it's a reduction in insulin resistance that is happening with that. I think it's changes in dietary habits that occur with that. I think there's multiple factors that come in there. I don't know of a direct anti-inflammatory effect of GLP-1 and there may be one that exists that I'm not aware of, but I think it's a multifactorial thing that is coming into play here. When we eat large amounts of foods and we stress our body with larger portions, and I think that has a pro-inflammatory effect. So another study was looking at effect on heart failure. And this is heart failure with preserved ejection fraction. In patients with obesity, this is the most common form of heart failure with preserved ejection fraction. And let me see if I can get this right. The Kansas City Cardiomyopathy Questionnaire Clinical Summary Statement. Or survey, survey. Yeah. And so it's a questionnaire that looks at patients with cardiomyopathy and how it impacts their function, their physical abilities, their quality of life, and saw a significant reduction in that with the use of semaglutide versus placebo. But this really impressed me the most. Six minute walk distance went from those on placebo only 1.2 meters up to 21.5 meters in six minutes. What a big difference that was. And so what we saw, the patients that were treated with these agents that had heart failure had a decrease in symptoms, had a reduction in their physical limitations that they could do more and function better in addition to their weight loss. So I thought that was really impressive and why I think this study in particular is going to be why semaglutide and maybe some of the other GLP ones will be considered a factor for the treatment of heart failure. So let's go on to a little bit about GIP. So GIP is also produced in the intestine a little more proximally. It also is stimulated by dietary. Oh, another question. Yeah. Okay, now it's on. So my residency program has like a 20 bed hospital but five cardiologists. So we're really big on the guidelines. Are those in the ACC guidelines yet? Because I would love to start prescribing that to more of my HFPAF patients. So I don't think it's hit the guidelines for that particular indication yet. Although Weigovi just got approval by Medicare for the treatment of cardiovascular risk reduction. And so I think that's gonna open up a window of treatment for patients because certainly that is a, that I think is the avenue that will get that covered. Just this week. Just this week that came out. So that's gonna be a huge game changer. I haven't seen what their criteria are going to be and how you determine who's at cardiovascular risk. Is it based on the calculation that we typically do for arteriosclerotic cardiovascular risk scores? But we'll see what the details of that are as they come out. And so GIP is also produced in the intestine. It stands for glucose-dependent insulinotropic polypeptide. And so it also accentuates glucose-dependent insulin release but it also increases glucagon. Now that sounds like something that would be problematic for diabetes but it only increases glucagon release when you're hypoglycemic. It doesn't seem to affect it when you're normal glycemic. And that effect is counteracted by the GLP-1 effect. And so that does in terzapatid which is the only agent that's approved now. We don't see that effect as being problematic. It increases gastric emptying. So that sometimes offsets some of the GI side effects that are seen with the GLP-1 agonist where people have a lot of retention in their stomachs. It's inactivated by DPP-4. And so terzapatid is the agent that's currently approved for the treatment of obesity. And so it too has a lot of pleiotropic effects, potentially beneficial in the brain. Also has a beneficial effect for beta cells. It increases lipogenesis which also doesn't sound like it would be a good thing for weight. But one of the challenges with weight is and what makes excess weight dysfunctional is that adipose cells become too big and they become dysfunctional in that way. So what this does is it makes the adipose cells smaller in essence. If you have more of them, I use the analogy, if you have a dozen people that want to go up in an elevator and there's only one elevator and everybody has to crowd into that, it gets hot and uncomfortable. If you had three elevators and everybody could go, four people could go into each one, it's very comfortable. And that's kind of what happens with the benefits with reduction of inflammation when those adipose cells are overly enlarged, they're inflamed and irritated. And so if we can make them smaller, they have less inflammatory effects, they have less insulin resistance. And so here we can see the comparison and there's a lot of similarities to what they do. They both can reduce weight, they decrease food intake. We talked about the differences in glucagon, a little bit about the gastric emptying effects. But I think what we're also seeing improvements in liver insulin sensitivity and muscular skeletal, skeletal muscle sensitivity, and I think and decrease fat deposition in the liver as well, which is going to be another exciting area of treatment. Terzapatide similarly has a titration schedule. When the semaglutide was first approved for obesity, there was a push that it had to get to 1.7 or 2.4. That hasn't really been necessarily the requirement for terzapatide that I've seen. So I think you can titrate to effect here more, which is what it should be. We should be titrating to effect because I see patients at fairly low levels of GLP-1 agonist have tremendous responses, particularly to weight. And so what we've seen is over the past few decades as these new medications come out, so these came out in 2012 to 2014, that we've seen progressive improvement in weight loss associated with that. But now we're taking another sort of quantum leap. And sometimes these agents are referred to as second generation. But also I have this up because we're approaching the effects of bariatric surgery with these medications. And I think that's a pretty exciting area for the future. So some of the key studies, the Surmount-1 study for terzapatide showed a 20%, 20.9% weight loss. But also what we're seeing, we saw significant weight losses at even at fairly low doses, 15% at five, 20% at 10, and 20.9 at 15. So lower doses produce significant effects. And here again, you're seeing at the 15 milligram dose, over 90% of people having at least a 5% weight loss. 83 having 10%. And now we're at 36% are having a 25% weight loss. So again, approaching those bariatric surgery numbers. This also is another study that looked at people that initiated a lifestyle change. So they would try to lose weight through lifestyle means. There was a lead-in period. They lost about 5% to 7% of weight. And then they were put on the terzapatide. And it still worked extremely well. It still brought weight down. Now a total 25% with a combination of lifestyle. So I wanna spend a few minutes, just talk about what are some of the downsides? What are some of the things? Because anything that becomes popular then starts to be trashed, right? So it's sort of the nature of the beast. And certainly there's contraindications. We know about medullary thyroid carcinoma, which is a rare form of thyroid cancer. But still we have to be aware of it. Multiple endocrine aplasia type two is a concern as well. But again, something that's very rare. Acute pancreatitis. Incidents of pancreatitis is slightly higher in those that are on these medications. Whether that's a weight loss effect or not or effect of the medication, but something to be wary of. For patients that have a history of pancreatitis, if it was a gallstone pancreatitis that they've had the gallbladder removed, I'm not particularly worried about that. But if it's related to other reasons, then I would be very hesitant about these medications. Anybody that loses weight is at risk for gallbladder disease. Hypoglycemia is a concern really only for those that are on insulin or saponioreas. So if those are anything that's gonna increase insulin levels. Acute kidney injury is primarily is seen in people that have had a severe nausea and vomiting. They've gotten dehydrated and then they go into a pre-renal kidney injury. Diabetic retinopathy are seen in patients with type two diabetes. That's likely related to rapid declines in glucose. So if we improve glucose very rapidly, we increase the risk of some microvascular complications, particularly retinopathy and neuropathy that can occur. Increased heart rate is seen. Suicidal ideation is a small effect. I think in part, we also see with bariatric surgery. I think when for so many people, food is such a joy in their life. And when you take that away or that disappears, that has an emotional effect on them and can increase depression and potentially suicidal ideation. So the question was, regarding side effects, what is the impact on muscle mass? And actually, I'll touch upon that, because that is something that we do worry about. So GI side effects are most common. They tend to be transient, though. And we actually see it more at starting doses than we see at higher doses. Once the patient is on it for a while, they can tolerate that. Sometimes you use medications to counter the diarrhea or nausea. That's fine for a short-term period, because it's typically transient. And sometimes you have to slow the escalation of doses, that you keep people at a dose for a longer period of time before you increase heart rate. You do see higher amylase and lipase, on average. Pregnancy, this also kind of hit the news recently, that ozempic babies are popping up, because it may impair oral contraceptives, but also significant weight loss can increase fertility. And so that is something to warn your patients, and shouldn't be used with breastfeeding. So one of the paradigm shifts that I've experienced with these, as somebody who treats obesity, is I, for years, have been trying to get people to eat less, right? Trying to cut down their caloric intake. Well, now, people come in, and they say, well, I skipped breakfast, I skipped lunch, I wasn't really hungry, had a half a sandwich for dinner, and that was it. You know, I'm like, whoa, that is not enough food. That is not enough calories. We need to make sure that patients are getting adequate nutrient quality, and particularly getting protein, and that really gets to your question of muscle loss, right? So that when you're not consuming protein, you're going to be increasing your risk of muscle loss. Because when you are losing weight, you lose both fat and muscle. And that's, you want to minimize that lean body, that lean mass loss as much as possible. And so the quality of the nutrient intake becomes very important, right? So you have to, if you're going to cut your calories down to a much smaller amount, you can't eat Snickers for that, right? You can't be eating candy bars as your source of calories, right? Because there isn't any nutrient value in that. You want to make sure that you're getting good quality nutrients. And this is something that's been done in bariatric, after bariatric surgery for years, right? So initially you do a clear liquid diet until you heal, but then it's, you want to prioritize your food. You want to prioritize your protein. You want to prioritize your vegetable intake. And actually I, there's a handout here, 10 tips for patients on GLP-1 agonist that I've included, that go into some of this, and you can download that. But you want to make sure you're getting protein and vegetables first, then maybe add fruit, and then maybe add some other foods, but you want to get adequate protein in the diet. And I also have my three Fs that keep people from, that help to minimize side effects with these agents. Don't eat too fast, don't eat until you're too full, and don't eat too much fat. Those are the things that tend to make people feel sick. So if they're feeling nausea, make sure those three are not a cause of that. And then physical activity becomes very important, including strength training. So, you know, walking is a great exercise, and biking and things like that. It's fine to do cardiovascular exercise, but you need to do some strength training too. You have to do some sort of resistance exercise. So combining protein and resistance exercise is going to minimize muscle mass loss, and that can counter that concern. Right, just got to, right, good quality food. So the future is really very exciting in this field. These are just some things that are in the pipeline. And I think it's going to be a big part of any medical practice, and can be a big part of any medical practice, the treatment of obesity, because we have tools now that we didn't have before. And so there's a GLP-1, there's a version of semaglutide, an oral version. So we know that oral semaglutide is used for diabetes, it's rubelsis, that has a maximum dose of 14. So this was titrated up, excuse me, I strained my back and every once in a while, I feel it. This was titrated up to a dose of 50 milligrams. So a much higher dose than what is available now. There's a combination GLP-1 with amlin, which again, synergistic effects. And we've done this for years with blood pressure medications. The same concept is applying in the treatment of obesity. The GLP-1 glucagon agonist, there's a number of agents there that are out. And I think this will be very important for the treatment of MAFLD, or now what is called MAFLD, or metabolic dysfunction associated steatotic liver disease. That used to be the term, that's the new term for non-alcoholic fatty liver disease. But I think these will play an important role in the treatment of NAFLD or MAFLD and MASH now. Ritudatride just published their results earlier this year, or actually last year, with a 24% average weight loss. And this is a triple-targeted receptor agonist, GLP-1, GIP, and glucagon. All again, decreasing appetite in the brain. And then also there's a small molecule GLP-1, or 4-glupron, which also has excellent data. And this medication is not in the GLP-1 or GIP or incretin categories. This is a monoclonal antibody called bimagrumab. And it has good weight loss data, but actually what is most interesting about the data on this agent is that you see an increase in muscle mass on this. It works on the actin pathway in the muscle fibers. So we don't see as big a weight loss, but what we see is a large fat loss and an increase in muscle mass, which is very interesting. And we'll see where that goes. So there's some 237 diseases that are caused or made worse by obesity. And treating type 2 diabetes, we want to really focus on that insulin resistance versus insulin control. I'm excited about the cardiovascular risk reduction, the MACE reduction. We see improvement in osteoarthritis, which I think are both weight-related and inflammation-related. We see the changes in fatty liver that is going on. What's also interesting is changes in addictive behavior. I've had people tell me that they don't, they're not interested in drinking as much. They don't really want to gamble. There's some people who were addicted to gambling, lose interest in gambling. Women have even told me they didn't want to go shopping anymore. They weren't interested in shopping. I thought that was a very interesting. That could really offset the cost of the medications. But we're seeing this, and that is describing the impact on the limbic system. So these are not just on the central appetite centers. They also impact the reward centers of the brain, similar to the bupropion, naltrexone kind of medications. We see improvement in mobility and reductions in chronic pain with all these. So I think it's very exciting to see where we're going with the treatment of obesity. Thank you for your attention, and thank you for the honor of this award.

obesity medicine

incretins

GLP-1 agonists

weight loss

bariatric surgery

dietary changes

cardiovascular disease

fatty liver

novel drug classes