34th AM (2023) - Medical Update: Advances in Weight Loss Treatment-Medical Update: Advances in Weight Loss Treatment

Medical Update: Advances in Weight Loss Treatment
Video Transcription
It's my pleasure to introduce Dr. Eduardo Grunwald, who is going to talk about an update on advances in weight loss management.  Dr. Grunwald is a board-certified internist and obesity medicine doctor. He's the medical director of the Center for Advanced Weight Management with UCSD Bariatric  and Metabolic Institute. Dr. Grunwald and his associates manage patients both medically and perioperatively.  As a clinical professor, he is very involved in teaching at the medical school on topics  of metabolism, weight regulation, and treatment of obesity and weight-related medical conditions.  He has served on national committees developing competencies for obesity education in medical  schools and also have authored guidelines on the use of medications for weight management.  His research includes obesity medicine education, bariatric surgery outcome, weight-related complications, and obesity drug development.  He has also participated in pharmacotherapy and clinical trials. With that, I welcome Dr. Grunwald and take it away. Thank you. Thank you very much.  Thanks for the invitation to present at this conference, and thank you all for staying here to listen to this with this beautiful weather.  I'm here from San Diego, so I know some of you are from places that are not quite as warm.  Before I get started, Dr. Lin had mentioned going to the beach, and as a local, I recommend if you have time to go to Coronado.  It's about a 30 to 40-minute drive, but they actually have, it's an iconic San Diego place, it's a hotel.  They actually have an ice skating rink right on the beach, so it's pretty cool to skate right on the beach.  Then you go over the bridge, and you can go to Little Italy in downtown, which has some amazing restaurants, so I highly recommend that. Speaking of food, let's get started.  I was listening to Dr. Weiss's fireside chat yesterday, and a lot of things that he was saying really resonated.  I want to just give a little bit of background of how I got started in this field without going into too much detail because I don't have time.  I was at the right place at the right time, and I was asked to become part of our bariatric surgery program at our institution when it was getting started.  I didn't really know much about obesity. There's not much education or training in obesity in medical school, as you all probably know.  As I started working with these patients that were undergoing bariatric surgery, it became very clear to me that I knew nothing about how the human body regulates weight.  I did a lot of self-education.  I became fascinated in the biology of weight regulation and snowballed, and we created a very large multidisciplinary program, which is occurring in most academic medical centers  now. That's how I got started in this field. What's also amazing to me, sitting in this conference for the last couple of days, is  how much parallels there are between our fields about the challenges that our patients face  in terms of bias, stigma, barriers to access and care. All that happens in our field as well. These are my disclosures.  I will be talking about some of the medications that are manufactured by some of these companies today. Here are the objectives for the next hour or so.  One of the things I want to do is hopefully make people appreciate that we really are going through a revolution right now, a medical revolution in terms of how we treat obesity  and other metabolic diseases with these new medications that are coming on the market. I want to describe the pathophysiology of obesity a little bit, because I think like  any chronic disease, it's very important to understand the physiology of what we're doing so we understand the treatments.  How to counsel patients in terms of the therapeutic options beyond just lifestyle interventions.  Then maybe for you guys, if you're not going to prescribe these medications, how to best collaborate with some of your partners, maybe in primary care, endocrinology, or some other  specialties for patients that may benefit. I do want to talk something about the hedonic behaviors, because there's a lot of intersection  and overlap obviously between what we do and what you guys do, and some of the biology actually through the central nervous system.  I don't think I have to tell this audience that we are still living with hunter-gatherer  genes, so that's where the story starts. We still have those genes, and it's been shown that about 70 to 80 percent of the variability  in our risk of obesity is heritable, so that's where we start. We all have different genetic predispositions. About 10,000 years ago, the agricultural revolution occurred.  I would argue that this is probably the biggest jump in our food environment, but we didn't see a jump in obesity. That has just come much more recently.  Then we had the industrial revolution a couple of hundred years ago. Again, change in the food environment.  This is what I call now the morbidity revolution, so that we have access to food everywhere we go, all around, every corner you walk around.  This is what I call the WALL-E revolution. I don't know who's seen the movie WALL-E, the Disney movie WALL-E, where humans really  don't even have to get off their ... They all kind of move around in these pods where they don't have to get up even to get a drink. The robots bring them drinks.  Robots bring them food. Now, with Uber Eats and DoorDash, you don't have to even get out of the house. You just use your phone, and the food comes to you.  Our environment, obviously, has changed. Just like you guys, our patients are very stigmatized. This is just an art from depicting Dante's Inferno a few hundred years ago.  Overeating was so stigmatized, so gluttony was one of the deadly sins, and this is the third circle of hell.  If you were gluttonous, it was such a sin that you were damned to roll around in sleet and human excrement, and then finally be eaten by Cerberus, this three-headed dog.  That was what you deserve for being gluttonous, and you think, okay, that was several hundred years ago.  Well, more recently, Willy Wonka ... The children in Willy Wonka are thought to represent the seven deadly sins, and Augustus Gloop was the gluttonous child, and he also was ... He  deserved to be taken up by the swamp and up the chute, and that's what he deserved for being gluttonous, but what's the reality? This is how we think of obesity now.  The triangles there represent our genetic susceptibility to gain weight, and we all have very different genetic susceptibilities.  On the left there in the green represents what we call leptogenic environment, so several hundred years ago, where our environment led us to have behaviors that would control  our weight, and you can see the green normal distribution there. In the red is our modern environment, so our genetic susceptibility hasn't changed at all,  but it's really been the environment, and if you look at the curves, they're typical normal distributions, so this suggests that this is a biological trait, like any biological  trait, and the only thing that's changed, as I mentioned already, is the environment, right?  So it's really the environment that has manifested our genetic risk for developing obesity, so this is a biological disease. This is not a lifestyle or behavioral disease.  Lifestyle and behavior are part of the problem, but we consider obesity now as a chronic metabolic disease.  So let me talk a little bit about the dark history in our field, as many of you may know. So we have not had much success in terms of treatment beyond lifestyle interventions until  recently, so this is really exciting for us to talk about our field now in the last 18 months or so because of the advances that have been made.  This is actually from a journal article in the 1960s, where it says, like mother, like daughter, it's always a woman, by the way, like mother, like daughter, obesity follows  a pattern, right? So this is a moral failure, it's a lack of willpower, it's some kind of weakness, right? That's what's reflected in this.  And this is, again, from a medical journal, but this was printed. And then sort of the history of our treatments for obesity has not been good.  So even back to the 1930s, with 2,4-dinitrophenol, which was a decoupling agent, it actually caused pretty good weight loss.  That's an interesting story behind it, I don't have time to go through it, but it also caused a lot of fatal arrhythmias and hyperthermia, et cetera, so not good.  So in the 1940s, we had the rainbow pills, which were a combination of barbiturates and diuretics and amphetamines, and that also had bad outcomes.  1950s was the era of just the amphetamine derivatives, 1960s amphetamine derivatives  with barbiturates, and then of course, the 1990s was the famous PhenPhen era, where Phentermine  and Phenfluramine was very effective for weight loss, but the Phenfluramine part of it caused valvulopathies and pulmonary hypertension.  More recently, rimonaban, which is an endocannabinoid receptor agonist, I'm sorry, antagonist.  In Europe, it was approved, but not approved in the US, and it was withdrawn from the market because of suicidal ideations.  And then, Sibutramine was another agent that was withdrawn about 10 years ago because of the SCOUT trial, which showed an increased risk of stroke, and then Belvique, which  was an interesting medication, it's a serotonin receptor agonist, was withdrawn from the market a few years ago because of some concerns of possible links to increased cancer.  So, this is very depressing, a few years ago, we were at conferences where every treatment we would come up with would get shot down, and in the 1990s, the pendulum swung to the  side where people were just saying, we should not be treating these diseases with drugs, this is just something that you need to do on your own, diet, exercise, and then that's  the final solution. Now, how do we treat obesity in our clinics? So, this depicts what the foundation of our treatment is, in the light blue circle there,  lifestyle intervention is always the foundation, so no matter what we do, we always address  it in one way or another, and the sort of darker blue circle there is our behavior therapy, so those are more intense strategies to help people interact with their environment, so  this is what Weight Watchers is based on, Jenny Craig, intense lifestyle intervention programs, that's the behavior therapy.  And then we add on to that other things, like pharmacotherapy, meal replacements, and even bariatric procedures, so let's talk a little bit about lifestyle interventions, because  if you ask many people, there's been many surveys done in society, and among health care professionals, and many people think that lifestyle interventions are superior  to all the other therapies, including bariatric surgery, so when we talk about lifestyle interventions, what are the best trials that we have?  So one of them is the diabetes prevention program, and many of you may remember this from medical school, this is a very old trial, three arms, it was randomized to Metformin,  lifestyle intervention, and a placebo group, and the goal here was to look at the progression  from pre-diabetes to diabetes, but of course, through weight loss and lifestyle intervention. And at the end of four years, the average weight loss was about 6%.  So if we look at the Look Ahead trial, this is another randomized trial in patients with diabetes, and they randomized them to a control group of usual care, and then another one  of intense lifestyle intervention, and after about four years, you see the mean weight loss is about 5%.  And then there's another study called the Pounds Loss Trial, and this randomized four groups into different dietary macronutrient compositions, and at the end of two years,  these were non-diabetics, at the end of two years, the mean weight loss was about 4%. Keep in mind that with these interventions, they're intense, they're research settings,  so it's much more controlled, it's much more intense than you would ever do in a primary care practice or psychiatric practice or any other practice, right?  So with the best gold standard care, you get about 5% weight loss. And that's what we consider clinically meaningful, is about 5% to 10%.  So the reason is that with 5% weight loss, it's been shown that you have improvements in multiple parameters, metabolic health, biomechanical, functional, even sexual health,  sleep apnea, et cetera, et cetera, et cetera. With 5%, you get significant reductions or improvements in health parameters.  10% is very difficult to do long term with just lifestyle interventions, and that's why we consider that range 5% to 10% sort of the clinically meaningful range, right?  So keep these numbers in mind. We also, I should point out that we look at percentage weight loss when we're looking at outcomes, right?  We don't look at the BMI, we don't look at the number on the scale, because that's how you determine the effectiveness, right?  The body tends to start kicking in metabolic adaptations based on percentage weight loss. So keep those numbers in mind.  So how do we compare all these different treatments to one another? As I mentioned, with lifestyle intervention, we tend to see about 5% to 10% weight loss long term.  It used to be that up until recently with pharmacotherapy, you could get somewhere between 10% to 20% in addition to lifestyle interventions.  And of course, bariatric surgery, we kind of see the range of like 25% to 35%, right? So that's kind of the comparative effectiveness of these treatments.  Now, why is excess weight a chronic metabolic disease? So if we think about most processes in the body, they're controlled homeostatically, right? So even red cell mass.  If you have surgery or you get in a car accident, you lose a lot of blood. Eventually, the body replenishes the red cell mass, right?  To homeostatic level, through homeostatic mechanisms. Same with sodium in our body, same with pH, right? All of these processes are homeostatically determined.  And fat mass is really no different, right? So the body likes to maintain our fat mass in a sort of a specific range. And it will do things to maintain the fat mass in this range.  And we're talking about weight, we're talking about our fat mass.  So how is this regulated? So it's the brain, the central nervous system, right? Can regulate, if we think about fat mass as a tank and  the body wants to maintain that tank, it's sort of in a steady range.  The brain has mechanisms to regulate energy consumption, right? So, or how much we eat. And all this is, most of this is subconscious.  It also has ways of regulating energy expenditure, right? So it can control the faucet and the drain to keep that tank level within a sort of narrow range.  Now like any negative feedback mechanism, you need sort of a signal. And one of the main signals that tells the central nervous system,  these are my long-term energy stores, is a hormone called leptin. So leptin is produced only by adipocytes, by fat cells.  And as you can imagine, if your fat cell mass goes up or down, the leptin levels go up and down. And that tells the central nervous system, okay, I need to replenish my fat cell  stores, my energy stores, or I've got too much energy stores going on and I need to bring it down.  Now that's a simplified depiction, but you get the picture.  In reality, it gets a little more complicated because you have many signals that are telling the central nervous system,  these are my short-term energy stores, my long-term energy stores. And we have to kick something in to sort of keep it in a narrow range.  You can see that some of the signals are hormones, signals from the vagus nerve. And at the end of the day, there's a structure in the hypothalamus called the arcuate nucleus.  And I don't need to go into a lot of detail, but there are some just basic concepts that are important. There's two main neurons in the hypothalamus, the POMC,  pro-opioid melanocortin, and the neuropeptide Y, NPY neurons. So the two different neurons that have opposite effects, right? So that's the homeostatic regulation.  That's going to regulate how much energy is consumed, how many calories are consumed over a long period of time, and energy expenditure, right?  And so, that keeps it in a set point range.  But then we have this cake up here, right? So the cake represents our mesolimbic system. And this is where our fields start to kind of intersect.  So there's obviously evolutionary advantages for us to want to consume fat and sugar. Because when I showed you our caveman genes, right,  we didn't have access to fat and sugar a lot. And we want high energy dense foods for survival. So that represents our limbic system,  which can unfortunately override our homeostatic system, right? So for people that are predisposed to this,  living in an obesogenic environment, that's the problem that we're dealing with. Now how does this translate into the clinic?  So when I'm seeing patients, there's three main clinical domains that are important. One is satiety. So how hungry is that patient throughout the day, in between meals?  That really is what satiety means. Satiation means, refers to meal termination. So when a person is eating, when do they stop eating, right?  What does it take to make that person full? And then the third one is hedonic eating, right? Their cravings, their control of eating, their impulse of eating,  all that, that's the hedonic eating part.  So I kind of try to get a sense of where the patient has a problem with respect to this.  So what happens when we try to diet and lose weight, right? So when you lose weight, by definition, you have to have a negative energy balance.  Otherwise, you don't lose energy stores. Once you start having a negative energy balance, there's some things that start happening in the body.  One of them is that there's a hormonal shift, and you have a subconscious drive to consume more calories. So that's the hunger part.  The other thing is that your metabolic rate decreases. So anytime you lose mass, obviously, your metabolic rate's gonna decrease.  But what's been shown is that your metabolic rate actually decreases more than you would expect for the loss of mass.  So that's adaptive thermogenesis, which means that your body's saying, hey, anytime you try to lose weight, the brain senses that as famine. You're going into a famine.  So let's slow down metabolism so that we don't starve to death, right? So that's one thing that happens.  The other thing is that the hedonic reward value of a given food goes up when you try to lose weight. So that donut is gonna be a lot more enticing  after you've lost weight than before you've lost weight.  And then gastric accommodation also goes up, right? So the sense of fullness is based on the vagus nerve and how it senses gastric accommodation. That's very dynamic, right?  So that will change. And that basically will go down if you have excess energy stored or it goes up with weight loss.  And here is a list of sort of the recent FDA approved medications that we have on the market. We've had Q-Symea for approximately ten years now.  That's a combination of Phentermine and Topiramate. And the mechanism is thought to be through norepinephrine reuptake inhibition  and maybe GABA receptor modulation with the Topiramate. In animal studies, Topiramate has been shown to increase energy expenditure. That's unclear in humans.  So the other one, these are medications obviously you guys are familiar with. Contrave is a combination of Bupropion and Naltrexone. So as you know, Bupropion affects dopamine  and then Naltrexone obviously through opioid receptors in the limbic system. But there is a interesting mechanism also that I think is more important actually.  So Bupropion actually stimulates POMC neurons, right? So these are the neurons that will suppress calorie intake and increase energy expenditure.  The problem is that when you stimulate these neurons, they secrete beta endorphin. And beta endorphin will actually, it's an auto-inhibition mechanism.  It will turn off the POMC neurons. So that's why Bupropion by itself is a very weak anorectic. And that's the rationale for adding Naltrexone  because with Naltrexone, you block that pathway. And then you augment the Bupropion response and that's why that combination was developed.  So then we move on to the GLP-1 agonists. I'm gonna spend most of the time talking about these. Liraglutide, three milligrams, which is succenda,  has been on the market now for about seven years or so, eight years. And then we have semaglutide, 2.4 milligrams, which is Wegovy.  That one was approved for weight loss about 18 months ago. It's been on the market, Androzembic, for diabetes for more than that.  So this is a comparison of the mean weight loss expectations of these drugs.  So we have, I didn't talk about Orlistat much, but you get about 5% weight loss long-term. With succenda, liraglutide, it's about 8%.  Then with Contrave, you get a mean weight loss of about 9%. And Qsimia, approximately 10% long-term. So remember, five to 10% is still a good, clinically meaningful weight loss.  So let's talk about the GLP-1 hormones, glucagon-like peptide one.  So GLP-1 is a naturally occurring hormone, and it's secreted by our GI tract, mostly the intestines. And it's stimulated by food, by nutrients, right?  So that's what stimulates GLP-1 secretion. And as you can see, it's one of the signals that relays messages to the central nervous system.  And this is just a rat brain micrograph here, showing that this is the arcuate nucleus down here, and it's stained for GLP-1 receptors. And you can see there's a very high density  of GLP-1 receptors in the arcuate nucleus. And you can see these receptors similarly in other structures, including many limbic system structures  that I'll talk about in some future slides. But you can also see that there's some GLP-1 receptors in other hypothalamic nuclei.  So the GLP-1 hormones act on the central nervous system.  This is what they do. So GLP-1, I just talked about the reduction in food intake, but it also, in the pancreas, will stimulate insulin secretion and improves insulin sensitivity.  And it reduces gastric emptying. It slows down gastric emptying, right? So it has all these mechanisms.  And it now is also showing to have some cardio protection as well.  So this is one of the questions I get often. We talk about diabetes medications that have a side effect of weight loss. Well, from my perspective, I ask the question,  why aren't they weight loss medications with the side effect of glucose control, right? So I think this gets to the crux of the question, is what are these drugs actually doing?  And I think to understand that, it's important to understand that we live in two metabolic states, right? One is the fed state, and one is the fasting state.  And I'm not gonna go through all the hormonal details there, but as you can imagine, in the fasting state, our glucose levels start dropping. Glucose, obviously, is the vessel  by which energy is transferred to all of our cells. And in the fed state, the opposite happens, right? When we eat, our glucose levels start going up.  So when our glucose levels start dropping, your insulin levels go down.  You also get hungrier, right? Because you wanna bring in more calories. The opposite happens in the fed state. Glucose goes up, insulin goes up. You wanna bring glucose down.  The brain says, hey, stop eating. So you're no longer hungry. The stomach movement slows down so that it's just not comfortable to eat more food.  You've all had this experience after Thanksgiving when you overeat, you just can't have another bite, except for that pumpkin pie, because the limbic system is still active.  So these gut hormones, consider them metabolic breaks, right? So when these gut hormones are secreted by food,  they sort of act as a metabolic switch to shift you from the fasting state to the fed state.  The problem is that they have a half-life of only about two or three minutes. So as long as those cells are being stimulated, the hormones are being secreted,  but they quickly are degraded. But this is what the pharmaceutical companies have done, is that they've changed these synthetic hormones.  They've added a fatty acid moiety that binds them to albumin, and they have half-lives now that can make them daily injections or weekly injections.  So that sense you have after eating lasts all day long. Right, and that's how these medications are very effective.  So let's show some of the data. So this is the STEP program. So these are the pivotal phase three trials for somatotide 2.4 milligrams, OEGOVI. And I'll talk about step one,  which is kind of the pivotal trial in patients with obesity, but without diabetes.  And this is a randomized controlled trial over about a year. Both treatment groups get lifestyle counseling, and you can see in the somatotide group after about a year,  you get about 17% weight loss on treatment. So very, very good results.  That's the mean weight loss, but when I'm seeing a patient in clinic, I wanna know how is that individual going to respond to treatment. And so that's where the categorical analysis  becomes more important. And here you can see that about 35% of patients  on somatotide lost more than 20% of their weight, which is a remarkable outcome.  The most common side effects, as you can imagine from a lot of these mechanisms, are GI related, nausea, vomiting, constipation or diarrhea, fatigue.  Most of these symptoms are very mild or moderate, and they kind of extinguish with continued use, so there's no problem. Only about 7% in the clinical trials  had to sort of stop the medication because of side effects. That's sort of my experience as well, it's about five to seven percent.  So now we have this new drug, we go visomaglutide 2.4 milligrams, and you can see that the effectiveness is much greater.  Now, let's talk about the newest drug, the newest kid on the block called terzepatide. So the paradigm now is that we have all these signals  that are produced by the gut, by fat cells, by the vagus nerve,  and they're talking to the central nervous system, right? And modulating how the central nervous system  really responds to the environment.  And terzepatide is a GLP-1 receptor agonist and a GIP agonist. So GIP is the other incretin, there's two incretins, incretin hormones.  So sometimes this medication is called a twincretin.  And you can see here GLP and GIP-1 both are secreted by the gut in response to nutrients. So we talked about GLP-1, GIP hasn't gotten a lot of attention until now,  but it has some similar effects. It does reduce caloric intake, it will stimulate insulin secretion, and it has interesting results in how fat cells store fat.  That's the reason why these combinations of GLP-1 and GIP are so incredibly potent for diabetes. I mean, this for diabetes is incredible.  It's under the name Monjaro, which you may have heard, and it was recently last week approved by the FDA for weight loss under the brand name ZetBound. It's exactly the same drug,  but the effects on adipocytes is what kind of drives their glycemic control. It's not really clear why when you combine GIP and GLP-1  has such more potent effects in the central nervous system, that's a complicated topic, but it does, and you're gonna be seeing more drugs with combination agonism.  So this was the trial that was published a few months ago in the New England Journal of Medicine. And same thing, there were different doses, randomized controlled trial  with lifestyle intervention in all groups. And now you can see at about a year, you have about 21 to 23% weight loss, mean weight loss, which is very remarkable.  Again, if you look at the dark blue bars there, which is the 10 milligram and 15 milligram, which is the two higher doses,  up to 40% of patients are losing more than 25% of their weight, which is truly remarkable.  And now if you compare all these drugs together, we have terzapatide, which has the best outcomes, and this is in people without diabetes, I should point out.  And this is one of the questions I get all the time. Now we're starting to see this overlap, right, between pharmacotherapy and bariatric surgery.  Our medical treatments are now approaching our bariatric surgery results. We're gonna talk about it at the end, but I don't think this is going to displace bariatric surgery,  but it's something that's important to know.  And I wanna talk a little bit about bariatric surgery because bariatric surgery is very misunderstood. I think there's a lot of misconceptions. It's extremely underutilized.  And I think every specialist should really know about what can be done with bariatric surgery because patients are gonna ask you, right? Some patients have very good rapport  with their psychiatrist, and they wanna know, you know, my doctor said I should have bariatric surgery. What do you think? So I think it's good to know a little bit  about bariatric surgery. So traditionally, we've thought about bariatric procedures as restrictive or malabsorptive. So the gastric band, which is not done much anymore  on the left there, just restricts how much food can go into the stomach. The sleeve gastrectomy, you're just removing about 80% of the stomach.  So anatomically, it's just a restrictive procedure.  And the gastric bypass is, you're creating a small gastric pouch and then rerouting the small bowel. So you're bypassing most of the stomach, duodenum and proximal duodenum.  And there's another procedure called the biliary pancreatic diversion, which is not done very much, maybe 1% of procedures, much more aggressive procedure.  So we used to think about these things as sort of just changing the plumbing, right? We're just changing the gut, and then you have less caloric absorption  or reduced intake because of the gastric volume. We don't think about, we don't think like this anymore. Now we think about metabolic surgery.  So all these procedures, except for the band, are now considered metabolic bariatric surgery. And why is that? Well, because we now know that when you make these  adjustments to the GI tract, you get all these other metabolic downstream effects, right? So you have changes in the gut hormones, changes in the vagus nerve signaling,  changes in the gut microbiota. And at the end of the day, it's really affecting the brain. So even though you're operating on the gut, you're affecting the brain.  And it's doing similar things to what I just described. It's reducing food intake, it's reducing your reward value of food,  and it's reducing that set point I've talked about, right? So with metabolic bariatric surgery, that set point goes down.  And that's the magic of these procedures. It's not just about making a stomach smaller.  This is a list of all, it's not an exhaustive list, but this is a list of medications that are currently in development. So now we have two highly effective drugs on the market.  In five, 10 years, we're gonna have multiple drugs on the market, just like we now have statins and hypertension medications and diabetes medications.  And we're gonna be treating this just like any other chronic metabolic disease. And I'm not talking about this because I, actually, one of the reasons is that this data is so new,  I didn't have time to put it in my presentation, but now we're seeing all these effects of these drugs on non or weight-related complications. We've seen data recently come out  with cardiovascular benefit, benefits for sleep apnea, benefits for renal disease, and we're gonna see more of this data coming out on the incredible benefits of these drugs.  All right, so I wanna shift a little bit and talk more about the cake.  So the limbic system, right? So I think this is where our fields really intersect, as I said before.  And I love this article that was in the New York Times a few months ago. And the title was, Some People on Ozempic Lose the Desire to Drink, Scientists Are Asking Why.  And what this patient that they interviewed said, that's what surprised me. He said, it makes you want to do all the things doctors have told you your whole life.  And this resonated so much with me because this is exactly what my patients tell me in clinic, is that people come to see me, want to do the right things.  They want to eat healthy, they wanna exercise, but they can't because there's a strong biological problem. And with these medications now, you'll hear this a lot,  it's turned off the food noise in my head, right?  I can now walk by the break room at work and that donut just doesn't call to me, right? And this is what, this has done, these medications have done  what all public health efforts have failed to do up to now. Right? I actually do some consulting work for investment companies and used to be that investors were interested  in the drug companies. Now I'm getting calls from McDonald's, fast food companies, candy companies, alcohol companies, because they're scared.  They're scared that everybody's gonna be on these drugs and they're not gonna be going to the drive-throughs anymore, they're not gonna be buying the candy anymore.  So like I said, this has done what public health efforts have failed to do up to now.  I'm gonna go through three cases because when we talk about these drugs and sort of hedonic behaviors, there's not a lot of human data.  So I think this is just interesting to go through. So the first case is a 47-year-old male that came to see me for weight management.  His max BMI was 39.9, he saw me with a BMI of 37. He had pre-diabetes, hypertension, dyslipidemia, fatty liver, chronic back pain, anxiety, typical patient that I see.  He was on amitriptyline, atenol, and gabapentin, all drugs that could promote weight gain.  He was a smoker, one pack a day for 15 years, but he was motivated to quit smoking.  We tried Contrave on him, caused some side effects, so he didn't like it. Four months later, he did lose 15 pounds with some dietary modification.  One year later, he came back to see me and had regained five pounds. So we actually put him on terzepatide plus seeing one of my dieticians.  He came back five months later, he had lost 25 pounds.  Then we had to put him on somaglutide, Wegovy, because of insurance reasons, and he had gained a little bit of weight but still was keeping a lot of his weight off.  And the interesting part was that he told me that when he was on terzepatide, he could not smoke more than one cigarette a day. He just did not have the urge,  didn't have it, just one cigarette was a max. But when I put him on somaglutide, it went up to 10 to 15 cigarettes a day.  He said he couldn't do more than that. So it was interesting that the different medications had different effects on his dose of smoking, let's call it.  So case two was a 51-year-old woman who wanted to have bariatric surgery.  She came in with a BMI of 43,  with hypothyroidism and dyslipidemia. She was a former smoker, no drug use, and drank socially, but occasionally would binge with her friends.  So 10 months later, she needed help because she couldn't lose enough weight to qualify for the surgery. So I put her on loraglutide.  She got lost to follow-up, come back one year later,  lost 10 pounds on loraglutide and still wanted surgery.  Surgery was canceled because the surgeons didn't, she didn't lose enough weight on the pre-op liquid diet  that they have to go through, that's a whole different story, but then I put her on somaglutide, right, so a more potent medication. She came back four months later,  she had lost seven more pounds, and she canceled surgery herself. She didn't want it, she thought she was doing so well with the medication, she didn't want the surgery.  And three months later, she lost another 10 pounds, so 32 pounds total, and 45 pounds from her max.  And she said previously she would drink one glass of wine per night to go to sleep,  and then when she would go out with her friends, four to 10 glasses in one evening.  But now she says she has absolutely no desire. She doesn't get any reward from drinking.  She doesn't have, she doesn't want to drink when she goes out with her friends. The desire's not there. She's in a nursing school, and literally she states  that it's changed my life. She feels more productive, she feels better. I don't know if it's from the lack of drinking, but there is also some evidence that these drugs  have some sort of neuroprotection benefits.  But she was very happy, right? She just, this alcohol drive was completely gone.  And this is not the first time I've seen this in patients.  So the last case is a 36-year-old female with a BMI of 52 with true binge eating disorder. Now binge eating, I think that term gets thrown out a lot.  Everybody's binges, which I don't think is the case. But this woman had true binge eating disorder by criteria, diagnostic criteria.  So I actually put her on list of example amphetamine,  increased the dose, and actually she did respond. She said there was significant reduction in her number, severity, and frequency of binge episodes.  And then I increased it to 40 milligrams, and she had lost about 35 pounds when I saw her on follow-up. But she said that she was starting to plateau, wasn't losing any more weight,  so I tried topiramate on her. She didn't tolerate topiramate. And then I started her on semaglutide. And you can see when I put her on semaglutide  that she really started losing weight significantly. But I think more importantly is the semaglutide almost completely extinguished her binging.  She had no urges to binge at all, or very rarely, right?  And you can see that weight loss that correlated there. And then we tried taking her off Vyvanse, and interestingly, she noticed that without the Vyvanse,  she started having a few more urges to binge.  But certainly the semaglutide she thought was much more potent. But we added on the lower dose of Vyvanse and she's done very well. She's lost another 80 pounds or so there,  a total of about 115 pounds of weight loss. So her BMI went from 52 to 33, which represents a 37% total weight loss. So when she first saw me,  I thought she needed a bariatric surgery. That was my recommendation to her. And 37% is more than actually I think she would have gotten with bariatric surgery.  So this is an incredible case.  There's not a lot of human data, but this shows sort of a review of the data that's available in animal studies and all the different areas of the brain  that have been studied with GLP-1 agonists and kind of their effects on substance use,  at least in animal experimental models.  And this shows one study here.  Here you can see that in the green is shows GLP-1 receptors in different parts of the limbic system. That key, the red there is a little bit, it's actually a mistake.  So if you look on the left side, the blue are dopamine cells and the red are in, I think, I believe astrocytes there, but in different structures. So if we look at a study here  looking at the ventral tegmental area, you can see that animals that were pretreated with Xcendin-4, Xcendin-4 is kind of an older GLP-1 agonist. This is a cocaine relapse model.  Their number of levers that they pushed for cocaine went way down there. You can see the two bars on the right is when they were treated with Xcendin-9.  Xcendin-9 is a GLP-1 antagonist. So if you block the GLP-1 response, they go back to their relapse. And a similar study was done in the nucleus accumbens  that on the left side there, treatment with different doses would have a dose response in terms of the number of times the animals pushed the lever for cocaine.  So some closing thoughts here because I thought I'd leave some time for questions. There's usually quite a few questions when I give these talks.  But obesity is a complex, progressive relapsing chronic metabolic disease, right? So it's more complicated than just a lifestyle problem.  When lifestyle efforts fail, you know, so if someone tries lifestyle and they do great, awesome, right? We don't need to do anything further.  But when they fail, which usually they do, biological interventions may be necessary.  And we now have safe, effective tools to help people living with complications of obesity. And we're starting to see more data on those benefits.  I showed you much more are on the way.  And these novel hormonal agents have benefits beyond weight reduction. And then this speaks to the cost, right? Because that's one of the main questions that always comes up.  These drugs are very, very expensive and they're not covered across the board, right? So that is something that we're still struggling with.  But I would say that if society fails to regulate the root causes of chronic metabolic diseases, which we have failed to do, then it has a moral obligation  to bear the cost of treating them.  We're already seeing now with terzapatide coming on the market, that Eli Lilly has brought the cost down compared to Novo Nordisk semaglutide.  And I think we're already gonna start seeing that competition bear fruit in terms of the cost reduction  and hopefully it'll improve access to many of our patients. So I'll stop there and thank you very much and I'll take any questions. Thank you.  You can start here. Sure. Fantastic. You're going to come back to tell us how to prescribe these, I'm sure, because I would anticipate that these are going to be the drugs we're  going to be using quite a bit in psychiatry, particularly addiction psychiatry. In the last slide, you said that it's a chronic disease.  Does that mean people need to be on the drugs for a lifetime? Yeah, that's the most common question I get. And since obesity is a chronic metabolic disease,  the answer is probably yes. Now, there are many patients I have that want to try stopping them, and that's not a problem as long as we follow them.  And if we need to, we can always restart them. I have to say that the majority of my patients don't want me to stop them. They feel so much better. They know.  They know that if I stop it, that food noise is going to come back. Also, we have to always ask, why are we treating the obesity? What are the benefits and the risks?  I, fortunately, do not do cosmetic weight loss. I treat very sick patients that would benefit from these drugs. For patients, the TikTok world and people  who are using these drugs for just losing 10 pounds, that's a different story. But if the benefits outweigh the risks, just like any chronic disease, just like diabetes,  or hypertension, or anything else, that's how we're going to probably use them.  Hi there. I'm Carla Marion Feld, your colleague from UC San Diego here. I want to thank you for your great talk. And we really, really appreciate not only  that you came to talk to us about this important topic that I think has implications for both of our fields, but I also heard you say that you attended  other parts of the conference and how much you're appreciating some of the similarities not only in the underlying neurobiology,  but the behavioral components of what we do and what you do. And so I just wanted to make that comment. In addition, I have a question. I think, in general, the consensus  is that what people are doing is getting way ahead of the science in terms of using GLP-1 and GIP medications for alcohol use disorders and tobacco.  And yet, we have so much anecdotal evidence. I certainly have it within my patients. One of my fellows is doing a research project looking at a case series right now around this.  And I have patients who are both coming to me having started these in primary care, and I have patients who are asking for prescriptions for these.  When and if they actually do get approved, I'm wondering if you could give us a little bit more on things we would need to know as we start considering  prescribing these things or even advising patients who are getting them through other means about any risks, about any sort of clinical pearls, about managing them.  Are there any harms that we need to be aware of before we're just, this is kind of a big free-for-all outside of cost? Yeah, I think the main thing is the GI side effects, right?  So how to counsel patients on what to expect in terms of nausea, how to manage that. Constipation is the most common other thing.  And using clinical judgment in terms of how you dose them. So the way that the label says to dose them is there's a dose escalation that happens every month.  So most people just write that, but you have to be prepared to really slow down the titration to limit some of those side effects, back off on the dose.  You can use Sofran temporarily or some other anti-emetic.  The mantra is go low and slow, so just to let your body get used to or accommodate to the side effects. The black label, the black box warnings are very rare.  So the most common thing is pancreatitis. The incidence of pancreatitis with these drugs is actually low, but maybe somewhat elevated.  Especially if people have co-occurring alcohol use disorder. Yeah, so exactly. Keep in mind that people who have significant alcohol intake or have had history of pancreatitis  were excluded from the trials, so we really don't know that risk. But that's something that I keep in mind is the alcohol use for sure.  Beyond that, and then there's very rare things like medullary thyroid cancer risk and MEN, which are super rare. So yes, I screen for all that, but it's very low risk.  And then people who have comorbidities that are on many other medications that are going to be affected by weight loss. So if someone's on insulin, sulfonylureas, blood pressure  medications, you have to monitor them carefully because some of these patients will lose weight rather quickly in the beginning and could have problems with their other medications.  What else? Those are the main things, really. I mean, they're fairly safe medications. That's super helpful. The beauty of using them in the primary care world. Thank you.  Hi, I'm Rufus. I'm a psychiatry intern at the University of Utah. I really appreciated your talk. And I guess I have two categories of questions.  One of them is more in the risk side of things, and one of them is in the excitement and the future directions. The risk side is if we begin to use this on patients  with alcohol use disorder, depending on where they have gone in their journey, they can often come in very malnourished. And so you want to encourage PO intake.  And I'm wondering if there's been studies done in terms of if this harms patients, their ability to take food or their ability to want to consume food.  And the other side is more on the future directions. I know DPP-4 inhibitors are also quite exciting in that they inhibit GLP-1 agonists and GIP.  And so have there been studies on the compounding effectiveness of those two medications? Thank you. So the first question, yeah, I mean, unfortunately, I don't treat people  with severe alcohol use disorder or any substance use disorder because they're usually not coming in for weight management. Usually, I mean, there's a few exceptions.  But yeah, you have to, again, use clinical judgment. I wouldn't start these drugs on someone who already is close to being underweight or low BMI.  So that's one thing. And then we do have to pay attention to protein intake. Whenever you lose weight, there is a reduction of lean body mass.  So there's about 25%, 30% reduction in lean body mass, which also happens with these drugs. So we want to pay attention to how much protein  or high-quality protein the patient is consuming, physical activity, all that. And then, of course, if they have significant vomiting, that could cause problems as well.  So yeah, all I can say at this point is using clinical judgment. But of course, if you have a patient with something they think could benefit from some kind of substance use problem  and they have weight issues, then this would be a good consideration. I think the other question was regarding DPP-4 inhibitors. So if I understood the question correctly,  they're not very effective for weight. They're weight neutral. And generally, we don't use DPP-4 inhibitors with GLP-1 agonists together. So I'm not sure if that was a question,  but hopefully that answered it. Hi. Great talk. David Crockford from Calgary. One of the things, like doing addictions for the past 25 years, is that people switch all the time.  Then they also have tons of trauma history. And you're probably all aware of the data of bariatric surgery and people with high ACEs scores.  They initially lose weight, and then there's a huge rebound with them. Is there any of this data that's looked at people with trauma histories, ACEs, high ACEs scores,  and so on, because that ends up dictating so much of the outcome with them? You're referring to early childhood trauma? Correct. Yeah. Yeah, there's some data on generally obesity  and childhood trauma. But in my experience, and what the literature shows, that generally, psychotherapy or any type of CBT is very ineffective for weight management.  So given the effectiveness of these drugs, I don't know. And I'm not familiar with any specific data regarding this. But these patients do just as well.  I don't know if that answers your question. I mean, I guess we'll wait and see, just because we're so used to watching people rebound. And relapse is so much part of addiction.  And so when we watch people, it'll be curious to see how this all kind of. Now, you're referring to bariatric surgery? Yeah, so there's data on bariatric surgery  with the people with the high ACEs scores of how they lose initially, and then all of a sudden, they gain a whole ton of weight back around it over time. There's also the data.  And I'm just wondering if we're going to see with the pharmacology as well. Yeah, so weight recurrence after bariatric surgery is a complicated topic, right?  So many times, it's not related to behavioral issues. I mean, obviously, we always address that. But we are now recognizing that there  are specific gene mutations that may be placing people at risk. There's more likely a physiologic and genetic risk rather than just a behavioral or lifestyle problem. Thanks.  Hey there. Dave Atkinson. I do adolescent addictions. But I used to do adolescent eating disorders. And from about the mid-2010s on, we  saw a newer prevalent thing in eating disorders, which was kids, a lot of them ethnically from the northern states of Mexico, but they would lose about 60 pounds  because their doctor recommended it. Go from like 194 to like 132, and everybody's happy. But during this process of doctor-recommended weight  loss, they just picked up anorexia with this drive. And so it was interesting, because now you started to see these kids with a history of obesity. They were picking up anorexia.  And I was wondering, with Govy and other things, have you seen any inductions of anorexia nervosa that followed this rapid weight loss? So with your experience, I'm not sure  if you're referring to the, you say, if I heard correctly, people going to Mexico? There was a trend in these patients. They were different than a lot of our traditional anorexic  patients, which was kind of like worried wealthy. A lot of them had an ethnic background from the northern states of Mexico.  So that was, I mean, but this is kind of like as a generalization. So those patients did, they presented with this different thing, where it was like they started out  with genuine obesity and doctor's-recommended weight loss, but then that kind of like turned into an anorexia. So I will say, interesting, I'm near Mexico, obviously.  We had that same experience, but many times, patients go to Mexico. In Mexico, you can get a medication called Ritotox, and it's very similar to the rainbow pills.  So it contains an amphetamine, barbiturate, some benzodiazepines. You can still get this. And many times, patients don't tell you they're taking that.  And that happens after a third visit, it comes out that they've been taking that. So I don't know, that may be part of it. So for the patients that I treat,  I have not seen one single patient where that's happened to. I personally think that pathophysiology, like anorexia nervosa, is such a completely different  pathophysiology than obesity that I don't think there's much of a risk, at least in adult patients. I don't treat pediatric patients. If I were a pediatrician, I probably  would be paying a lot more attention to those issues than I do. Because as you probably know, the American Academy of Pediatrics came out with recent guidelines saying  that we should be using these medications and bariatric surgery more in adolescents than we are. But just like this hasn't come up either,  but there's a lot of reports now in the media of suicidal ideations in some people on these drugs. Again, we don't have any conclusive evidence.  But if I have a patient that I'm concerned about, I do follow them a little more closely, more cautiously.  Hi. Thank you for being here. Thank you for an interesting talk. My question, I think you touched on a little bit, but I'm hoping you can expand.  I've noticed a social trend, particularly in younger generations, of wanting to reconceptualize obesity as a risk for disease rather than a disease in and of itself.  And I think this is primarily due to the intense shame and self-loathing that can come from a culture of body shaming and fat phobia.  And so I'm, because that can cause that shame and fat phobia and all of that can cause such profound psychological effects, which can then cause profound physical effects.  And that's the end that we see as psychiatrists. So I'm curious your response to that perspective. I think it's both. I mean, it is definitely a risk factor for other diseases,  but it's also a chronic disease, just based on what I showed you with all the physiologic things that happen when you try to lose weight  and how the body tries to maintain a set point. You know, how society looks at weight and how our society prioritizes being lean is a problem, right?  And unfortunately, I think of a lot of what happens on social media is sort of a liability for our field, you know, because we  don't want to treat this as a cosmetic problem, really. These drugs are really designed for health benefits, not for cosmetic weight loss.  But there's no way getting around, in our society, we just can't get around that. You know, looking at obesity, even with these drugs, looking at obesity as a will, a problem  with your moral character, a flaw in willpower, what have you, that's just a problem we have to deal with. I'm Tom Weingarten from Sakai, Minnesota.  I'm an addiction psychiatrist, but also a general psychiatrist. Worked out of the hospital, my own clinic, and I've had thousands of patients gain 40,  50 pounds on atypical anesthetics. And I've never seen any of those other things you say work, except for this and bariatric surgery.  And lots of people are afraid of the bariatric surgery, but it's a lifesaver. I got to work on the bariatric surgery service 35 years ago at the University of Minnesota.  And it was actually originally set up to show that lowering cholesterol saved people's lives. And this obviously does so many good things.  But the biggest problem, one, is getting it, because there's no supplies. Two is, insurances are starting to deny it. And three, everybody throws up a lot, and they're sick.  What do you do about that? I mean, I've put it on Zofran, et cetera, but do you have any great ideas of how to prevent that? Second of all, if you don't do the titration,  you're in trouble. Someone skips doses, that's when they really have problems with the vomiting. Now, I'm on Ozempic. I have been for years for my diabetes. It's helped quite a bit.  But again, every time I go on a bigger dose, I felt sicker. What do you do about that? So regarding the side effects,  that many people should not be vomiting.  There's a problem if that many people are vomiting. Nausea, yes, but vomiting should not be that common.  So you've got, again, you've got to, sometimes I'll put someone on the lowest dose, and I'll just keep them there for three months, right?  And I won't go up until, if I have to use an anti-medic for a short period of time, that's okay, but I don't keep people on anti-medics forever just to stay on the medication.  The most, the number one thing that causes, I think, a lot of vomiting is eating foods that are high in fat or greasy foods. That causes a lot of nausea and vomiting.  Most people kind of learn that and then kind of avoid those foods, but I do counsel patients on that as well.  So, and I'm sorry, can you repeat the first part of your question? You answered it. I mean, avoid fats. And you know, you do use anti-medics, except you don't lose them for a while.  So it doesn't last. I mean, the- It should not last, right. That's something I found too. Yeah, about five, like I said, about somewhere between five, 7% of patients  may have to stop the medication because of GI side effects.  So- Do you know if anybody's doing studies for cocaine on using this? That was a great slide, but do you know anybody who's doing that? For pain, you said?  Using these meds to stop, to help with cocaine. Oh, cocaine, yeah. Are you doing studies on that? Yeah, I think there is one study that's being done right now,  but the data isn't available yet. The studies that have been done for, there's been a smoking study and I believe an alcohol study,  very small studies, very short term, and they were using exenatide, which is one of the very, very beginning, earlier GLP-1 agonists that are very weak. So with these newer drugs,  there's no literature yet on, for any, as far as I'm aware, for any substance use.  So ribelsis is an oral semaglutide for diabetes, not for weight loss. At that dose, so it's not absorbed very much. So the bioavailability is very low.  At the doses available for diabetes, it doesn't do much for weight loss. A little bit, it does. It's being studied right now at much higher doses.  It will be probably approved by the FDA at higher doses. Has similar results as the sub-Q dose, but the dose has to be much higher.  I'm going to just interrupt for a second. What an outstanding talk. Thank you, thank you. Thank you.
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