Pharmacology: Pediatric Obesity 2017

Uh, and now, I think, uh, Chris is uh gonna introduce our next speaker. OK, bye everybody. Hello, everybody. It's my honor to actually introduce our next speaker. Um, uh, Mark, Stephanie, I had on my schedule that I was supposed to go next. Are we doing Claudia next? We're doing Claudia next. Yes, got you. I'm sorry. I got you. But, um, you know, it's, it's, it's great to be, um, introducing, um, Uh, Claudia, Claudia actually like Christine and I, um, are general pedia general pediatricians. Um, we had a long discussion, uh, I was having some discussion with some colleagues saying how general pediatrics really is such a logical outgrowth, um, logical place for us in pediatric obesity to get started, cause we have to handle a variety of things, have to be a little versed in everything. We really, pediatric obesity management really is about, um, Uh, being a jack of all trades. So, with that, I'd like to introduce Claudia Fox. Claudia is actually a general a general pediatrician from, uh, University of Minnesota. She did her, um, training at medical school training at the University of Minnesota in pediatric residency and fellowship also at the University of Minnesota. Um, she is a leader, um, and medical director in pediatric obesity. Um, her area of interest and one that is really critical at this point are higher-level interventions for pediatric obesity. Um, as is the case in a lot of areas in pediatrics, um, we do not have enough data on how kids respond. To higher-level interventions. And for that reason, we asked Claudia to speak to us about medications and pediatric obesity. Uh, interestingly, uh, Claudia actually ran an entire conference on this. I think it was last summer. Um, it was very well received. So with no further ado, I'd like to introduce Claudia Fox from Minneapolis, who's gonna be talking about this topic. Great. Thank you very much, Chris, and thank you to uh the organizers for inviting me to present today. These are my disclosures. I do receive research support from Novo Nordisk and I will be discussing off-label use of medications for the treatment of obesity in children and adolescents. This is an outline of what I'll be um discussing today. First, we'll, um, review why we should even be considering pharmacotherapy for children and adolescents with obesity. We'll cover a little bit about what we know, uh, about pharmacotherapy in this age group. I'll touch on eligibility criteria, that is patient selection, and then close with a little bit about the future of obesity medicine. So first, why should we even be considering pharmacotherapy for children with obesity? Many would argue that medications are unsafe, perhaps addictive. I've heard from some families say that they don't want their children to rely on these medications for weight management. I've heard some practitioners say that using medications is a cop out, that all these kids need to do is eat less and exercise more, and still others say that pharmacotherapy is really not necessary for obesity, that perhaps obesity is just a little bit extra adipocity, and what's wrong with that, particularly if a child's metabolic panel is normal. Let me tell you about one of my patients. He's 15 and he's 400 pounds. He has impaired fasting glucose, high triglycerides, sleep apnea, and high blood pressure. So he is far from the agile, nimble, happy go lucky teenager that he ought to be. Um, yeah, sure, he's not on insulin yet and he isn't requiring a lipid lowering agent. And he only needs one antihypertensive right now to control his blood pressure, but for sure, in time, he's gonna experience metabolic decompensation and uh very likely premature death. We know too that obesity doesn't affect just our physiological system, it greatly affects our psychology. These are excerpts from kids who carry extra weight. One says, I don't fit in the desk at school, so I have to sit alone at a table. How mortifying for her. Another kid says, I have no friends because people don't want to know anyone who is fat. I'm disgusting. So clearly the psychological toll is extensive. Now if that's not the worst of the story, we know that kids who carry extra weight are going to grow up to be adults who carry extra weight, particularly those with severe obesity. From the Bogaluzsa Heart Study, which is a large longitudinal study, we found that Uh, of 12-year-olds with a BMI at the 99th percentile, all of them will grow up to have BMIs greater than 35, excuse me, greater than 30. 88% will have BMIs greater than 35, and 2/3 will have class, class 3 obesity. So this um extra weight is not going anywhere. So why consider medications for severe pediatric obesity? This is a progressive, chronic, and debilitating disease. Now you might say, well, that's what lifestyle modification is for. Um, we should have these children meet with a dietitian, meet with a physical therapist, meet with a psychologist. Well, let me tell you about another one of my patients. She's 15. Um, she's been heavy most of her life and her BMI was 35 when she was 8 years old. She's engaged in multiple attempts at lifestyle modification. Um, and some of these even met the recommended 25 hours of intervention. Here's her growth chart. So this one is our typical CDC growth chart showing age and BMI and you can see it's not particularly helpful. This one, on the right shows BMI, um, as a percentage above the 95th percentile. So here's the 95th percentile. We have 1.1%, 1.2, 1.3%, etc. uh, above the 95th percentile. These charts were developed by the team in Denver. To help us better depict what's happening at these higher, higher BMIs. And as is now customary, we define severe obesity as BMI greater than 1.2 times the 95th percentile. So this kid, as you can see, these are all of her different attempts at lifestyle modification therapy. Every time, she's actually did pretty well. She was able to at least hold her BMI stable, perhaps trend it down just a little bit, but two points. One, the change in BMI is uh minimal, very limited, and two, the change is not sustainable. Once the intervention is removed, her BMI then increases. It wasn't until we started pharmacotherapy did she have notable, uh, notable, um, outcomes. Now, this, uh, limitation of lifestyle modification, particularly in older kids, is not unique to that patient. There are a lot of studies that are are demonstrating this. This is one, from uh quite a few years ago now. It was a Longitudinal observational study that looked at the effect of lifestyle modification therapy in kids who had smaller BMIs, BMIs less than 3.5, and those with heavier, heavier BMIs, and they looked at it according to age groups, 6 to 9, 10 to 13, and 14 to 16. And you can see the younger kids in both groups actually fared pretty well. They had some change. But look at the adolescents. These older kids with a severe BMI hardly had any effect from lifestyle modification therapy. In fact, only 2% of these teenagers with severe obesity demonstrated clinically significant uh BMI reduction. This is another study that looked at the response to lifestyle modification therapy according to different sizes. So we have kids who are overweight, obese, and severely obese, and they are followed up at 3 months, 6, and 12 months, and you can see. There's incrementally decreased effect as kids got bigger, and by 12 months, uh, by 12 months, it's not even statistically significant um for the kids with severe, um, severe obesity. This study took it up a notch. They compared inpatient lifestyle modification therapy to an outpatient program, and these kids were inpatient for 6 months. And then, and then they were all followed for 2 years after that. And what's notable is that, yeah, during that inpatient treatment, kids lost, um, had a really good response, much better than the outpatient, but unfortunately, at the end, at 2 years, there wasn't a statistically significant change. So another reason to consider pharmacotherapy for kids with severe obesity is that for some of them, lifestyle modification therapy is often just insufficient. It's not durable, and the kids don't achieve clinically significant weight reduction. So what's going on here? What's the problem? We certainly can't blame the patient. What we know is that obesity has significant biological underpinnings, and lifestyle modification doesn't usually affect those underpinnings so well. So briefly, I'm going to describe some of the homeostatic and then non-homeostatic mechanisms of obesity development. First, the homeostatic mechanisms, these are responsible for helping us feel hunger and then also feel satiety. The hypothalamus in our brain integrates signals from multiple areas of our body. We have signals coming from our adipocytes, from our intestines, from our stomach, from our pancreas. Um, more specifically, leptin from our adipocytes acts on our brain to decrease hunger, GLP-1, or glucagon-like peptide one hormone acts on receptors also in our hypothalamus to decrease hunger. Um, in contrast, we have ghrelin increasing our sense of hunger, and then insulin interferes with those anorectic effects of leptin right at the level of the hypothalamus. And all of these hormones have been identified as potential targets for pharmacotherapy to help manage obesity. Now this slide depicts what's happening down, uh, downstream at the level of the hypothalamus. Uh, this section is the arcuate nucleus. I want to draw your attention to these POMC cells, just a limited depiction of what's happening here. So when leptin stimulates these PAM C cells, They promote decreased food intake by secreting alpha MSH, melanocyte stimulating hormone, which in turn stimulates this melanocortin 4 receptor, MC4R receptor, which in turn decreases food intake. Notable for pediatrics, mutations in this receptor account for the most common single gene mutation that causes early onset severe obesity. Now, I include this slide because it shows us um a, a potential mechanism by which medications can impact the functioning of these um satiety um pathways. Bupropion, now tetrexone, in combination has been FDA approved for the treatment of obesity in adults. And I want uh illustrate how it works because it, it's very interesting. Bupropion, the antidepressant, acts on those POM T cells in our RQ nucleus. It stimulates them to secrete alpha MSH like I mentioned before, which in turn stimulates. Excuse me, secretes out the MSH to stimulate the MC4 receptor, and then you get decreased hunger. But when the POMMSi cells are stimulated, they also secrete beta endorphin, and that beta endorphin acts through a feedback loop to inhibit POMC activity. So you get relatively less alpha MSH with stimulation by bupropion. Scientists got smart and said, what if we block that auto inhibition? The beta endorphin with naltrexone, an opioid receptor blocker, and this way you can get relatively more action going up through um alpha MSH. So that's 11, it's the proposed mechanism by which this medication can work. Now in addition to the homeostatic mechanisms that contribute to obesity, there are many non-homeostatic mechanisms, and these are much less well defined. We have sensory processing. We have the emotional valence of food. We have reward. We have executive control. So these uh these processes include things like eating for emotional comfort or eating um highly palatable food because you have poor um executive control. Um, Those are briefly just a gross overview of the homeostatic and non-homeostatic mechanisms of obesity. Now, these mechanisms also account for weight regain, not just weight gain, but weight regain once you've lost weight. I want, this is illustrated very well in one of my other patients. This is a sixteen-year-old girl. She's been heavy most of her life. Her typical diet is not very good. She often skips meals. She eats a lot of processed food. She says she's always hungry, so she has very um very um poor sense of satiety. Yet she denies emotional eating. She, um, has no binge eating. Past medical history is notable for fatty liver disease. So we started her on a program of lifestyle modification therapy, and she struggled for a while, so then we added some pharmacotherapy, and in 10 months, she was able to lose 36 pounds. So that's pretty good, actually more than 10% of her body weight. But then she hit a wall. She states that she couldn't lose any more weight, and in fact, her weight was starting to creep up a little bit, and she swore up and down that she didn't, she hasn't changed her eating, and review of her dietary intake was really notable for, in fact, she didn't seem like she was eating all that much. So, what's going on here? Um, we thought, well, is she intentionally misreporting how much she's eating? Maybe she wants to save face. She's been doing so well and she doesn't want to disappoint us. It's possible Or maybe she's just she's just not aware of how much she's eating. She's unintentionally misreporting her intake. Or maybe she's accurate. Maybe it is true that she's hardly eating anything and gaining a little bit of weight. So to figure out a little bit more about what was going on, we performed indirect calorimetry on her to see what her resting metabolic rate was, and for her, her predicted um resting metabolic rate was 1800 calories, but when we measured it, it was only 1000 calories. So it was true. She was, is accurately reporting that she's hardly eating anything and yet not losing any weight. And the reason for this is that her metabolism has dropped. This phenomenon is called metabolic adaptation, and as you lose weight, your body kicks in compensatory mechanisms that promote weight regain. This was illustrated very nicely in the 1990s by Rudy Leibel. He brought adults into a lab and had them either gain weight or lose weight, and you can see with weight gain, you have an increase in your energy expenditure, but if you lose weight, you have a decrease in your energy expenditure. There seems to be sort of a, a plateau. If you lose 10%, you have a decrease in your Resting metabolic rate, and that losing more weight does not seem to push that down any further. Since the 1990s, we have um a much better idea of some of the biology that is promoting these changes in um resting metabolic rate. So what we now know is that when people lose weight, they experience an increase in hunger, a decrease in satiety, and an increase in the preference for highly palatable foods. At the same time, they also experience an increase in metabolic efficiency. Together, these promote weight regain. So to Help sustain that weight loss, likely we're going to need a combination of pharmacological interventions and other interventions to help offset this biology. So another reason to consider medications is that obesity does have significant biological underpinnings that need to be addressed for ongoing sustained um weight loss and stabilization. Now, bariatric surgery addresses this biology quite well, in fact, and indeed, it is right now the most effective and durable treatment we have for severe obesity in adolescents. Unfortunately, it's not very accessible, um, nor is it very much desired by many patients and their families. And, uh, doctors in Jamkowski are gonna talk more about bariatric surgery. Later on. So, Regarding what medications we know about, um, the, the field right now is pretty small, but we're, we're learning more and more. So currently, There are only two medications that are FDA approved for use in children and adolescents. One is orlistat, and the other is phentermine. So orallistat is a lipase inhibitor. It blocks the absorption of about 30% of fat. It is FDA approved for kids 12 and older. Side effects are related to the GI tract and are pretty intolerable, particularly for adolescents. This slide illustrates the results of the, um, probably the largest um RCT examining orlistat in adolescents. They, uh, it, it included about 500 patients. And you can see at the end of the year, the placebo subtracted difference in in BMI was about 0.8 units favoring the Orlistat group. So some outcome, but not the greatest, and they're, like I said, the notable side effects really limit its its use. Phentermine is a stimulant. It's an amphetamine and it promotes um appetite suppression by releasing norepinephrine. Now, in the 1950s when it was first FDA approved, the age range at that point was given as greater than 16. However, there have not been any um RCTs in adolescents that have been more than 1 month's duration. Among adults, the mean weight loss is about 3.5 kg, and the side effects include potential for abuse, increased blood pressure and heart rate, and GI symptoms. Uh, I will note though that among studies in adults, there have not been signs of a withdrawal, no withdrawal symptoms upon abruptly stopping the phentermine, nor has there been reports of increased blood pressure in adults, probably because they're losing weight. Uh, in, in our experience, we do see kids get some diarrhea in the beginning of treatment. Now this is a medication that we do use sometimes in our clinic in select patients. It would be considered off-label in kids who are 16 and younger. Our group did a chart review that looked at our outcomes. We found 25 of our patients were on phentermine only for 6 months, in addition to our usual standard of care therapy lifestyle modification program, and compared those to 274 kids who were only receiving the standard of care treatment. So the difference at the end of 6 months was pretty notable, about a 4% uh decrease in BMI favoring the phentermine plus um lifestyle modification group. Now there's been a, a lot of medications that are not FDA approved for pediatric obesity that have been studied. Uh, among the most commonly studied are metformin, enetide, and topiramate. This review, um, is quite extensive and, and details a lot of the outcomes for the other, uh, medications. But regarding metformin, we don't know exactly how it works, but we do know that um after many, many studies, we can expect about a one unit decrease in BMI. Uh, exenatide is getting, uh, or other and other GLP-1 agonists are getting a, a lot more attention, uh, lately. So this is a, a hormone that's secreted by our intestines. Uh, there are receptors in multiple parts of our body, including our heart, our islet cells, and in our hypothalamus. This is a medication that's uh used primarily to treat type 2 diabetes in adults and has been, um, Its sister medication, loraglatide, another GLP-1 agonist, has recently been FDA FDA approved for obesity in adults. The proposed mechanism of weight loss is that it may slow down gut motility such that people have a, a longer sense of fullness, but it seems like that the primary mechanism by which it promotes weight reduction is by acting on receptors in our hypothalamus. Um, our group, um, research group led by Aaron Kelly, uh, has conducted two small pilot studies examining xenotype for severe obesity in adolescence, and we're in the process of conducting a much larger Uh, RCT. Uh, this slide illustrates the results of one of the small pilot studies. It was about 25 patients, and you can see, um, in the 1st 3 months, this was the double-blinded portion. There was a, a placebo-subtracted effect of about 3% in uh BMI favoring the xenotide group. So sort of a, a modest decrease. Topiramate is a medication that is used quite extensively in the adult weight management world and has multiple uses even beyond obesity. Um, there are quite a few large randomized controlled studies in adults that demonstrate its efficacy for weight reduction. There's also some, um, RCTs that demonstrate that it can decrease episodes of binge eating in those with binge eating disorder. This is another medication that we use in our clinic. Again, it would be um considered an off-label um use, non-FDA approved for the use of, uh, for the use in pediatric obesity. And this slide demonstrates our, our, our chart review. We looked at in the blue line, these were kids who were taking topiramate only and no other medications. They were, uh, I'll back up and say all of these kids received lifestyle modification therapy. The kids in the blue received only topiramate. The ones in the black line were those who received topiramate, but they also had other medications on board. They may have been taking stimulants, which decrease weight, or they may have been taking atypical antipsychotics, um, which increased weight. So they were sort of a, a dirtier group, if you will. For the clean group, you see that we found about a 6% decrease in BMI at 6, at 6 months. Our group also did a randomized control trial looking at the effect of um topiramate. In adolescents with severe obesity. This clinical trial had a slightly different um um model. We started off with a meal replacement phase, an induction phase, if you will, and then these kids after their induction phase were randomized either to topiramate, 75 mg a day, or placebo. And though the kids lost weight during the induction phase, the meal replacement phase, by the end of this study, there wasn't a statistically significant effect between, um, between the two groups. Even though there wasn't a notable effect, we did learn quite a bit from this study. We learned one, that topiramate at 75 mg a day was actually quite safe. We did an extensive battery of neurocognitive testing to look for any cognitive deficits and did not find any signal whatsoever. We also learned that, boy, some kids are real responders, um, and some kids not at all. And if we can identify what makes a kid respond to a particular medication, then we might be getting somewhere with um better overall effects. Um, and then last, we also learned that likely, as we're seeing in the adults for um truly effective weight management, mm, even adolescents and kids perhaps are going to require, um, polypharmacotherapy. That is, they're gonna likely need more than one medication to achieve a clinically significant effect. So now, what about who? Which kids, which patients um are appropriate for medications? This is a very fuzzy area. There are no clear guidelines. Um, these are recommendations that were put forth in 2007 by the Expert Committee guidelines on obesity Treatment, um, published in pediatrics. So this guideline suggested that first, that there should be significant weight-related health risks. I'm I'm not so sure about this. Um, some would argue, why should we wait until a kid has hypertension and LVH or has frank diabetes before we start medications. Um, to address their obesity. So this one I, I, I'm not so sure about. The next one, failed structure lifestyle modification therapy. This one too, I, I'm not sure that it is appropriate for all patients. We know from the adult literature at least that Early success in the weight management process predicts long-term weight loss success. If I have a 300 pound patient sitting in front of me, um, and I don't provide pharmacotherapy and send them home with only lifestyle modification therapy, He's likely not gonna come back, um, because he's gonna be very frustrated that he's not going to see too much uh results with lifestyle modification therapy alone. So I think in, in select patients, we certainly need to, um, be, this isn't so straightforward right now. So that's, I'll just leave it at that. Um, it's another recommendation is that patients and families need to understand the limitations of the medications, absolutely. Um, these medications do not work in a vacuum. They help you adhere to your eating plan. If you don't have an eating plan, they do nothing. Um, patients should be referred to a tertiary care center. Tertiary care centers are flooded with these patients. I think what we will likely be seeing hopefully in the sooner rather than later future is the development of a cadre of pediatricians who are comfortable in the specialized treatment of obesity, particularly severe obesity, and perhaps we can have more of these practitioners. Around the country to increase access to the specialized care. And then finally, uh, medications should be used only as part of a multimodal weight, um, management program, and, um, absolutely, they cannot be used in isolation. They don't work in isolation. I, I included this slide to remind me to tell you that obesity is a chronic disease, and some people wonder, well, how long will this patient need to be on medication, and the, the answer is indefinitely. Um, once you stop the medication, the weight is gonna come back. You don't develop dependence on it, you don't rely on it, um, Any more than you would develop a reliance on an antihypertensive agent to treat your um high, high blood pressure. So just like in uh the case of high blood pressure, you stop the antihypertensive, your blood pressure is gonna go up. That's the exact same case for obesity. You stop the weight management medication and then your weight comes back up. So, now, uh, a little bit about the future. Where are we going? Um, this is actually quite bright. Um, There have been quite a few medications that have been recently FDA approved for adults only. These include combinations of topiramate and phentermine, uh, loraglatide, the GLP-1 agonist that, um, I talked about earlier, naltrexone bupropion combination that I also discussed, and lorcatrin, which acts on the serotonin system. These medications are FDA approved for people who are 18 and older when the BMI is greater than 30 or greater than 27 in the presence of weight-related comorbidities. So, and I, I imagine that many of you out there have pediatric patients with that degree of obesity and comorbidity. So, um, many of these or some of these are in the process of, of, uh, being examined in the adolescent population as the pharmaceutical companies, um, patents are running out. So, um, the future options, uh, are, is looking brighter. But I also know that medications are not going to be the only story, only story. Um, medications are going to be one part of the treatment armamentarium. We will likely see that medications used in combination with other interventions are going to give us the best outcomes, whether it's Psychological interventions like mindfulness or um devices like a balloon, so using medications after device therapy or before device therapy, and also medications in combination with bariatric surgery. Again, either before or after bariatric surgery. I have, I have at least one patient who has had bariatric surgery and has been slowly uh regaining weight that I started on uh pharmacotherapy. Also, I think the future is gonna hold um A better assessment of predictors of response. I think in time, we'll be able to identify particular genotypes or even um phenotypes that may predict a favorable or worse response to a given pharmacotherapy. So here are my take home points. The first is that lifestyle modification is for sure the cornerstone of treatment for obesity, but it has significant limitations. And that lifestyle modification, monotherapy ignores the biological mechanisms that are at play in the development of obesity and the sys the, the maintenance of obesity. In the current state of evidence regarding the safety and efficacy of meds for obesity and pediatric population, no doubt it's, it's weak right now, um, but we're making a lot of headway and the future is promising. So with that, I'm uh going to end and turn it over to the moderators. Thank you. Hey, thank you. That was fantastic. And this is certainly an area with lots of new information coming out and um I guess I still have a lot of apprehension about using medications and using them for the long term in these patients, especially since we're talking about starting something in a teenager. Can you give some more information about what's out there about the long-term use? Right, so, you know, we have to weigh the risks and the benefits. If you have a teenager who has severe obesity, they're living with that obesity for decades longer than, say, an adult who develops obesity. Obesity later on in their life. So for sure, we have to think about the long-term risks of a, of a medication, but you also have to weigh that against the long-term risk of carrying 100 pounds extra for decades, um, decades at a time. Um, we also have to keep in mind that some of the medications that we're talking about, um, for example, topiramate, have been around for decades and have been used in pediatrics for decades, um, and it's FDA approved down to age 2 for seizures. So we do have some information about long-term use for some of these medications. How, how do you get them approved for by insurance companies to pay for it? How do you, how do you fund this? Um, insurance companies cover, um, topiramate, um, Many insurance companies do not cover. Um, medications that are specifically indicated for obesity, for example, phentermine. Phentermine is pretty cheap though, so some patients can pay for it out of pocket. Yeah, we, we've certainly run into that issue about getting things approved. I had, um, a really interesting a patient. She was 535 pounds when she came to us, and she turned 18. So therefore I was able to get medication started on her. But I actually had to go through an approval, uh, you know, they got denied. And I didn't even write for like a combination. I wrote for the topiramate and the phentermine separately, and, and still got denied and it was still a whole another month-long process and You know, that's right. So, but that you bring up an interesting point that 17 18-year-old who's 500 pounds was likely what, 200 pounds when they were 10 or 11, and we need to be intervening then before she gets to be 500 pounds because when she's 500 pounds, even bariatric surgery at that time is um You know, the outcomes for that are going to not be the best. Yeah, well, and, and this particular patient, we're doing the medication in preparation for bariatric surgery down the line because she's in no way. In good shape for it, yeah, right, right. Mhm. So Chris, do do you use these medications at all in your practice? You know, I do not, um, but I, I think, you know, Claudia brings up real points and things that we know about bariatric surgery. We just need to be thinking and and kind of pushing, um, on, on getting more, uh, things out there for our kids with severe obesity. They really suffer and we just intervene too late. This point, Claudia, I had a question for you. Wait, one, I just want to say one other thing with respect to bariatric surgery. Um, it is, it is seen as actually more acceptable than pharmacotherapy, which I find kind of interesting given that it is arguably a much, um, uh, riskier, irreversible, um. Intervention and yet and and granted, it is certainly controversial, but I also think that it's not nearly as controversial as using pharmacotherapy, which I find kind of odd. Victoria, do you, do you use, uh, Victoria Rogers, I don't know if you have your audio up. Do you, do you use medications in your practice at all? Uh, I think you're muted. There you go. Can you guys hear me now? Yeah, yeah, so, um, Mike Dudekian runs our countdown clinic, and he uses them sparingly. I think he has some of the same concerns that have been brought up already. Um, I, I, I think this is a fabulous conversation though, Claudia. I think you bring up great, uh, ideas about and, and the research about where we should be going, and then we also have that apprehension of where we are now. It is. Fascinating though I do think bariatric surgery is more accepted in such a funny way. So Mike does use them a lot. There are other clinicians around our state and our region who are really very interested in providing more management and treatment in their offices, so the medical modalities are becoming a lot more acceptable to them. John, did you have a comment? Nothing. I think Chris had one more question. Chris, did you have another question? Yeah, I did have just a quick one, and I may have kind of missed this when you presented it, Claudia, but you know, we, we, for those of us who've worked in bariatric centers, you know, there's the, the effect on, um, physiology after bariatric. Surgery is always seems like it's out of proportion to the weight loss, you know, that there's something hormonally going on that corrects diabetes before the weight loss occurs and all these things happen. What are, what are the um current think, what's the current thinking about like, Are there any ideas about what medications that we will be able to use that will mimic that bariatric effect? I just wonder if you know of any, you know. bariatric things that we've learned from bariatrics that are going to have an application and I do know that is a hot area of research for sure. Um, I know that GLP-1 agonists have can be similar but not nearly to the extent obviously that bariatric surgery um can provide, um, but so I know GLP1 is involved. I'm not, I don't know, um, frankly. All, all of the, the nuances of what the biological changes in bariatric surgery are that could potentially be mimicked with medications, but you're, you're spot on with that's where science is moving. Yeah, I know we're, we're nearing the end of our time. We need to take a break, but Claudia, thank you so much. This is really interesting. It's a, a new area for a lot of us and certainly some apprehension as we sort of wage our way through it. But you and the program that you put on, all that really is helping us, I think, get to the best place so we can care for these kids, and we have more than one option on the best way to do it. So thank you so much for, for presenting here, and I think we're going to take a 10 minute break and then we'll be back. See you at 10:45 Eastern time.