Chapters Transcript Video The Latest and Greatest in the Management of Pediatric Obesity- A Look at Incretin-based Therapies and Bariatric Surgery Doctor Srinivasan is an assistant professor and pediatric endocrinologist here at U CS F. She completed her medical school at the Pondicherry Institute of Medical Sciences and her pediatric residency at Suny Downstate and Tufts followed by a fellowship in pediatric endocrinology at Harvard N gen. Her clinical focus is on di on diabetes and obesity. And she is active in research related to pharmaco genetics and therapeutics for youth with prediabetes and type two diabetes. We are so excited to have her with us today that I will hand it up to you. Thank you so much Sarah. Um And thank you for the um invitation um to present at grand rounds. It's always um such an um uh a great opportunity to present to this incredible community. So I'm really happy to be here um is um so today I will be talking about the latest and and maybe the greatest in the management of pediatric obesity. I look at um increment based therapies and bariatric surgery. Um Here's my disclosure and here's the outline of my talk today. So I'll start by um laying out the current landscape of pediatric obesity. Um And then we'll launch the majority of the talk I hope to spend on the incretin based therapies for pediatric obesity. And then at the end, I'll also touch upon bariatric surgery um for pediatric obesity. So we all know that we have a real um problem on our hands right now when it comes to childhood obesity, one out of three Children in the United States are overweight or obese. So every third child is either overweight or obese. Um And then when we look at trends in childhood obesity, these are also alarming. So shown here are data from the end ha study and showing the trends in childhood obesity from the 19 sixties to 2018, 2017, 2018. And it's further divided by age group. Um The younger Children shown in the blue and then the um older Children shown in green and you can see that there's just been a steady increase um in the um um the prevalence of obesity and even though there's maybe been a few like blips and some um down trends and um stable trends overall um in, in some of the preceding years. Um overall, the trends have been only going upward and this only goes up to 2018. And we all know that since the COVID-19 pandemic, these um trends um look even worse. And I just wanted to also share um the trends in type two diabetes or type two diabetes is one of the downstream consequences of childhood obesity and the trends in childhood type two diabetes also run parallel to the trends in obesity. So we've seen a steady increase um in pediatric type two diabetes. Um in particular, um this disproportionately affects youth of color. So here is a look at the numbers for obesity in Children and adolescents again, data from the N Haine survey. Um So in 2017, 2018, the prevalence of obesity was 19.3% and affected 14.7 million Children and adolescent in the United States. So if you break this down by age, you can see that this affects the older Children more than the younger Children, but that the younger Children, the rates are still pretty high in the younger Children. So 12.7% among 2 to 5 year olds, 20.7% among 6 to 1211 year olds and 22.2. So 1/4 a 25 1 in four among 12 to 19 year olds. And then further, when you look at this bi racial and ethnic group again, um almost um one in four among Hispanic Latinx and non Hispanic black Children, 16.6% among non Hispanic white and 9% among non Hispanic Asian Children. I would um note that even though the rates seem lower in non-hispanic Asian Children, there's now increasing evidence to show that Asian Children are at higher risk of metabolic diseases that lower BMIs. And so the traditional cutoffs that we use for um defining overweight and obesity may not be quite appropriate for Asian youth. And so, even though this number looks lower, it doesn't necessarily indicate um that they're not at high risk. Um and then obesity in one parent increases the risk of obesity by 2 to 3 fold and up to 15 fold. Um if both parents have obesity, and then we all know that obesity is not a consequence of personal choices. Though obesity has long been stigmatized as a as a as a potentially reversible consequence of personal choices. We all know that this is not the case. Obesity is a complex multifactorial disease. And there's so many contributors to childhood obesity stemming from individual level five factors and going to family and home environment, neighborhood and community factors and um going all the way up to policy factors. So some of and this is by no means a comprehensive list. These, they just touch upon some of the major risk factors. So the individual risk factors. So genetics, genetics plays an important role in developing obesity, which is why um Children in the same environment or Children who are eating this similar diets, not all of them will go on to have obesity. And that is probably um related to the genetic predisposition. Parental obesity is a significant risk factor for obesity in the offspring, maternal gestational diabetes and then depression in the child. Um is also an individual risk factor. And then when you come to the family and home environment, there are numerous risk factors including parental feeding styles, snacking behaviors, um dining out um the ways in which family meals are undertaken, screen time, sleep, depression, um adverse childhood experiences or aces. Um and then psychosocial stress and then um neighborhood and community factors. Um So the school environment, um systemic racism and this is a risk factor that actually can go um stems um across multiple levels of risk factors, access to fresh food, access to safe physical activity. And then at the policy level, um factors such as marketing of unhealthy foods and food insecurity. Um So it's really, really important for us to tell our patients that this is not something that they could just do to themselves. But there's just so many risk factors that contribute to an individual child's risk of developing obesity. And the unfortunate truth is that the majority of obesity in childhood will track into adulthood. Um So um a, a child who is um obese um is very high risk of becoming an obese um of having obesity as an adult, there's also a very strong genetic component to obesity. Um The heritability of obesity, common obesity is about 40 to 70%. And I just also want to distinguish that there's two there's sort of two types of obesity. When you look at the genetic predisposition, there's monogenic obesity and these are the very rare forms of obesity that are caused by the single gene disorders. Like for example, the MC four R um gene mutation. So this causes early onset severe obesity, single gene, high genetic effect, rare. And then it the environment and these Children will develop obesity regardless of the um environmental influence. And then the more common form of obesity is the polygenic obesity where um there isn't a single genetic variant but there are hundreds of variants in, in, in many genes. And each genetic variant only has a very small to modest genetic contribution. So no single variant can individually cause somebody to have diabetes. But it's the contribution of all, it's the additive contribution of all these genetic variants. Um And then again, this is a more common form of um obesity with a low penetrance and environment is a key determinant um in um in, in somebody with um genetic predisposition going on to actually develop obesity. So, like I said, the most common form of obesity, the polygenic is the polygenic form of obesity. But there are less common forms of obesity. I think it's important to know what these are. So that in clinic, in, in clinics, in our clinics, we know what signs to look out for and to screen when appropriate. But again, these will be overall very rare compared to the more common form of obesity. So the monogenic single gene disorders, like I said, the, the MC four R leptin leptin receptor, um uh deficiency, the PC deficiency. Um all of these, the one thing to note is that most of the monogenic disorders there really isn't. Um, uh, most of them don't have any classic physical findings or um things to look out for. And these are most, um often they manifest as very early onset um of childhood obesity. So, obesity less than the age of five or less than at the age of two. So that's sort of a tip off for the monogenic. There's all of the syndromes and um all of these syndromes like Potter Willie. Um they have their classic um um and they have um their classic clinical findings that go with these syndromes, neurological um causes brain injury, brain tumor, um after cranial radiation, hypothalamic obesity. Um endocrine causes a note that the endocrine causes for obesity is a very, very short list. Um So any Glucocorticoid excess, both um Cushing Syndrome and then any exogenous um Glucocorticoid exposure as well as um pseudo uh some forms of pseudohypoparathyroidism can cause um obesity, um psychological depression eating disorders and then many of the drugs. So many of the antipsychotics and glucocorticoids, tricyclic antidepressants all can cause um obesity. So I just wanted to walk through this framework um for the diagnosis and management of obesity. This is from the um endocrine society's guidelines. Um um The American um the A AP also has um an approach to diagnosis and management of obesity um in their latest guidelines. But I I also, I just like this particular version of this particular algorithm because I think it's helpful um to tease out some of the non common forms. So anybody, so we start off with the BM migrator than the 85th percentile which defines um overweight in childhood. And so the key branching point is that if there is any sort of abnormality in the history of physical exam, that's sort of maybe the first tip off that this is not a more common form of obesity because the majority of obesity will have um a normal history and physical exam. And I'm not talking about sort of the physical fee related to obesity like acanthosis. But in general, there's not gonna be any other um physical um abnormalities in the history of the physical exam. So, if there are any abnormalities, then you wanna look at what they are. So the attenuated growth velocity is a big red flag for an endocrine cause. Um because in the common form of um um obesity, there will be no um um uh there will be no attenuation of the linear growth velocity. In fact, many Children might have even a slight acceleration of their growth velocity secondary to the obesity. So, if there is any attenuation in linear growth velocity, that is a major tip off that there might be an endocrine issue. Um Any neurodevelopmental um abnormalities is um maybe a tip off for any of the syndrome it causes. And then if there's CNS injury, that's a sort of hypothalamic cause, obviously, we should always be screening. Um um um asking about the um the drugs that patients are on because many of them can be, um can contribute to obesity and maybe we should be having conversations with their mental health providers to see how we can optimize their physical and their um mental balance, their physical and their mental health. Um And then, um and then again, um when there is developmental um delay, um some of the um that al almost always, um it's useful to do genetic testing, either for uh Prader Willi syndrome or to look for the other causes. And then um when there is no abnormality on history and physical exam, no developmental delay, but there is still rapid onset and very early onset obesity. That's when you think of these monogenic forms of obesity, um like the leptin leptin receptor POM C MC four R. And um in those cases, um genetic testing um could be warranted as well. So it's just a few practical considerations. Um Like I said, the majority of cases of childhood obesity are caused by exogenous causes. Um routine lab evaluations for endocrine ideologies are not indicated unless like I said, the patient stature or height velocity are attenuated, hypothyroidism, rarely, rarely, almost never causes obesity. So, um it's not useful to measure thyroid um levels when a child is obese. And in fact, um, the TSH levels can be just very minimally elevated in obesity. And oftentimes this and lead us down an, an, an, an unnecessary work up, um, for thyroid issues. Um, when again, very rarely is the thyroid ever the cause. Um, for the obesity, insulin levels are in general not helpful because, um, um, when we're, um, looking at the obesity and the risk for developing type two diabetes, your insulin level um is not gonna help you with that because um as long as um a child has um enough beta cell reserve, um they're not gonna develop type two diabetes, so they could have the highest insulin levels. Um But unless they start to then progress to beta cell decline, they're not gonna develop um diabetes. So again, the quantification of the insulin levels does not help us um with anything and then genetic testing should be considered for very early onset of obesity. Um And for clinical features of genetic obesity syndromes or a family history of um extreme obesity. So, as I hope I made a case to say that aggressive management of childhood obesity is needed and this is needed to prevent co morbidities and complications because we just have had such increasing and alarming trends in obesity. So with that, we'll move on to the incr incretin based therapies for pediatric obesity. Um This is just one slide to show all the other drugs that are used in the management of obesity and all the drugs that we had before we had the incretin based therapies. Um Metformin, we're all very familiar with the FDA approval is for type two diabetes. Metformin really does not cause much weight loss at all. In fact, it's probably pretty weight neutral and there is a little bit of weight loss initially. Um when you start the medication and that might be related to the G I side effects um or list that is FDA approved and just in a light based inhibitor, it's approved in the 12 plus. It has some really nasty side effects like Storia fecal urgency and flat lens. And I can't imagine any adult, let alone any teenager who wants to be on a drug with that kind of side effects. Um A set melanite is an MC four agonist. Um And so this is approved for certain types of monogenic obesity. So this is one of the reasons why it might be useful to um a screen for those um do genetic testing for those monogenic types of obesity. So, previously, we would do monogenic testing and then we really wouldn't do anything different. But now that there is a medication for some of the forms of monogenic obesity. Um I think there is utility in screening for these monogenic forms, especially in the very early onset and very aggressive forms of obesity. Um Phentermine um is um a central norepinephrine uptake inhibitor and also non selectively inhibit serotonin and dopamine reuptake is approved um for a short course in 16 in the 16 plus age group. Um and can have some side effects including uh blood pressure, dizziness, headache, tremors, dry mouth, stomachache, Topamax carbonic anhydrase inhibitor is the FDA approval for binge eating, but it is also used in the treatment of obesity. Um Some the side effects are there are quite a few side effects. Um the most important of which are the cognitive um slowing. Um And then the Liz um dexamphetamine or Vance, which is the brand name um is a stimulant, a DH D medication approved for binge eating disorder. Um again, does have some side effects and then also Kimia, which is now approved is a combination phentermine, Topamax um drug um which is also um used and can be effective in some cases. Um but it is more expensive than the individual phentermine and Topamax. But again, so most of these drugs um uh is um up until this point, we didn't have too many options. There are some options like the phentermine and Topamax that are um um can be useful, but obviously do have side effects. So, um the introduction of the incretin based therapies has just been a huge landmark um in the treatment of childhood obesity and then also in type two diabetes. So, before we talk about them, I want to introduce you to all of the hormones that we will be talking about. So when we say the incretin hormones were um referring to G IP and G LP one, I'm throwing in Glucagon there because there are also some um therapies that target the Glucagon receptor. So just some basic introduction to what I call the G hormone. So the G IP is the gastric inhibitory polypeptide. So G IP and G LP one are um they, they are hormones that are secreted. Um in the intestine, the G IP is secreted from the upper gut, the K cells of the intestine and G LP. One glucagon like peptide um is secreted from the lower gut. Um The cells glucagon is um we all know um is secreted from the alpha cells of the pancreas. All these um hormones have receptors that are G protein coupled receptors and agonist activity at all of the receptors. And in particular, the G LP one and G IP um receptors induces weight loss. And it's this phenomenon that is captured by all the um inert based therapies. So, the incretin based therapy simulate what is called the incretin effect, which is a natural phenomenon that happens um that um that sort of a natural physiological phenomenon. And what this um is is that um the fact that oral glucose leads to a greater simulation of insulin secretion than IV glucose even when the same plasma glucose levels are achieved. So shown here is data where participants are given both o oral glucose and IV glucose, oral glucose shown in blue and IV glucose shown in green. Um So you can see from the upper panel that the glucose levels are maintained the same with both forms of insulin, with both forms um of glucose. But the oral glucose actually simulates stimulates a higher degree of insulin production um than the IV glucose. And this sort of the difference between um the insulin levels is thought to be the increment effect. And this is again attributed to those um inter inro hormones. So those gut mediated hormones um that cause a higher production of insulin. So again, what are these? Again, G LP one versus G IP versus Glucagon GOP one, which is the first um in croton hormone. Um that um uh the GOP one receptor agnus were the first group of therapies. Um is a hormone that causes increased insulin secretion but also causes delay in gastric emptying. Um And then a very important thing I wanna mention is that the increase in insulin secretion for both G LP one and G IP is proportionate to the um to the glucose level in the body, which is why the these hormone, these drugs do not cause hypoglycemia because the insulin secretion is always proportionate to the degree um to the glucose level. So, unless somebody is on insulin, um these medications on their own will not cause hypoglycemia. Um G IP similarly causes increase in Glucagon sec. Uh insulin secretion. Actually, their effects on glucagon secretion go in the opposite direction. In addition, G IP also causes increased glucose and triglyceride uptake as well as triglyceride um storage. And then Glucagon. Again, Glucagon is sort of a surprising addition, I think to this makes Glucagon, as we all know, increases glucose levels during hypoglycemia. But interestingly, Glucagon also had some catic effects where it stimulates adipose lipolysis, decreases food intake, slows gastric emptying and increases energy expenditure. And so again, um in combination with G LP one NG IP receptor agonist activity, um Glucagon receptor agonist can also um promote weight loss. So, here is a timeline for the inert based therapies. We are now in 2024 and so all of this kind of started um very recently in 2020 with the introduction of the first D LP one receptor agonist, which was um approved in Children, which was Lyro Glu Tide, which is now FDA approved for um the treatment of pediatric obesity in ages 12 and up. Um I wanted on many of these slides um from this point onwards for the inro based therapies are modified um from one of our amazing pediatric endocrine fellows, Sujata Sitaram. And so I wanted to give her a shout out for putting together such creative signs. Um So here is um the study that led to the approval of lyra glutted. So this was a randomized placebo controlled trial of 251 youth with obesity and or um plus or minus dys glycemia. They were ages 12 to 18 years and then they received doses that were escalated up to 3 mg. Um And you can see the absolute change in their BM I from baseline in the placebo group shown above compared to the lyro glutted group, which is shown below. And you can see that there was definite um increased um uh weight loss in the lyro glutted group complete co compared to the placebo group. Um up until the end of the steady period, you, you'll also note that after the study ended, um there is weight regain in both groups, placebo and the lyro glut, but the rate of weight regain is higher in the lyro glutted group compared to the placebo group. Um And then this is my brand name marketed as um Sina. It comes in a pen where you with um a pen like an insulin pen where you have to attach pen needles. Um and doses can be titrated up to 3 mg. Um There is also study um under um underway for uh evaluating leo glut in young Children again. Um Le glut is a daily injectable medication. Um So there is a a study scale kids in Children who are between the ages of 6 to 12 years um which is underway. And so we expect to have results from that in the next couple of years. So, um hopefully more options for the younger kids. Um and then more recently, um big news was the approval of semaglutide um for the use in pediatric obesity. So, semaglutide is a once weekly um injectable medication um marketed under the brand name of Wago. Um Ozempic is the um is the parallel drug against selo type, but that one is actually um marketed for diabetes. Um So this is the study that led to the approval for selo in you that's called step teens. Um This was a 68 week RCT of um 201 Children, 12 to 18 years with um obesity. Um And you can very clearly see that um Children in the sema glutted group lost um um more weight. In fact, those in the placebo group actually ended up gaining some weight. The main change in BM I from baseline um was 16% weight loss change in BM I with the Semo glo tide versus a 0.6 gain in the placebo group. And then interestingly, the placebo subtracted weight loss with semo glu tide was 17%. Um And this is actually higher than the comparable 12.4% that was seen in adult. So definitely um a high degree of weight loss more than that's what's seen with lyro glutted. Um Also, again, um note that at the end of the study period, when the drug was withdrawn, there was weight regain in both groups, but the weight regain was higher in the semo glo tide group compared to the um uh compared to the placebo group. Um There's also a study of selo tide that is underway in younger Children, 6 to 12 years old, it's called step young. Um The study um this is ongoing again, we expect results in the next couple of years. Um So then more recently, um if we thought that was big enough news then and even sort of bigger news was the um introduction of Terza. So Terza is a G LP one G IP receptor agonist. So those two drugs that the two G LP G IP that we saw before this particular drug has agonist activity on both the G LP one as well as the G IP receptor. Do note that Ter Zette is not approved in Children, it is approved in adults 18 plus, but it is not approved um in Children. Um So this is a study um that shows the use of Ter Zett in adults with obesity. Um So they use the Ter zip is a once weekly injectable medication. Um three doses, 5 mg 10 mg and 15 mg were used in the study. Um And you can see the change in um body weight percentage change in body weight with the three doses compared to um placebo. So this was 2500 adults mean BM I of 38 40% of them had prediabetes and baseline weight was 231 pounds. Um So there was meaningful, clinically meaningful weight reduction in all three doses and on the highest dose of 15 mg, 40% of participants lost greater than 25% of their total body weight with improvement in cardiometabolic factors with the average weight reduction of 52 pounds. And um interestingly, this is the first investigational drug to deliver more than 20% weight loss from baseline. Um So very exciting. Teret is marketed as Munro for diabetes and Z bound um for um um and, and uh Z bound for obesity and then Monro for type two diabetes. Um And then um many of us who work in the pediatric obesity space have started to use this drug um off label in Children. Um because um of um uh it increased in apparent increased efficacy compared to even selo type. Um tide withdrawal does lead to weight regain in adults and this was um tested in Surmount four, which is the name of the trial. So this is 783 adults on average who are 48 years old were initially in an open label phase where they were titrated um to take the maximum dose of Terzic that will tolerate. So that's the Terzic lead in period in the tide lead in period. On average, there was about 20% decrease in body weight. And then these um participants were randomized to either receive placebo or continue receiving teret and those in the placebo group actually had a 14.4% weight regain. So they kind of almost regained all of their weight. And then those in the teret group continued to have weight of um, 5.5%. Um um, weight weight loss. Um So definitely it's very clear that discontinuation of these in Croton based therapies does lead to weight gain. Um, um And so that's important to note. Um So, you know, a lot of, a lot of times we know we get questions like, what is the, what is the off ramp like? When do we stop these medications? Um, I think so far, the approach that we think makes the most sense is to consider that, you know, obesity is a chronic, um, disease just like, you know, hypertension is and diabetes is, and most chronic diseases require staying on medication, um, for a long duration of time and maybe even life long. Um, because, um, unless something really dramatic happens, you have surgery just weight loss due to like, um, um, um, other factors. But most of these, most of the time, I think these are chronic, uh, this is a chronic disease that will, um, um, need chronic medication use. And so I think that is sort of, um, a frame shift that we're seeing. Obviously, we don't have a lot of long term data on any of these drugs because these are all very recent. So, you know, I think we need to wait and see what the long term side effects are. But so far, um that's the approach that we think um makes the most sense. Um Turn Hepati in adolescence is coming soon. Um adolescence with type two diabetes, that data is probably gonna be out first or past peds and then um a little bit later, we'll see the data in um um for adolescence with obesity. So this is kind of where we are at present. We have um a leo glutted and sema glutted that we can use. And then um Ter zip aide, which is approved in adults will be hopefully approved in youth soon. Um and um is available um commercially. Um However, this is all that we have uh in the pipeline for the incretin based therapy. So there's been incredible drug development um in this area with many studies that are underway. Um So we've talked about the G LP one and the G LP one G IP receptor agonist. So, um there is a drug which is an Amylin G LP one receptor agonist. So, Amylin is cosecreted um with insulin. Um There are Glucagon and G LP one receptor agonist. Um that studies that are underway um There is what we call the triple G therapy. So the G IP Glucagon and G LP one receptor agonist, re re Tacher Tide um which is currently um the phase two um results in adults are very promising and show greater degree of weight loss than even the um G LP one GP or the dual receptor agonist therapy. And I think very exciting for pediatrics is that there are several oral G LP one receptor agonist therapies that are underway. Um There is currently uh ribs is an oral G LP one that is approved for use in adults. Um but uh the efficacy doesn't seem to be as good as the injectable semo glutted. Um but higher do there are studies of higher doses of oral semo glut are currently underway as well as other drugs. The or four glip um is another drug. Um And I think it would be really exciting if we have um oral options um available in the future. And then there's even a monthly um G IP receptor antagonist um G LP one receptor agonist um study um that is underway again with promising results. So just a lot of excitement in this space, many drugs um that are in the pipeline. Um And I think um over the next couple of years um will hopefully um have even more tools to use um in the management of um pediatric obesity. So how much do these medications cost? They cost a lot? Um And how do they do? So just here's another nice comparison um that um again, Sujata and one of our other mentors Lee Kaplan in Boston put together. Um So oral list, which is the oral drug, which is very hard to take and nobody takes, um, is, uh, has maybe a mean BM I change of like 0.5. Um, it's about 280 do lyro glutted. All of the injectable glb ones are of the order of about 1400 to $1500. You can see that the degree of weight loss is greater with semo glutted compared to lyro glutted. QIA is the combination phentermine, Topamax drug, um, um which is about $200. You can buy the f the phentermine and the Topamax individually don't cost as much, but the combination is much more expensive. Um, and it causes reasonable weight loss. And then, um, obviously, bariatric surgery, um, will have the greatest degree of weight loss, but some of these medications seem a good time. We're getting closer and closer to the degree of weight loss that you'll achieve with bariatric surgery. So I think that's something that's really interesting to note. So, what about side effects? Um, so there are definite side effects to incretin based therapies, um, that we have to consider. Um, initially there can be nausea, vomiting, diarrhea, some dyspepsia, um, sometimes some, um, um, uh, some Children do well on, um, um, um, um, PPIs, um, to help with the dyspepsia trick that I learned from one of my, um, obesity colleagues, Doctor Patria Sai. Um, and a lot of times even if, uh, patients don't have the side effects on the lower doses as we increase the dose some of these side effects may become more prominent, um um infrequent dizziness, headaches. Um So if pancreatitis is suspected, we have to um discontinue. So, um this is often a tricky one because a lot of times um um a a Children with obesity may have elevated triglycerides or um as a result of their other metabolic um abnormalities. Um it is not an overall contraindication, but it's definitely something to be uh to look out for. So we, I always say um after starting the medication, if you start to have any severe um like abdominal pain or anything, definitely stop the medication, we should be getting labs and if somebody already at baseline has very high triglycerides, um then we should be uh tracking the triglycerides to make sure that it's not worsening, um renal insufficiency. Um So it shouldn't be um used in um those with renal insufficiency. Um, obviously, uh the DPP four is the enzyme that um um breaks down the G LP one. And so it shouldn't be used in combination of the D PB four in a bitter. Um It, the risk of hypoglycemia is only present when it used in combination with insulin, but otherwise there isn't there. And then in rodent studies there, um the use of these inro based therapies can cause have caused benign and malignant thyroid um C cell tumors. So, these are um medullary thyroid cancers. Um, humans have far fewer C cells and the expression of the GLQ one receptor in the human CC cells is low. Um that, that being said there is a black box warning against um the use of this medication in um um patients with a family history of medullary thyroid carcinoma. So it's very important to ask for this. Um Again, medullary thyroid carcinoma is super rare. And so um you know, hopefully that won't be too many um people some practical points. So dose citation should be done until the maximum tolerated dose is achieved. I think this is something that we're getting better at initially when these drugs came out, we were starting the medication and then seeing patients back in a couple of months and then increasing the dose. But then we're realizing that uh the optimal way to titrate these medications is to do it at a four week frequency. So I'll, I'll often say start at this dose and then um um either do it, it's very hard to do check ins that frequently depending on the patient. I might ask them to send me a Mychart message saying, can you let me know how you're doing on this dose? And I can tell you to go up on the next dose or sometimes if depending on the type of um medication there are, if it's a pen that can be titrated up, I'll tell them to go up on the dose themselves. Um Injection teaching can be done with a quick demo. I usually always carry a pen with me, um, in my backpack or by watching the video on the manufacturer's website. Interestingly, this is something that was probably something that we were all worried about injections and pediatrics. I can't tell you how many times the, like, this is oftentimes not the biggest obstacle for patients. Many of them are, have family members who have diabetes, um, seeing injections, um, is not something new. All of these medications come in, these um these pens that are pretty simple to use. So oftentimes that is not a huge barrier. Um and it's usually something um that can be sort of quickly um taught and most patients are, are are, they're, they're so, you know, desperate to and, and, and, and, and, and you know, wanting help that they um the injections are often not a barrier. Um and I often always say the needles are much smaller than like, you know, say the flu shot needle or other like a vaccine needles. And so um most um once they start on the medication, we very rarely hear that the injection part um is um a barrier in continuing therapy. Um uh just to note just some practical logistics that Victoza Saxenda, Victoza Laro glut, Saxenda, Ozempic and Wi Gobi which are sema glutted, require pen needles to be prescribed. Um So we usually prescribe the smallest size for pediatrics. So the BD ultra fine nano 32 gauge four millimeter needles. Um the um uh to the betide to the Munro ZEP and they come with the, um, they, they, they, those pens have a needle attached, so you don't have to prescribe a separate needle. Um And so, um so just a practical point um in some cases, however, medical management may be inadequate in preventing the onset of complications. And so, um in those cases, I think, um you know, there is a role for bariatric surgery for pediatric obesity. Um So here are the indications for bariatric surgery in adolescents. These are based on the um A SM BS S pediatric, um which is the American Society of I think metabolic and bear surgery, something along those lines. Um There are 2018 guidelines. Um So the indications are BM I greater than 35 or 1 20% of the 95th percentile. Um with a clinically significant comorbidity, this can be obstructive sleep apnea type two diabetes, um, intracranial idiopathic hypertension, um uh Nash Blound disease, Skiffy GERD hypertension. So, um any of those clinically significant core mobidity or A BM I that is greater than 40 or 100 and 40% of the 95th percentile whichever is lower. Um and then um the um and then the ability, this is um often, um this is assessed by a psychologist but um the ability and motivation to be able to adhere to recommended treatments pre and post operatively, including the consistent use of micronutrient supplements because there is a period of time, both preoperatively and postoperatively where these um Children will be on a liquid diet and have very um strict limitations on their diet. They have to take um vitamin supplements lifelong. And so it's important that patients understand this and um know, are able to um um uh and are now able to adhere to this regimen. And that's what is assessed with the psychology assessment, some contraindications of medically correctable cause an ongoing substance abuse problem, any medical psychiatric psychosocial cognitive condition that prevents adherence to the post operative dietary and medication regimens. Some of these are also there's exceptions on a case to case basis. It kind of depends on the individual child, their family, um and um their um their risk factors and then um current or planned pregnancy within 12 to 18 months of the procedure. There's two primarily two bariatric surgeries that are currently done. The UN Y is almost now is being phased out, but this was the um most common um bariatric surgery um that was um done until recently, but it's now been um overtaken by the sleeve gastrectomy. So this is a procedure in which a small stomach pouch is created. And then the first portion of the small intestine is divided as you can see here. Um And hopefully you can see my um mouse, the bottom part of the small of the divided small intestine is, is brought up and connected to the stomach pouch. And this is how food will um pass through and then the top portion um is connected to the root, the small intestine further down. Um And so that um sort of the, the, the hormones um and everything from the small intestine and the proximal part of the small intestine will go read will go join and mix with the food that's coming through here. Um Again, not done at all anymore. Um Laparoscopic sleep gastrectomy is a procedure in which 80% of the stomach is removed, creating a tubular stomach, um greater than 80% of the bariatric surgery procedures in adolescence or sleeve gastrectomy. Um and then the surgical and nutritional complications are mm much less common than seen with the ruin. Why? So what are the mechanisms of weight loss and glycemic control in um in um bariatric surgery? Um improvement in blood sugars in those with diabetes is often evident within days to weeks following surgery and is actually often independent of weight loss. Um Children who have bariatric surgery have a subjective decrease in appetite and increase in postal. Um And then mostly we also think that there are changes in the neuro endocrine hormones, which is why um so decreased ghrelin levels increase in postprandial total peptide yy and increased G LP one. which happens acutely after surgery and then increased postprandial total um bile acids as well as beneficial changes in the gut microbiome here is the um five year outcome of um of the RU NY surgery because this is sort of earlier data. This comes from a consortium called Teen Labs, um which is a consortium from which we get most of our pediatric bariatric surgery data. So this is the study that shows bariatric surgery outcomes ruin why um surgery outcomes. Um between 100 and 61 adolescents and 396 adults, the adolescent shown in blue adults shown in gold and you can see that there's market weight loss and comparable weight loss in both groups. So about 30% we change um in both the adolescent and the adult group um by about six months and then this is sustained um at five years. However, remission rates for diabetes and even for hypertension are significantly higher in adolescence compared to adults. This is a data from the same study that shows remission for type two diabetes in the adolescent, shown in blue compared to the adults shown in um gold. And you can see that the remission rates are higher for those with diabetes. Potentially suggesting that interviewing sooner with something like pediatric surgery and adolescence actually um is very beneficial for their um um other comorbidities and complications um because they're probably more early on in their disease course compared to adults. So this is definitely very promising data. Um there are obviously complications. So there there are short term surgical complications as well as long term complications which include nutritional complications, iron, vitamin B, 12, vitamin D and thiamine deficiencies that for which they require lifelong supplementation. There can be impacts on bone density. There's increasing um knowledge about their mental health needs and how they may have mental health issues. Um prior to bariatric surgery, this is compounded by existing mental health issues that are probably present um in the case of obesity and then there can be a need for um, revision um surgeries. Um I just wanted to point out the U CS F does have a growing um bariatric surgery program. Um It's run um by, it's run on the West Bay side but accepts um patients on both sides of the bay, um, run by um doctors Lon Vu, who's the pediatric surgeon and doctor Patria Sai, um uh who's a gastroenterologist and also, um, and um, also part of the team are um Dana Morgan P A and then Sarah Inrn, um to place referrals. Um You can, um, you have to put in referrals. If you're at U CS F, you have to put in referrals to both um gastroenterology and surgery. And then in the comments, right, that it's for the pediatric bariatric surgery um program. Um And then you have to mark off that it's West Bay. Um, oftentimes I also recommend, you know, sending, um, if you have trouble through, go just going through the standard referral process or you find that it's denied. It's really helpful to maybe send a message to Dana and Sarah. Um They're, they're fantastic, really responsive and can um if you're having any problems, they can help you troubleshoot and um and give you a more personalized response. Um So summary and um take home points. Um, obesity is a complex multifactorial disease that is increasingly affecting Children, aggressive management of childhood obesity is needed to prevent early onset of co morbidities and complications. Androgen therapies, induced clinically significant weight loss. Lyro glutted, marketed as Saana is approved as a daily injectable option for pediatric obesity. And then semo glutted wiggle is approved as a once weekly option. Many, many newer incretin therapies in the pipeline, which is very exciting and then Maria bariatric surgery may be needed in certain cases and there are um favorable outcomes that are being um observed in adolescence. So with that, um thank you so much for your time and attention. Um feel free to reach out to me. That is my email address. This is our um pediatric endocrine um division at one of our um graduation events where we're all being very silly. Um So shout out to um my fabulous colleagues and the fellows in the division. Um I just also just two things I wanted to let you know that we do have um a lifestyle medicine bariatric surgery meeting on the 1st 3rd day of the month um between 4 to 5 p.m. by Zoom. We uh during this meeting, we sort of discuss topics related to obesity, bariatric surgery. And then um we also discuss any cases um that were referring to bariatric surgery. So, um everyone is welcome to join. Um and especially if you have any referrals for bariatric surgery, it's sometimes useful to um directly speak to the bariatric surgery team at the meeting and present your case. And so, um everyone is welcome to join if you uh would like the Zoom link, um uh the calendar invite or the Zoom link. Um Just shoot me an email and I'm happy to share um and then any trainees um in the audience um come do an elective with us. Um um We always, we love working with trainees um and um and then welcome your um participation. So thank you all so much again. Thank you so much. This was such a wonderful introduction to all these incredible and, and numerous new options for obesity. Um We have a bunch of questions so I'm gonna start speeding through them. I'm gonna stop sharing, Sarah. Is that? Oh, sure, that's fine. Yeah. Um We have two on uh testing for monogenic obesity. Is there a gene panel or one stop shop that pediatricians can order and or is it better for pediatricians just to refer to endocrinology if they wanna test for a monogenic cause? Yeah. The great question. Um The one that we've most commonly be doing now is a panel through Rhythm pharmaceuticals. So Rhythm pharmaceuticals um actually has these free test kits that they send to providers or you can just do a salivary. Um You can just do a swab and send it out. It's really simple to do. You just get a signature from the parent and it comes with the shipping label. When you go on the Rhythm Pharmaceutical website, there's a way to access the kids. We, I think that is the easiest way because it's free to the patient. You can definitely do um sort of commercial testing panels, but then you have to um which, which do exist but then you have to battle with insurance and all of that. So we have been using the rhythm pharmaceutical um um um kit um June Tester um as you all know, in the Oakland side um has also has a lot of experience with this. And so, um that's what I run. So usually in our clinics, we usually have a couple of those kids on hand, they're pretty easy to do. Um and they are completely free to the patient. So I would probably um go that route and then yeah, feel free to reach out to me separately if you wanna talk more about that. Ok, awesome. Thank you. Um Can you address if any of these drugs are drat agentic? And if so should the kids be put on birth control if they're going on them? Um Good question. The um of the incretin based therapies, we do not think that they are teratogenic. Um And so we have not been um placing um kids on um birth control. Some of the other um uh uh non inro based therapies can be teratogenic. So that, but the inro based therapies, no, in fact, the weight loss probably in a lot of, a lot of cases um does cause like i in, in kids who are not having their periods, it might actually have them resume their periods. And so they are at higher risk of um becoming pregnant. So it is probably a good idea to talk about birth control in general because if they might be they um because they will have resumption of their Menzies in a lot of cases, but we haven't. Um there isn't any evidence to suggest that these drugs are teratogenic. Ok. That's super helpful. Um The slide that you showed about pricing is that pricing per year or per month or per dose? Uh it's per month, right? It's, yeah, it's really expensive and sort of similarly, what's your experience recently been with insurance coverage for these therapies, both for kids, with medical and with private insurance? Another great question. So very happy to note that we've actually been really successful with coverage for public insurance. So medical um we actually have more trouble with the private insurance companies and so often it will require insurance um like appeal, but actually um so far we've actually had a lot of success insurance wise. That being said I should have, I meant to say this before. We have had such supply issues with the, um, with the injectable G LP one. So the, um, especially right now, so semo glutted, we go v Ozempic, there is such a shortage of these medications because everybody is on it. Um, and, um, uh, um, and so that has been a real problem that we're facing because what will happen is that we'll start the medication, the, the the patient can't find the dose or we'll go up on the dose and they can't find the next dose. And a lot of times these are again families with limited resources and so they're not able to like call multiple pharmacies figure out where the doses. So that is a huge barrier. Um Right now, even more than the insurance approval is the availability of the drug thankfully right now, the Terza type. So the Munro and the step bound that is widely available. So we've kind of all, I feel like we just keep jumping ship. We went from Leo Glu type to semo glute. We're now on the sort of Terza um bandwagon, but um that is widely available. So we've all of us in ecr kind of are now slowly shifting to that. Um But insurance approval per se for public insurance, as long as they meet the obesity, um cutoffs has been really promising? OK. Are you even shifting patients who are on Lyro glutted over to Mount Gyro or are you able to do that? Is there data about that? Yeah, good question. So yes, I've been doing that. Um I kind of we never, we're now not using the lyro glutted anymore just because we find that the other drugs are more effective. But yeah, Semo glut uh we've been so that the MRO dose is again, mro are Z bound because I think most of the people in this audience are going to be prescribing for those with obesity, not diabetes. So that is that bound is FDA is not approved in the 18 and younger. In many cases, it can, we're still prescribing it and you know, mo most of the time we're getting it covered some issues. Um and then, um but we are uh transitioning from the semo glutted. So usually the lowest dose is 2.5 mg a week, going up to 15 mg. If somebody is already on a uh semo glutted, sometimes we just go straight to the 5 mg dose because they're hopefully the G I side effects are not as pronounced if you've already been on another G LP one. Ok. Um, from your perspective, do you think it's appropriate or safe for pediatricians, primary care, pediatricians to start prescribing these therapies in the office? Absolutely. Absolutely. I do. I, I don't, I think that um there are just not enough um, you know, special knowledge and appointments to, um, uh, for these patients. And I think, um, and then, uh, that I think li really limits the access of these medications to the wider pediatric population. So I think it's absolutely safe to start. Um, the, the, the, like I said, I don't think the injection, it, it definitely takes a little bit of time and I know that, you know, our amazing, you know, primary care colleagues are so limited in time because of the volume of patients that you see. Um But hopefully that is not a huge barrier for many of our patients. A lot of times I just ask them like, I'll be doing something else. I'll be like you sit in this room and then you watch this video and I'll come back and you know, you don't need to have any questions. Um And so um absolutely, I think it's safe. We're obviously always there for questions and support, but I think absolutely can be prescribed and should be prescribed um by primary care. OK? And right now it sounds like the drug that you are having the most success with for that pediatricians could also be emulating is the step the step down the moun gyro equivalent. Oh, this is, yeah, that being said, yeah, that bound is not a yes, I would not approve. I would probably start with the semo glut the way gold um as the first dose just because you don't want to run into, uh, as, as, as the starting point for now until maybe, I think even in one or two years, I think the T zip or the zep bound will be more like, um, use probably start with the semaglutide unless again the shortages are a big issue. So probably, maybe checking to see that the one or two pharmacies that your patients most commonly go to if they have supply of that medication. Otherwise I think it's reasonable to give Zep bound a try um to see if the insurance covers it. Yeah. Ok. Can you comment on um, labs that you would get at onset? Like when you first prescribe and then how frequently would you get follow up labs? Yeah, I don't get any additional labs. Um for these medications, it's the same lab that we get for. Um, so for um o obesity screening. So a hemoglobin, a one c a comprehensive metabolic panel uh primarily to look at the liver transaminases and the creatinine just on first path to make sure that somebody, the rare case that of somebody with um with um with renal um dysfunction and then um the lipid panel. Yeah. Um the lipid panel. So that's the third one. again, just to eyeball, the triglycerides, I don't get any additional labs. Um Usually those are once a year labs unless they're abnormalities. I probably will get them sooner. Maybe 3 to 6 months later. The only, I think, um, caveat is that in Children with really high triglycerides, I think it's worthwhile to, um, monitor the triglyceride levels on this medication for the risk of pancreatitis. So, somebody has elevated triglycerides after starting treatment. Maybe in one or two months I might recheck the triglycerides to make sure most of the time. I think it will go down because if they lose weight it will get improved. But in those you just definitely want to, um, um, keep an eye on that. But other than that, no other, um, routine lapse. Ok. Awesome. Um, and then sort of a question about contro, you know, this has been a controversial topic about whether and how much to intervene in pediatric obesity. And, um, what do you say to advocates who might say that bariatric surgery in a child is mutilation before the child could truly consent to this permanent change. That's a question. Yeah. So, you know, it's a, so I think, you know, these are, we're obviously not, we're talking about adolescence for the most part. So bariatric surgery is not done in very young Children. Most of the time we're talking in about Children who are at the minimum 12 plots who are, you know, post or, and late pubertal. Um, so, and the, and there is an extensive, it's not sort of, it's not like you can't make an appointment to have bariatric surgery. There is an extensive six month evaluation process both from a medical process, but both also from a psychological process. And I think that's what the psychologist actually, um, evaluates is whether this child had the understanding of what the procedure is. Um, and whether the child understands what are the, um, like, what, what are, what's needed be both pre and post in terms of the diet and the need for supplementation. Um, how, and, and the other thing I will say is these and, and, and, and bariatric surgery can prevent these Children from getting complications like diabetes and those that have diabetes, it takes their diabetes, puts their diabetes in remission, improves their quality of life. I mean, in the few patients that I have done, like, it's literally, it's not for everyone. I'm not saying that it should be done without careful thought, but the what the patients that do go through this process, it can be really transformative um and improve their quality of life, their confidence. Um And I've had like a recent patient who like always comes to me, he's always wearing a hoodie. He doesn't talk much. He had surgery now. He's like all of a sudden just like open, he's hanging out with friends. He's just like, so again, not to be taken lightly. Um but it can be very favorable for, for some Children. Ok. Thank you so much. I really appreciate your time. We all do. There are some unanswered questions. So I think participants if you have questions remaining, feel free to email them to our speaker. Um And she's happy to respond and I think she's also agreed to provide her slides. So Christina Fernandez will email those out afterwards um as well. Thank you again so much, Sarah and thanks to all of you for some great questions and um for your attention and time. Bye. 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