Chapters Transcript Anti-Obesity Medications for Pediatricians Jennifer E. Sprague, MD, PhD, presents on childhood weight stigma linked to health consequences. All right. Well, good morning everyone. Welcome to Early Bird rounds. We'll go ahead and get started for the morning. Today we have Doctor Jennifer Spragg who is specialized in pediatric endocrinology, and today she'll be speaking on anti-obesity medications for pediatricians. Um, so Doctor Spragg is using, uh, Barb Burke's computer. uh, Barb was so nice to help us out this morning because Doctor Spragg was having a few technical issues, so, um, We also couldn't figure out how to change your name, so we'll see Doctor Spragg right there uh through Barb's computer, um, and I will be pulling up the QR code for you all at the end to scan for credit and there will be time at the at the end for questions like usual. So we'll go ahead and hand it over to Doctor Sprague. Thank you, Madison, um, and thanks, Barb, for letting me use your computer since my camera never works in Teams for some reason. So I'm talking today about anti-obesity medications specifically focusing on their use in um primarily in adolescent population. To ants. So I have two disclosures. I'm a site investigator for research studies with Eli Lilly and Rhythm Pharmaceuticals. I am not discussing the specific trials that I have been involved in. Um, I am doing some discussion of off-label use of medication. So I always start with a side note before we start. Words matter a lot. We're talking about obesity, and that is a very sensitive subject for many patients. So what you say and what your office staff say to a patient have a really big impact on How receptive that patient will be to your medical guidance and either whether or not they'll return to your office. Um, we, you know, our clinic very, very frequently encounter patients who have had really negative interactions in the healthcare setting, um, that have really turned them off to things and made them avoid medical care or very sensitive about, um, what they're going to be told. And so paying attention to your words, using Non-judgmental patient first terminology, avoiding words that um can be triggering, um, is really, really important. And that's because weight stigma is linked to a lot of health consequences. So weight stigma, I'm talking about all those negative characteristics that we may associate with patients who have high weight, lazy, unintelligent, unintelligent, poor willpower, not successful, lacking self-discipline, non-compliant with treatments. Um, that stigma. Increases individual health consequences, so it can lead to worse eating choices, lower physical activity. Think about if a patient with a high weight feels judged and they are thinking about going to a gym or even going to a walk. They're worried about people watching them because of this negative stereotype. Um, they may avoid those activities. There's increased risk of psychological disorders, depression and anxiety. These patients may receive substandard. Medical care because of this weight stigma, the patient is thought of by the providers as having these like personal failings that led to their health consequence. Everything gets attributed to their high weight, and there's not a full investigation of their complaints, so diagnoses can be missed, or there may be decreased healthcare utilization, um, because they want to avoid the situation where they feel judged. And that also leads to increased bullying and obesity not being treated as a disease. There are also public health consequences, so the stigma decreases the societal and environment um the there's disregard for societal and environmental contributors to obesity. It's gonna decrease um obesity prevention strategies, increase health disparities, and increase social inequalities. And in the end, that can increase morbidity and mortality. Now, to try to reduce that stigma and reduce um the effects, we need to be aware of our own implicit biases. So this is from the Harvard implicit bias test that you can take online. There are multiple different um characteristics that you can take it for. This is the test for heavy versus thin people associated with positive or negative words. In data from 2004 to, I believe it's 2015, um, of all the takers of this test, more than half had an automatic preference for thin over heavier people. Um, less than 20% had an automatic preference towards heavier people. So there's a lot of implicit bias and being aware of that bias can help you be more aware of the words you're using and how you're interacting with these patients. OK, so we talk all about obesity, but, and we think about it as increasing, um, comorbidities, increasing health consequences. But can weight loss improve long-term health? I think that's an important question to ask first. For that, we turn to a diabetes model. This is data from the diabetes prevention program. This is adult, not pediatric data. Um, this is an older trial. This was published in 2002. So in this trial, um, patients were randomized to placebo, metformin, or a lifestyle intervention. In the lifestyle intervention, the goal was 7% weight loss, which they achieved, and they achieved this through decreasing caloric intake, increasing physical activity, um, with activity being at least 3 days a week, but they did allow individualization of specific activities. And the important thing that we learned from this study is this initial decrease in weight, patients lost about 7% of their body weight, reduced the incidence of type 2 diabetes dramatically in that lifestyle intervention group. So at 3 years, those patients who had received the lifestyle intervention had a 58%. lower risk of having developed type 2 diabetes. At 10 years, it's still 34% reduced risk, and at 15 years still reduced 24% compared to the placebo group. So weight loss can change the long-term outcome, can reduce the risk of these um comorbidities developing over time. However, weight loss is difficult to maintain, it's difficult to achieve, and difficult to maintain. So the first graph here is the percentage of US adults with weight loss um maintained for at least 1 year. About a third of individuals could lose greater than or equal to 5%. Only a small portion could lose greater than 20% and maintain it for at least a year. That is backed up by what we saw in the weight regain in the diabetes prevention program. So, most of that weight loss was in that 1st 6 months of the intervention in the lifestyle group, um, mostly maintained up to a year when they were still receiving some intervention. After a year, there was a trend toward weight regain, and that's backed up in other studies as well. So it's hard to keep weight off. And that brings us to thinking about obesity as a chronic disease. It's a waxing and waning disease. It's relapsing and remitting, so patients may lose weight, they may gain weight, and there are many, many factors involved in this, including access to care, obesity bias. Their environments, childhood experiences, racism, health equities, and we need a team approach to the treatment. So, we're pediatricians, so it's a patient and the family and the healthcare team working to support the patient in maintaining the healthiest lifestyle that they can. And so we're gonna think about developing an obesity treatment plan, nutrition, physical activity, behavior, bariatric surgery are all potential components. We are focused on pharmacotherapy today. And that's because the AAP guidelines that were published in 2023, for the first time, recommended considering pharmacotherapy as a first line treatment um in certain populations. So patients with obesity defined as a BMI greater than the 95th percentile, who are at least 12 years of age, you can consider medication at your first encounter. Lifestyle intervention, motivational interviewing, still recommended across the board. Pharmacotherapy is not a standalone, um, but it can be brought up much earlier versus in the past it was recommended to have a trial of lifestyle first, and then if you failed, you can consider pharmacotherapy. Um, and the reason I think we've had this shift is because we have a better understanding of weight set point. Classically, you would think about, this is really just a balance of energy expenditure and energy intake, setting the body weight, but really it's much more complex. Biological factors like the in utero environment, if the baby was born. SGA or LGA, they're going to have an increased risk of obesity. There are specific susceptibility genes and epigenetic modifications that can increase the risk of obesity. There are many environmental factors, food availability, social determinants of health, the built environment, are there sidewalks or playgrounds so that these kids can be active or not. Um, and then behaviors, um, as well, so physical activity choices, cultural factors, psychological factors, is there emotional or bored eating going on. And diurnal life pattern, do they have a disordered sleep schedule, um, that can be contributing to weight. So there are many, many factors. It's much more complex than just how much did you eat and how much did you exercise in determining where the weight goes. And set point the highlights that in that a lean person tends to stay lean a patient with obesity, um, even if they lose weight, there are shifts in, um, hormonal signaling. We'll talk about leptin, um, but Other hormonal signals to increase hunger, to try and regain weight, um, increase desire for high calorie foods. There's also a decrease in metabolic rate in patients who have lost weight, trying to get them back to their weight set point, where their body wants to be, and that's really hard to overcome. So that's where medications come in. Now, the regulation of hunger is quite complex. This graphic shows you many of the hormones involved, um, so I mentioned leptin. Leptin is a hormone made by adipose tissue. It's increased with greater adiposity. It decreases hunger, um, but we can't just give leptin to all people and bring down their hunger. It's been tried, it doesn't work, um. But that pathway is important for um for satiety, and patients who are deficient in leptin or deficient in the leptin receptor have a monogenic form of obesity. Ghrelin is a stomach hormone that's secreted in times of fasting to increase hunger. All of the signals, um, go through the hypothalamus and the arcuate nucleus and the paraventricular nucleus, and the signaling is through um the leptin receptor, um, containing neurons that. Those neurons are also known as the Palm C neurons, and they secrete a hormone called alpha MSH that signals through a receptor called MC4R to decrease hunger. Um, and so the interplay of these hormones is gonna regulate the appetite and regulate weight. So we have multiple anti-obesity medications that are approved by the FDA. In general, the ones that are underlined are approved for pediatrics, and so we're just going to talk about the ones that approved in pediatrics, that's orlistat, some of the GLP ones, phentermine, topiramate and sat melanotide. And you can see in the graphic, they work in multiple different sites. This table is just a summary of those medications. The earliest approval came with Orlostat in 2003, with the exception of phentermine approved in 1959. We're using adolescent as sort of a, a broad term, cause phentermine is approved for 17 plus, um, and the most recent approvals coming in 2022. So let's start out with orlistat. Orlastat is a lipase inhibitor. So normally when you eat food, you have to have lipase to break down fats in the gut to allow it to be absorbed across the duodenal mucosa. Um, orlistat is a reversible inhibitor of lipase, so those fats in the gut don't get broken down, and there's about a 30% reduction in the amount of fat absorbed by the gut. Um, orlistat has to be taken with meals in order for it to work. So this is data from an adolescent orlistat study, um, comparing it to placebo. You can see that there's about a 1 point change in BMI with oralstat treatment, about a 2 kg loss in BMI with orlostat treatment, um, but there was weight regain over time in this trial. Orlostat is associated with a lot of GI side effects. So it's causing fat malabsorption. Patients get fatty, oily stools, they may have oily spotting. Um, they often will have abdominal pain. They may have increased gas, and sometimes, um, discharge when they pass gas. So it can be some pretty unpleasant side effects, um, that might discourage many patients from taking this medication. Again, it's taken 3 times a day with meals. The weight effect with this was relatively small, and as you're gonna see in the next group of slides, it's less than with the more recently approved medications. Um, the GI side effects deter a lot of patients from choosing this pathway. Um, I have seen a couple of patients who did choose it and liked this medication because they had lifelong constipation, and it actually helped their constipation. OK. What we hear about most in the media is GLP-1 receptor agonists. So GLP ones, um, GLP-1 is a gut hormone um involved in insulin and glucose regulation. So these drugs were initially approved as diabetes medications. The first one was actually approved back in 2005, um, and there have been additional approvals of other drugs over time. They work by increasing insulin secretion in a glucose dependent manner, which decreases glucose, they also decrease glucagon, um, side effects come primarily from effects on the stomach slowing gastric emptying, but we think about them in this category of anti-obesity medications because they affect the central nervous system, signaling through that hypothalamic center to decrease appetite. And so we have two that are FDA approved for weight loss. Lorraglotide is what we're going to talk about first, because this had the first approval. So I'm gonna show you adults and then adolescent data for each of these medications. So loranglotide in adults, this was a trial of 18 and older, um, patients had to have a stable body weight, so they weren't having dramatic changes in their body weight. Had to have an elevated BMI of at least 30 or at least 27 with comorbidities, and they were randomized to daily injectable loraglotide, targeting a 3 mg per day dose. They also received standard lifestyle counseling. This is a big study, um, over 2000 individuals were randomized to lraglotide, over 1000 randomized to placebo. In the graphs, the top graph shows change in body weight, um, blue is the loreotide, gray is the placebo, and you can see that there is a more significant decrease in body weight with the with the loraglotide compared to placebo. It's about a 6% uh placebos uh subtracted change in body weight, so the difference between the lralotide and the placebo. Um, the middle graph shows the percent of patients reaching different weight loss thresholds. So we said 7% was the target in DPP. Generally, it's between 5 and 10% body weight loss. That's considered clinically significant to reduce the risk of developing comorbidity. These are complications of comorbidities. So leaglotide in adults, just over 60% reached the greater than 5% weight loss, about a third reached greater than 10% weight loss, almost 15% uh reached greater than 15% weight loss. So this got FDA approval several years ago. They then replicated the same trial in an adolescent population. So now we're talking 12 to 17 year olds. It was a very similar study design, so stable body weight. Um, they didn't they, in adolescent studies, they generally don't use a flat BMI cutoff. We use our BMI percentile, so BMI greater than the 95th percentile. Um, but it was the same dosing plan, 3 mg per day of loreglatide, still a lifestyle intervention, a much, much, much smaller trial. So, remember, in adults, the trial was over 2000 individuals. In adolescence, it was 125 got randomized to loraglotide, 126 randomized to placebo. Um, actual baseline BMIs were pretty similar though, 35, so it would be a comparable um degree of adiposity. In these patients. So our graphs, um, look, they're, they're laid out slightly differently from the last slide. Again, placebo is in gray, loralatide is in blue. Um, so here we're looking at the change in BMI instead of change in weight. And adolescent studies are always reported, are almost always reported as change in BMI because these patients are still growing. So they may gain. Weight, but they're also gaining height, and so their BMI may improve even if their weight goes up. Um, there's almost a 5% placebo subtracted difference between loreglatide and placebo, um, 4% change in BMI. The middle graphs, blue again is loreglotide, gray is placebo. Showing individuals change from baseline BMI and you can see there's a shift towards the left and more patients falling farther below the line in the loraglotide group compared to the placebo group. Um, and so this got FDA approval for adolescent weight loss, 12 to 17 year olds in 2020. Now, just last month, Loraglotide in Children was published. So this is looking at 6 to 11 year olds BMI greater than the 95th percentile, again using the same dosing, um, still a lifestyle intervention, a pretty small trial. 56 were randomized to loragatide, 26 to placebo, um, but these are the kids that have fairly severe obesity. 37% had class 2 obesity, meaning BMI greater than 120% of the 95th percentile, 39% had class 3 obesity, BMI greater than 140% of the 95th percentile. Um, if I was considering using this medicine, those with more severe obesity is who I probably would consider it for, not those children who are falling in that lower end of the obesity range. Um, this trial, again, it showed a similar difference, like a It's 7% difference in BMI change, um, placebo compared to lraglotide. They did change the colors in this graphic, so here placebo is blue, lraglotide is this orangey color. Um, there was a a gain in body weight in the placebo group. There was an initial loss in the lorelotide group and then gain back to baseline. But again, these are much younger kids, they are growing, so we expect some weight gain. And then the bottom two graphs are that similar breakdown of the individual's BMI change or um loss or gain um and a shift towards the left in the loraglotide compared to the placebo. So, this is not FDA approved yet, um, so to be determined if it's going to get FDA approval based off of that data. Um, so with, with GOP ones, there are several contraindications. Um, in RAT studies, there's an increase in C cell hyperplasia, so this is contraindicated in a patient with personal or family history of medullary thyroid carcinoma or MEN2 due to that potential risk of increasing that cancer, it's contraindicated if the patient has a known hypersensitivity reaction and in pregnancy. Other cautions, a patient with a history of pancreatitis, this can increase the risk of pancreatitis, so I generally don't use it. I can increase the risk of gallstones, so use caution in any patient who's had a history of gallbladder disease, um, there's a small risk of hypoglycemia. Prescribing loraglotide, again, this is a daily injectable. Um, it is, so dose titration happens on a weekly basis because it's a daily injectable. So you can get to your full dose after about a month of titration. Um, it can be given any time of day without regard for mealtimes. If you miss a dose, it's recommended to just take the next scheduled dose. If you miss more than 3 days, it's recommended to restart your titration. And if you are on your maintenance dose, your 3 mg dose, and patients are not losing weight or not reducing their BMI by at least 1% after 12 weeks, it's recommended to stop the medication. It's a subcutaneous injection, so it's given similar to um an insulin injection on the arms, abdomen, thighs. You could also give it in the buttocks. So side effects with this medication are primarily GI. Nausea, vomiting, diarrhea are quite common. Some patients did have hypoglycemia, um, so that is a relatively uncommon risk. Dizziness, I'm gonna point out, uh, because it does fall in the greater than 10%, um, in the extended group, and maybe because these patients, if they're eating less, are also potentially drinking less and getting dehydrated, so pay attention to hydration. OK. So imaglotide, Loraglotide um is daily. Seaglotide is a weekly injectable. Here's our adult data trial is a similar design, so it's age 18 plus, BMI 30 or above, um, or 27 and above with comorbidities. It is weekly simaglotide up to a 2.4 mg. Per week dose associated with standardized lifestyle counseling. Again, a pretty large study, 1300 patients were randomized to simaglotide and 655 randomized to placebo. Most completed the trial. Um, if you look at the graphs, we have placebo and gray again, saglotide in blue again, um, the The difference between the two groups is larger than what we saw in the loraglotide um group, and if you look at the bottom graphs, symaglotide in blue, placebo in gray, about 50% of the symaglotide patients lost at least 15%. Of body weight. Um, so I think it's helpful to have a reference of our most powerful tools, our most powerful tool, I would say for weight loss is still bariatric surgery. The average weight loss with bariatric surgery is 30% of body weight, so we can get half of that with the magnetide in average in an adult. So then there's a simaglotide in adolescent trial, same design, age 12 to 17, BMI greater than the 95th percentile, same dosing as in adults. Again, a much smaller study than in adults, 134 patients on simaglotide, 60. 7 on placebo. Um, and again, we see this large difference, about 50 15% BMI loss in the imaglitide group compared to the placebo group which had very minimal change in BMI. Um, 50% of patients reached that 15% BMI loss, and the middle graph show those that individual distribution. So, again, shifting towards the left, shifting towards loss, um, in the patients who receive some magnetide compared to the placebo. This got FDA approval for adolescent youth at the end of 2022. We do not yet have a published child study. Um, for simaglotide. So prescribing simaglotide contraindications and warnings are essentially the same as loraglotide. With the addition of diabetic retinopathy can worsen as glycemic control um improves. This is, both of these drugs also have diabetes approval in adults. Um, loraglotide has diabetes approval in adolescents. Seaglotide does not have diabetes approval in adolescents. Um, so treatment initiation is a very low dose, 0.25, and then it's a monthly up titration, so it takes 5 months to reach your target dose. If you miss a dose and the next dose is at least 48 hours away, it's recommended to take it as soon as possible. Um, if it's less than 48 hours, then skip and just resume the next scheduled dose. If you miss more than 2 doses, you have a choice to resume the dosing as scheduled versus reinitiating and follow the dose escalation. I think I would make that decision based on the severity of the patient's side effects so far. Side effects are pretty similar to what we see with loraglotide, so nausea, vomiting, diarrhea, all very common. Dizziness is on here again. Hypoglycemia did not make this higher list, um. On the Seagletide, unlike the Laraglotide. These are what we hear about most in the media, and the side effects are very, very common. So I just have a couple slides on strategies to reduce side effects. They have to do with changing eating habits, food composition, and lifestyle. So, we're slowing down gastric emptying with these medications, so eating more slowly can help. Smaller portions can help. Not lying down after a meal can help. Um, Increasing meal frequency. No straw is on here because if you're drinking with a straw, you're also putting air into your stomach, so your stomach is more full, and so that's gonna increase your risk of these side effects. Um, food composition, lower fat, um, clear drinks, not bubbly drinks, avoiding sweets, spicy or canned foods. Anything that might make reflux worse is potentially gonna make these side effects worse. Um, and getting out and moving is also quite helpful. For patients having side effects, um, choosing really crackers, apples, things that are calming to the stomach after, um, taking the GOP one can be helpful. Avoiding strong smells can be helpful. Hydration is really, really important. Um, smaller meals can reduce vomiting as well, and then hydration. Um, constipation can also be a problem and constipation sometimes will improve with hydration and increasing fiber. Now, almost everyone is gonna have come across a patient asking for compounded sagnotide. When you're getting it from the regular pharmacy, we're talking about Wagovi that comes in a pen device that you can see at the bottom. If someone says they want some maglotide, they are probably talking about a compounded form that's gonna come in a vial. This is allowed by the FDA because of the drug shortages, so it bypasses some of the patent rules, but it comes with some additional risks. And so I personally do not prescribe um compounded simagnotide. The challenge with it is, um, the, the form that's approved by the FDA that's in the pens is a base form. The compounded might be a salt form, so it may not be an equivalent drug. Compounded pharmacies sometimes add additional ingredients like B12, B6, alcarnitine, NAD. We don't know what those things are going to do, and then there's a risk of overdose. So, um, you're drawing this out of a syringe. If your patient has the wrong type of needle or misunderstands the instructions, there's a very real risk of giving. A very different dose than what was intended. So the graphic here on the right shows an insulin needle, um, two different types of syringes. The intent was to prescribe 5 units, and a patient received 50 units, so a 10 times overdose. So you have to be very, very cautious if you do choose to prescribe this. OK, we're gonna move on to different drugs. So phentermine is approved for age 17+, um, as a standalone. It's an anorexiogenic drug, it's acting through dopaminergic pathways, we think, um, to increase satiety or decrease hunger. Um, there are a handful of adolescents or younger studies, um, so this was a study that looked at a retrospective adolescent case control study, um, and in Red is the standard of care, and blue is the average phentermine plus standard of care, and you can see there was greater weight loss in the patients who did receive phentermine. It is approved as a short-term adjunct to lifestyle, but some states will limit its use to 12 weeks because that's what the initial trials were. It's available as a daily pill. You should avoid taking it in the evening due to effects on sleep. Monitoring is monthly for 3 months, and then at least every 3 months, check weight, waist circumference, blood pressure, monitor for CNS side effects, and signs of primary pulmonary hypertension. Adverse reactions with phentermine include increased blood pressure, tachycardia, arrhythmias, cardiomyopathy, um, so a lot of heart things, insomnia, irritability, anxiety, um, it's also contraindicated if you have hyperthyroidism or glaucoma, history of drug abuse, um, recent use of MAOIs, pregnancy or breastfeeding. OK, we're gonna move on to topiramate. Topiramate does not have an FDA approval as a standalone anti-obesity medication. Um, it is thought to be acting on gaurgic neurons to decrease hunger, um, and we know from its use in other conditions, and we'll see in the combined phentermine topiramate, um, some weight loss effect. So this is off-label use of retrospective chart review of just topiramate in abolescence, um, the blue is topiramate overall, and the black is topiramate only and the black is overall. So including those same patients, you can see there's a little bit more weight loss in the patients who did receive topiramate, but it's not very much in this small retrospective chart review trial. There was a pilot randomized control trial that looked at meal replacement, followed by topiramate in adolescence with severe obesity, so they started with meal replacement, which is going to significantly reduce calories, and then they added topiramate, Blue is the group with topiramate, red is the group who received placebo after the meal replacement. You could see lower BMI so uh greater BMI loss in those that received topiramate compared to those that received placebo. So topiramate is approved for treatment of seizures, H2+ and migraines for H12+. It is not FDA approved as a standalone for weight loss, but it does get off-label use for obesity sometimes. Starting use is 25 mg daily and you can increase weekly up to 75 to 100 mg daily. You would consider this in a patient who's got a really strong hunger. They never fill up, potentially in binge eating. Um, atypical antipsychotic associated weight gain, night eating does have an adult indication for binge eating disorder. However, it's teratogenic. They need to be seen monthly for 3 months, and they need a BMP at 3 months. So the biggest question that comes up with topiramate is what about their birth control? Because topiramate affects P450 metabolism, so it actually it can affect ethaneol estradiol metabolism. It does not affect uh noreendrone metabolism. This looks at the peak ethanol estradiol level in patients on topiramate at different doses. Um, so the squares is baseline, ye 2, the triangles is when they're on 100 mg of topiramate daily, ye 3 200 mg daily, ye 4 400 mg daily. You can see that there's minimal difference between the baseline and the 200. The 100 and even the 200 of topiramate. There's a bigger drop in peak with the 400 of topiramate. ACOG um gives us some guidance on gynecologic management of adolescents and young women with seizure disorders using topiramate. So what they say is topiramate at doses less than 200 daily does not significantly affect pharmacokinetic levels of birth control pills that contain 35 mcg of ethhanyl estradiol. Um, so this is like orthocycline, it's gonna be a bigger dose than something like loestrin. So typical doses of topiramate used to treat other disorders like migraines are not considered to decrease contraceptive efficacy. Side effects with these, um, so paresthesias, you can have brain fog, depression, language problems, so word finding difficulties, psychomotor slowing. There's a contraindication with glaucoma if they have a history of suicidal behavior or ideation, and metabolic acidosis can worsen with these. So if they have a history of metabolic acidosis, this would not be the drug that I would choose, um, because we are affecting Gabba sign signaling and it's a seizure medication. Um, it could precipitate seizures if you had acute discontinuation. So if a patient starts this and then decides it's not working, you should wean off the drug the same way you ramped up slow, go down slow. Um, a side effect that I really like for this medication is carbonation dyscasia. So what this means is patients who are being treated with topiramate often think that soda tastes bad, so I found it useful to help get patients to stop drinking soda. So a beneficial side effect, sorry. OK. So that was all off-label. However, we do have phentermine topiramate as a combination that's got FDA approval in both adults and adolescents. Um, so I put them both on the same slide just because I spent a lot of time on the GLP ones. In both of these graphs, um, patients were randomized to placebo. Um, a mid-dose phentermine topiramate combination or a high dose phentermine topiramate com combination, so blue is placebo, um. Red is mid-dose on both graphs, and then the adult, they used green for the high dose, and the adolescent, they used yellow for the high dose. Um, you can see that there was a significant reduction in weight from baseline in the adult, um, treated versus placebo, and in the BMI with treated versus placebo in the adoles. Essence and significant portions of the patients reached these higher weight loss effects. So in the adolescence, about a third reached 15% weight loss in that higher dose. Um, about 40% reached greater than 10% weight loss in the high dose. Um, so this is FDA approved for adolescent use, 12 and up. In addition, phentermine topiramate had some change in metabolic parameters. Um, this is the adolescent data. There was an increase in HDL with treatment, um, and there was a decrease in triglycerides. So you, some markers of metabolic improvement that you saw in these trials, which we haven't necessarily seen in some of the other medication trials. Um, looking at adverse events, adverse events are pretty common, but they were pretty common in the placebo as well. I'll point out specifically psychiatric disorders was significantly increased, um, meaning like depression was increased, uh, in the treated compared to the placebo group. So use caution in patients with anxiety or depression. So in summary, phentermine topiramate decreased BMI and weight circumference more than placebo. In adults, it was about 3 to 5% weight loss is clinically meaningful. Um, we don't know the clinical threshold. Um, it's not fully agreed upon, but it seems like we are meeting these likely beneficial thresholds with ventrom to pyramates similar to what we did with GLP ones in adolescents and lipid parameters also improved. Who is eligible for this, so you need to be 12 or older, BMI greater than 95th percentile, contraindicated in pregnancy, contraindicated in hyperthyroidism, contraindicated in glaucoma, and don't use right after you stop an MAOI. Your toxicity warnings, fetal embryo toxicity, um, cognitive impairment, metabolic acidosis, and kidney stones are my biggest concerns. OK. Two slides on this drug. This is called cemlanotide. Um, so this is um a drug that's targeting specific defects in those hunger signaling pathways. So this is a genetic obesity drug. Again, we have leptin signaling through the leptin receptor on these POMC neurons, um, that then secrete alpha MSH signaling through MC. are to decrease hunger. If you have a mutation anywhere in that pathway, you have genetic forms of obesity, severe early onset obesity. And so this drug is FDA approved for POMC mutations and leptin receptor mutations. It's also FDA approved for Bart beetle. These are the data from POMC and leptin receptor, um, the first. Part of the graph shows the weight loss on treatment. Then there's a pinkish part that's withdrawn, and you can see some of the patients regained some of the weight. It was a relatively short withdrawal. And then they restarted, um, and the POMC continued to lose. The leptin receptor did not have a big, as big a response, but, but it did get FDA approval, um, for treatment of very specific forms of genetic obesity. OK, so we have a lot of choices. How do we pick what to use? So I found this study really interesting. Again, we're using adult data, um, and this would be very, very challenging to do in your own clinic, but I think it gives us hope that we can, um, Over time develop strategies to make the best choices for individual patients. So in this study, they did very specific um lab-based characterization of individual patients types of hunger. So they characterize them as hungry brain, they their hunger signals just never shut shut off, they're never full, um, and they put those patients on phentermine topiramate. Hungry gut, um, that was patients who had ra rapid gastric emptying. They put those patients on the ragatide. They had a slow burn group, meaning they had decreased, um, resting energy expenditure, so decreased metabolism, um, Those patients on phentermine and those who had emotional eating, um, naltrexone bupropion is contrave. It is not FDA approved in adolescence, so I didn't talk about that at all, but they put that group of patients on, uh, naltrexone bupropion. And what they found is that when they compared the phenotype assigned medication treated patients to non-phenotypes, the provider just picked whatever medication they thought would be best. The blue is the phenotype, the red is the non-phenotypes. There was a greater weight loss in the patients who had been phenotyped compared to the non-phenotypes. So potentially in the future, we may have tools that help us pick what is going to be the best fit for our individual patients. Right now, we don't have that tool available to us yet. So final thoughts, I would consider anti-obesity medications for any patient who's 12 and older, who weighs at least 60 kg and greater than the 95th percentile for BMI. But again, this is a very large population, so. I don't think this is appropriate for every single patient. Um, I do think it's a discussion you should keep open, and especially in patients who are coming to you with class 2 and 3 obesity, they are likely to need more than what they can achieve with just. Style of therapy, but they may not be ready to do treatment with a medication right at the start. Obesity is a chronic disease. If you stop treatment, weight generally goes back up. That's that weight set point. The body wants to get back to where it was before and it's gonna change hormones and metabolism to try to get there. There's a lot of limitations with these medications, so there's insurance limitations and drug shortages that limit access, weight loss medications as a class are not currently covered by Missouri Medicaid or Illinois Medicaid. So if you're trying to prescribe a GLP-1 for a patient on Medicaid in the current state, I would be very shocked if you were able to get it approved. That said, we've been advocating at the state level to try and improve insurance coverage, so maybe it will be covered in the future. There's variable coverage by private insurance. You don't know until you try. Uh, I would be very cautious with compounded simaglotide just because of the, the dose risk, the the chance that it may not be the exact same drug, and the additives that we don't know what they're going to do, and intensive health behavior and lifestyle treatment should always be part of your plan. And that's it. Happy to take questions. Thank you, very nice presentation. Um, we do have one question in the chat. I'll pull up the QR code um for everyone to scan for credit while we take questions. Can you hear me? Yeah, yes. You can hear me? Yes. OK. Hi. My name is Leland Lacobb. Your, your lecture was fascinating. Thank you so much. Uh, I have an obvious question that I'm sure has occurred to everybody and you're hinted at it at the, at the very ending. We know as far as the GLP-1 drugs go, you know, uh, Ozempic is covered for type 2 diabetics and uh we goy, uh, love the TV commercials, uh, if you have a CV problem with your obesity, cardiovascular, um, But, again, when you're talking about teenagers on GOP-1 drugs, what is this really costing these families? I mean, we go, we used to be over $1000 a month. I mean, I mean, are you getting feedback from the families on the cost of these drugs? if it's not covered by insurance, it's generally not accessible because it is still extremely expensive and it's potentially a lifetime medication. So, um, yeah, it, it's challenging to get and that's where you potentially think about some of those off-label medications. Qima is approved, phentermine and topiramate are not FDA approved, but you can prescribe both of them individually and get a similar drug effect. Um, Amy Hawk asked in the chat, Venterino pyrami, she has a patient who's achieved good results. Should I try to wean? Um, are there guidelines? Amy, we don't. It, it's a chronic med you could try to wean, but if they regain, I would probably go back. They're likely to regain unless they've made really long-term sustainable changes and even then it's very difficult to maintain. Thank you, Doctor Laco for that question. We really appreciate you um both asking questions either through the chat or by unmuting. Um, does anyone else have any questions? We'll give you another minute or so to unmute or to type it out in the chat. Or did we get another one? I don't know, and he said thanks. I, I have a question about um long-term effects of this medication. I know that it hasn't been around for that long, but in adult studies, do they show tolerance developing or blocking antibodies or anything like that? Walking antibodies, I think are pretty rare. Um, from a weight perspective, I don't think we have really long-term data. Um, we've used this, this class of medications since 2005 for diabetes, and if people can be on the long term, but I don't think we fully know yet. Good morning. Can you hear me? Yes. OK, great talk, um. So many choices, but as a primary care physician. I'm a little reluctant to even start these medications because I don't have the full complement. So, how many primary care physicians are using some glutide and some of the medications? Do you have an idea? Uh, I don't think very many are yet, um, but I think over time we are gonna need to develop pediatricians comfort with these medications. I don't think there's enough specific obesity providers to take care of all these patients. Thank you. Any further questions? Well, if not, we really appreciate everyone's participation and um Doctor Sra your time this morning. We, yes, we'll send out the slides, um, Doctor Hill. Um, but yes, we really do appreciate everyone's participation and Doctor Spragg, your time this morning for giving this presentation, and Barb, thank you so much for letting us use your computer. Um, if anyone has any further questions, please reach out to me or Doctor Spragg. I know her email was on that last slide. And I'm gonna put in the chat what we can expect for next week's early bird round, and hope everyone has a great weekend. Created by Presenters Jennifer Sprague, MD, PhD Assistant Professor, Pediatrics Fellowship Director, Pediatric Endocrinology Co-director, Pediatric Health Start Program View full profile
