Justin Ryder, MD- 2024 Pediatric Bariatric Surgery Update Course

I have the pleasure of introducing Justin Ryder. We're very excited to have you here. He is the vice chair of Research for the Department of Surgery at Laurie, so he spends a lot of time with Tom up there, and I love your exercise, physiology background, and of course, expertise in pediatric obesity. So, welcome. Thanks for having me. And um I'm gonna cover three research hot topics that I think are on the horizon. Um, I think most of them have been alluded to today, but I'm gonna try to contextualize them uh with some data and where I think, uh, really the field needs to go in order to both advance care, um, but also understand how we can maybe have some complimentary, um, Uh, benefit of both surgery and medications as well as some basic science. So I've got 3 slides. Uh, so next slide, please. So these are data that were presented at ASMBS over the summer from Teen Labs. We hope to have them published soon. We're actively working on it, but what we found at 10 years doing latent class analysis was 4 phenotypes of responders. So you can see in the black group, these are Our superior responders, if you will, which was about 18% of the cohort who lost a significant amount of weight, about 45% was their nadir, and they were able to maintain that weight loss out to 10 years. It's pretty remarkable. In green is what I would consider to still be a great response. Individuals that lose about 35% as their nadir for weight loss and keep a little over 25% off out to 10 years, still a great response in blue, but we still have, we have a third of the cohort that doesn't quite lose as much as other individuals or are 50% high responders, if you will. And tends to have about the same amount of weight regain as our green group, but since they don't lose as much weight to begin with, their 10 year BMI change is still is 12%. And while it doesn't, you know, appear to be great, as it was alluded to earlier, that's about what we're seeing with Somaglatide as a mean response in adolescence at 1 year. And so even at 10 years, that blue group, while it's not an ideal response, is still going to kick somaglatide's butt in terms of in terms of response. And then we have in red. I think a response that nobody would want to see in a child that's undergone a bariatric surgery procedure where they don't lose the ideal amount of weight and within 4 years they're back to their mean weight and really they overshoot and What's going on with these individuals? Do they have underlying syndromatic obesity, genetic causes of obesity? We really don't know. But I think the fundamental question becomes what's causing this heterogeneity, and I think we need to study it. You know, in teen labs, we identified that there was the only predictor of response was 6 month weight loss of 10 month change. Or a 10-year change and nothing else, nothing else that we could put into the model, whether it was demographic factors, clinical characteristics, um, looking at measures of social determinants of health. Nothing other than six month change was predictive of this response. So I think really the first hot topic for research is trying to understand this variability. And then also really trying to think of how we can implement interventions when we do identify non-responders and what those appropriate interventions are. Is it going to be medications? Is it going to be a combination of medications, which medications, lifestyle, switching. Or adding on an additional surgical procedure like a duodenal switch. I think we, those are some really important unanswered questions that we um need to investigate. Uh, next slide, please. So as was alluded to earlier, we're starting to see some medications that might have equipoise or comparable outcomes to surgery. On the right, we have data from teen labs again instead of split out by our latent class analysis, this is by surgical procedure type. Again, we presented this over the summer at ASMBS and hope to have it published soon. But really we're not showing any difference in room wide gastric bypass and sleeve gastrectomy out to 10 years in teen labs. And you can see pretty clearly that at 2 years, the weight loss is about 30% in both sleeve gastrectomy and rear and wide gastric bypass. It's pretty similar to the adult, the most recent trazepeide data, which is Eli Lilly's dual GLP-1 GIP receptor agonist, which is showing 25% weight loss at 72 weeks. And You know, I think we do need studies that compare medications to surgery, and I think also to address some of the critiques that the AAP guidelines have of surgery, I think they need to be in the form of randomized trials. There are some ethical considerations with that. There are definitely some challenges to recruiting patient populations, but. We're always going to get a grade of C for bariatric surgery from these, these policymakers and these advocacy organizations until we have true randomized trials of surgery versus an alternative therapy that has the potential to have the same benefit. We can't randomize kids to lifestyle because that's just unethical. And now that we have these newer age agents. I really think that the time is right to do a really well characterized robust surgical trial versus some of these new anti-obesity medications because we know that there's other outcomes other than weight that are important. There's psychosocial outcomes, there's. Morbidity outcomes. Cost is definitely a challenge, and I think that we're really at the precipice or at a right time to answer some of those questions. And then the third hot topic that I have for us next slide please. We really need to, I think, take a step back and try to understand why we're seeing some of the responses that we see. We know bariatric surgery works. We know that it's better if you do it younger, but the question is why. It can't simply be that it's duration of disease driven. And even if duration of disease was 50% of the reason why. A bariatric surgery is more effective in adolescents than it is in adults. There's still a lot to be learned from that other 50% of it's not just simply duration of disease, and I think really the remission of type 2 diabetes question in adolescents versus adults really brings that to the top for me. What are the underlying mechanistic reasons? Is it genetics? Are there things that we can learn from a, from a protein level or from a metabolite level looking at mechanisms and pathways of response, because this is going to lead to new therapeutics. It also is going to help us identify individuals early who might be super responders to surgery or those individuals who Maybe have, have uh surgery and then they also need to be hit with about 4 or 5 other medications in, in order to see uh what we would hope to see as an ideal response. Uh, but we, we need to, I think, go back and start doing some mechanistic studies in adolescents to characterize this a little bit better. And that's all I've got for you. And so that's like 3 $15 million dollar ideas. So you're welcome. Well, with that pitch, I'm sure that there will be a sponsor out there listening in the audience that wants to contribute so that's right. Question, Justin, um, which I think you, you're probably already thinking about and lots of us, us have think, have thought about is, you know, so, obviously, especially in the, in the, in adolescent group. All patients are not created equal, right? Like we have a far, like in the adult cohorts, it's far easier to To get a, a slightly more homogeneous, uh, patient population. Do you have any thoughts in terms of like pre-op or not pre-op, but like pre-enrollment or screening, uh, you know, should we be doing, should people be thinking, who are designing these studies be thinking about genetic screening and maybe not, you know, you're not gonna find MC4R heads or necessarily, you know, homozygotes or leptin deficiency or any of that stuff. But if you use like the, the rhythm panel, you might find some of the, you know, potential other um Variants of unknown significance. Yeah, you know, it's like, it's like on, uh, what was the Princess Bride? What was it, the, uh, rats of unusual size. It's the same thing, variants of, uh, unknown significance. Um, any, you know, so thoughts on that. Yeah, I think there's a lot that we can learn from our oncology colleagues who really maybe 30 years ago started using genetics as a way of honing precision medicine techniques, and it took about 20 to 30 years to actually for for the uptake of that to impact patients, but I think there's a there's a huge space for evaluating on a large scale genetics and trying to identify preoperative predictors of response or pre-treatment predictors of response cause I don't think this question is exclusive to surgery. Um, but I I would go beyond genetics because I think that there's metabolic pathways that are perturbed with obesity that that are super relevant to response and that may or may not have genetic origins. Well, but if you if you don't combine it with their zip code, then you're missing, you know, a lot of the influence of, you know, factors that we can't measure with a needle. Yes, you know, so my cohort in DC. You know, what, 66%, 60% black, 20% Hispanic, 20% white, or 20% other. I've always complained about the drug trials like trazepetide and imagotide of basically being 70% white, if not higher, and not really in urban places. So I think that's gonna be actually a big issue with real world data, uh, about how the ALMs work because I don't, I know they don't work like they've been shown to work. Uh, because they don't work like that in the patients I was treating, which is why I'm a somewhat of a, a doubting Thomas, but I do think zip code is also super important. And if you could, you know, figure out ways to, uh, include more urban, more kids of color, that would be great. Yeah, well, as many of you know, I've been trying for a little while now to get funded the first randomized trial of AOMs versus sleeve gastrectomy, and, and, and in that trial, when we do get funded to do that work, because it is absolutely necessary, we will have a diverse inclusion and Enrollment in that study because it is so important. Clinical trial diversity is abysmal. The drug companies know it and they know that it needs to be addressed and they just never do address it because they, they prioritize timeline over quality, I think sometimes, um, which is really unfortunate. So we could also look at bringing in from different parts of the country when you get this big funding. Because like we're our population is 80 85% black and again different socioeconomic issues and racist and all that sort of stuff so let us know because we'd be happy to bring some patience to that.