Episode 377: GLP-1 Anti-Obesity Medications Update-Efficacy, Muscle Risk, and Future

0:00 [SPEAKER_02]: Welcome back to the Barbell Medicine podcast, I'm Dr. Jordan Faganbaum, and today we're tackling a topic that has fundamentally changed the landscape of health, weight management, and chronic disease, the rise of anti-OBC medications, specifically GLP-1 receptor agonists. [SPEAKER_02]: Whether you're an athlete, a health or fitness professional, or just someone trying to navigate your own health, you've heard the names of Zampic, Wagovi, Manjaro, but the story has evolved rapidly and so has the data, and this podcast will provide an update on these medications.

0:27 [SPEAKER_02]: Are they just for weight loss or do they also help with other medical conditions? [SPEAKER_02]: And just what does the data say about efficacy, side effects, and the loss of muscle mass? [SPEAKER_02]: To help us out, I have two of the best minds in the business. [SPEAKER_02]: First, the second most handsome doctor in North America, Dr. Austin Baraki, and OBC Medicine Expert Dr. Spencer Nedolsky.

0:44 [SPEAKER_02]: Welcome to the show guys. [SPEAKER_00]: Am I the third? [SPEAKER_02]: Uh, I don't know. [SPEAKER_02]: I just assume that everybody that we ever have on the podcast is in the top 10. [SPEAKER_00]: Okay. [SPEAKER_00]: I'll take that then. [SPEAKER_00]: Yeah, but I can get honestly. [SPEAKER_02]: No, that's just, yeah, for sure.

0:56 [SPEAKER_02]: But, you know, people are like, are you Jordan? [SPEAKER_02]: Do you, are you the most handsome? [SPEAKER_02]: No, no, no. [SPEAKER_02]: This is the inside joke. [SPEAKER_02]: And if you're a long time listener of the show, you know who this is the most handsome, Dr. North America. [SPEAKER_02]: But anyway, uh, Dr. Baraki, what's going on?

1:07 [SPEAKER_01]: Hey, I'm doing okay. [SPEAKER_01]: I'm glad to have Spencer here to cover this topic. [SPEAKER_01]: I'm attending on the wards in the hospital at the moment, but uh, they're able to sneak away and set some time [SPEAKER_02]: Yeah, and then if you guys don't know who Dr. Spencer Nidolsky is he's been on the show.

1:21 [SPEAKER_02]: I think you've been on our podcast a few times. [SPEAKER_02]: We've been on your podcast We actually met when I was in medical school in Virginia. [SPEAKER_02]: I believe you were in residency at the sea. [SPEAKER_00]: Yeah, yeah, shout out to your foot Jordan drove up in his M4 while he's in med school And I was like Jesus Christ.

1:36 [SPEAKER_00]: I don't I'm resin and I'm freaking poor [SPEAKER_02]: Well, yeah, that barbell medicine money, you know. [SPEAKER_00]: That barbell, that barbell, that barbell. [SPEAKER_02]: Yeah, can you before we pop into this? [SPEAKER_02]: We do have a lot of questions and a lot of stuff to get to, but real quick, Spencer, can you give people just a rundown who may not be familiar with what your background is and what you're doing now?

1:56 [SPEAKER_00]: Yeah, very quickly, NCAA Athletes, I was a heavyweight wrestler, UNC Chapel Hill, actually went to Michigan State to play football. [SPEAKER_00]: I wrestled there as well and went up transferring, trying to do both. [SPEAKER_00]: Realize it wasn't Bo Jackson, had to pick one sport, ended up going with wrestling, then went to Med School, went to Virginia College, Vosio-Pathic Medicine at the time, that's what it was called.

2:16 [SPEAKER_00]: It's now Edward Viad, something for Virginia College. [SPEAKER_00]: went to family medicine residency at VCU in Newport, news in Virginia after residency at 2014. [SPEAKER_00]: That's what I met you, Jordan, then I specialized into obesity medicine and lipidology, really interested in innovating delivery care models.

2:37 [SPEAKER_00]: And so we all work together at a startup called SteadyMD. [SPEAKER_00]: Very quickly started doing all sorts of other stuff. [SPEAKER_00]: made a company called Sequence, which was bought by Weight Watchers, I then left Weight Watchers to recreate a new company and kind of an evolution, an online Cardium Metabolic direct-care model practice called Vineyard.

3:02 [SPEAKER_00]: So that's the just really, you know, if we have a podcast called Docs who live, so we're all, we're all meat heads here, a lot of meat flown around in this podcast. [SPEAKER_02]: And then Dr. Barack, you're actually starting with Vineyard, you're gonna be taking some online patients starting in December, I believe.

3:18 [SPEAKER_02]: Is this the big, is this breaking news? [SPEAKER_01]: This is breaking news, I suppose it is breaking news. [SPEAKER_01]: I mean, yeah, so Spencer and I have known each other for a while in the telemedicine space work together for a while in the past at stadium D. And I've been doing telemedicine, I guess since 2017 or so, maintained a panel of primary care patients was doing essentially full scope primary care, metabolic health management.

3:39 [SPEAKER_01]: cardiovascular risk management, things like that. [SPEAKER_01]: So this is something that I've been doing for a while, but I think am intending to expand, given that there's a lot of need out there for it, and Spencer is certainly a leader in this space, and we're in this shared communal space of docks who who lived who are interested in this topic, and so.

3:58 [SPEAKER_01]: Yeah, I felt like a natural next step to expand my existing practice in a way that is well supported by the organization that Spencer set up, and I'd be happy to have him speak a little bit about how he has it set up and what we're doing there. [SPEAKER_00]: I'll now be not the strongest doctor at my...

4:18 [SPEAKER_00]: Yeah, so the concept is so everybody knows about we're going to talk about these GLP-1 receptor agonists and just the field of this, it's kind of cardiometabolic medicine I would call it. [SPEAKER_00]: It's not the old kind of obesity weight loss doctor is just focusing on the scale and pounds lost where, and if you obviously people follow the barbell medicine discussions were talking about lipid management, probably a lot of blood pressure management and glycemic management.

4:42 [SPEAKER_00]: It's really this concept of cardio metabolic, so not just pounds lost, those translate into a lot of cardio metabolic improvements, but you really got to think of this person in their contacts and their comorbidities, so like if they have cardiovascular disease, what if they have liver disease, all sorts of these different angles and it might, it's going to require smart people like Dr. Baraki too.

5:04 [SPEAKER_00]: think through who are the right candidates for each of these types of medicines. [SPEAKER_00]: So that's what we're doing. [SPEAKER_00]: We really think of it as like a hate to use the cliche term of holistic care, but really holistic, cardametabolic care that focuses on obesity, but really wrap around care.

5:21 [SPEAKER_00]: Online. [SPEAKER_02]: That's great. [SPEAKER_02]: Yeah, we'll put links to that if you want to work with Dr. Brocky. [SPEAKER_02]: If you want to check out Vineyard, we'll put that in the show notes. [SPEAKER_02]: Let's get into this podcast. [SPEAKER_02]: We'll start a little bit. [SPEAKER_02]: I take a step back.

5:34 [SPEAKER_02]: So before we get to the drugs, Dr. Brocky, can you quickly explain what GLP1 actually is and how it influences our body's function, especially appetite and like feeding behaviors. [SPEAKER_01]: Yeah, that's a super huge question, and we're going to keep this discussion, you know, this part of it, the basic science side, I think a little bit high level.

5:52 [SPEAKER_01]: So GLP1, you can think of as a hormone. [SPEAKER_01]: These are little peptide molecules that our body secretes from one area of the body and up traveling through the bloodstream and having effects on distant organs and sometimes on more nearby organs. [SPEAKER_01]: And so GLP1 or Glucogon-like peptide one is a hormone that is released from the cells of our intestines, usually after food ingestion.

6:12 [SPEAKER_01]: It has a few different effects on increasing the secretion of insulin from the pancreas, decreasing secretion of glucogons, slows down gastric emptying, but also we found that these receptors are pretty widely distributed throughout the body and all sorts of tissues and including in the brain.

6:28 [SPEAKER_01]: And this is part of how we think that they have a role on impacting and regulating things like appetite and feeding behaviors and things like that. [SPEAKER_01]: But that they are so widely distributed leads to a lot of the other kind of potential benefits and some of the potential downsides that will end up talking about a little bit later, and I think that that's probably about a sufficient level of depth as we need for now.

6:49 [SPEAKER_00]: Anything important you would add their Spencer. [SPEAKER_00]: uh... the incretent effect with these drugs are uh... sixty fifty's or sixty's injected glucose into people's veins versus having people ingest glucose and like i don't know if it makes sense that if you injected glucose straight to the veins the glucose gets to your pancreas quicker there's a bigger release of insulin as opposed to kind of this delayed [SPEAKER_00]: Uh, increasing glucose in your serum, but what they found out is that people at drank the glucose had a larger insulin response area under the curve total amount of insulin release.

7:30 [SPEAKER_00]: And so they called it this incretent effect. [SPEAKER_00]: They didn't know what the hormones were. [SPEAKER_00]: They some intestinal secretion of a hormone. [SPEAKER_00]: So incretent, they were like, alright, incretent. [SPEAKER_00]: Then it wasn't until later they found the various incretents out there.

7:42 [SPEAKER_00]: And so the GLP-1 was obviously the one that they started going towards for big pharma. [SPEAKER_00]: Some cool history there. [SPEAKER_00]: But yeah, that's the only thing I would add. [SPEAKER_00]: It's just a really interesting story of how they discovered this. [SPEAKER_02]: uh... you have between that and gila monsters there's a really interesting background here but for another podcast so uh... to doctor nidolsky this is something i've seen you talk about and people certainly are gonna ask about it uh... you know here about natures ozemphic or like natural ways to boost this glp one hormone that doctor baraki just described uh... do we actually need drugs for this like do we need pharmacological doses to actually get an effect here

8:20 [SPEAKER_00]: Yeah, so this kind of goes back to the history of this whole figuring out for big farm out how they how they tried to develop these drugs. [SPEAKER_00]: We have an enzyme called DPP4. [SPEAKER_00]: Dipeptyl peptidase 4. [SPEAKER_00]: It's breakstowner-owned natural incortensored in GOP-1 being one of them.

8:37 [SPEAKER_00]: So he breaks down within a minute or two. [SPEAKER_00]: So even if we increase our own natural GLP one, it doesn't necessarily have the effect on appetite that we'd see with these receptor agonists, we do actually have, and I don't know if you've talked about in the podcast, drugs that inhibit our own DPP4, so like citiglip then if people [SPEAKER_00]: I've heard of that, or genuvia, if you know, the brand name.

9:01 [SPEAKER_00]: And those can increase our own natural GLP one by like two to three fold, but we see glycemic benefits, like blood sugar benefits, but not really weight loss or appetite. [SPEAKER_00]: Differences. [SPEAKER_00]: So we can just briefly chat about the healer, the healer monster. [SPEAKER_00]: I don't know if it's healer, healer.

9:17 [SPEAKER_02]: He's like a jiff or a giff, you know? [SPEAKER_00]: Yeah, it's a good thing. [SPEAKER_00]: Yeah, it's a good thing. [SPEAKER_00]: It really matters. [SPEAKER_00]: He's a little lizard's out in the desert that, um, [SPEAKER_00]: They were studying them for, there's a few reasons why, but they thought it might have something to do with blood sugar, and it was serendipitously, they found that the venom was similar to our own, there was a part of it that was similar to our own GLP1, but it was resistant to breaking down by our DPP4.

9:44 [SPEAKER_00]: So I was like the first drug by Edda came out of Exanotide, and [SPEAKER_00]: Later, they've developed these GLP-1 receptor agonists to basically be resistant to our own GPP-4. [SPEAKER_00]: So natures, so natures, I just did a video of response video. [SPEAKER_00]: There's an intern, a medicine doctor saying, you got to eat more fiber and take probiotics to increase your own GLP-1.

10:06 [SPEAKER_00]: That's how ozempic works, and it's like, no, these drugs are their own agonists. [SPEAKER_00]: natural enzymes, the DPP4, and that's what makes them so powerful because then they can stick around longer and hit the receptors differently and actually get to the brain to have those appetite effects.

10:29 [SPEAKER_00]: Even if we increase our own natural GLP1, there may be some glycemic benefit, but we're not going to see much of an appetite difference. [SPEAKER_02]: Yeah, yeah, I've talked about a few times that like, yeah, you can increase your own GLP one a bunch of different ways. [SPEAKER_02]: Uh, unfortunately, it's usually not large enough and it's not long enough lasting to have the same effects as these medications.

10:49 [SPEAKER_02]: So anybody is trying to sell you a GLP one supplement, you know, or like a way to increase your own GLP one. [SPEAKER_02]: Uh, yeah, you can just ignore them. [SPEAKER_02]: That's basically a good way there. [SPEAKER_02]: All right, back to Baroque. [SPEAKER_02]: Now the science is moving quickly here.

11:02 [SPEAKER_02]: So can you walk us briefly through the evolution of these medications from first short acting injectables? [SPEAKER_02]: I think you had to do them twice a day to now we have agents that hit multiple receptors like Trezzepotide and it even some new oral stuff that's coming down the pipeline.

11:17 [SPEAKER_02]: Can you talk about this? [SPEAKER_01]: Yeah, I think a brief overview of the helpful. [SPEAKER_01]: And it's been really interesting and fun. [SPEAKER_01]: I think Dr. Nodolsky probably shares this because the period during which we went through most of our medical training exactly overlapped with a lot of the development and dissemination and uptake of these medicines.

11:33 [SPEAKER_01]: Like I vividly remember being in the endocrine clinic, the first time I ever heard of the name OZEMPIC and I didn't not have anywhere near the appreciation for what it was gonna become or turn into at that moment in time. [SPEAKER_01]: I was like, oh, this is just another new medicine. [SPEAKER_01]: like any others whereas you know at the time we were still you know still prescribing these DPP for inhibitors like said a glimpse in all the time even though I recognize like this doesn't really work that well but it's kind of what we have for this particular you know situation where the patient wants an oral pill or something like that but anyway so yeah we had the original discovery of Indogenous or like natural the GLP that our that our body makes on its own that only lasts again for a minute or two before it's broken down and if I had to

12:17 [SPEAKER_01]: kind of engineering the molecules to do a few different things. [SPEAKER_01]: One, to make them last longer. [SPEAKER_01]: So going from, as you said, Accentatide, the first one was a twice-date twice a day injection, which didn't even really work all that well. [SPEAKER_01]: Extending it from twice a day to once a day with a medicines like Leraglutide that came and was approved in 2010, whereas Accentatide was approved in 2005.

12:37 [SPEAKER_01]: I just point out the years so that people who question, do we have enough experience with these medicines? [SPEAKER_01]: They have been around now for a couple decades. [SPEAKER_01]: So longer duration of action from twice a day, to once a day, to once a week with medicines like by gerion or ozampic, de laglutide, and some of the most recent ones are all once a week in general.

12:57 [SPEAKER_01]: And then we have upcoming ones in the pipeline that are gonna be once a month, potentially longer, which will come with their own pros and cons to have drugs that act that long in duration. [SPEAKER_01]: The other general trend that has happened with engineering of these peptides and these molecules is that they have increasing potency.

13:15 [SPEAKER_01]: So they achieve more of the effects that we're looking for, so more potency in terms of better weight loss effects. [SPEAKER_01]: and better glycemic effects in terms of blood sugar and diabetes control among others. [SPEAKER_01]: And then the last aspect of the engineering that's important is less undesirable side effects, so better tolerability.

13:34 [SPEAKER_01]: So the medicines over the years going from that first generation back in 2005 to the next generation around 2010 of [SPEAKER_01]: Laraglutide, Victosa, Sextenda, things like that, to the 2018, Samaglutide, Ozzampic, Wegovi, and then most recently, drugs like Tersepotide, Zepbound, for example, and then most recently the ones that are kind of in the pipeline we're anticipating probably within the next year or so is going to be some of the oral medicines.

14:00 [SPEAKER_01]: And then some of the even more potent, what we'll call multi-agonists or tri-agonists like Routhatch Routhatch Routhatch, however that is exactly going to be pronounced. [SPEAKER_01]: And so all these just general tend to gradually last longer, more potent good stuff, and less bad stuff, or better tolerability.

14:15 [SPEAKER_01]: I would summarize as the evolution of these medicines over the past 20 years or so. [SPEAKER_02]: Yeah, that's a good summary and things are moving quickly and it seems like daily or weekly that oh look a new phase two or phase something trial comes out and this one is oral and you can only have to take it you know every so often which ultimately I think people are going to prefer more than the injections but cross that bridge when we come to it.

14:36 [SPEAKER_02]: Last thing before we start getting into some of the clinical data that has emerged recently on how effective these things are is this concept of food noise. [SPEAKER_02]: This is all over social media mainstream media has picked it up as well. [SPEAKER_02]: Dr. Nidolsky, can you talk about this concept of food noise like what is it and how does it relate to this topic?

14:55 [SPEAKER_00]: Yeah, you know, so, it wasn't really, it didn't really come out until these medicines so much. [SPEAKER_00]: There were the, there was this concept of it and it's always kind of been a thing probably an evolutionary thing because we got to seek out food and think about food to survive. [SPEAKER_00]: But somewhere along the ways, it's likely related to our disregulated appetites and why we struggle with helping people lose weight and keep it off.

15:20 [SPEAKER_00]: But people are just thinking about food. [SPEAKER_00]: Now, [SPEAKER_00]: when people are trying to articulate, I've asked, I don't know how many hundreds of patients about like, how would you describe it? [SPEAKER_00]: And what they describe, it's not a craving, so cravings are usually something specific.

15:35 [SPEAKER_00]: So like, after dinner, I really want some chocolate or potato chips or whatever. [SPEAKER_00]: Something very specific, it's not hunger. [SPEAKER_00]: Everybody knows what hunger is. [SPEAKER_00]: You've gone all day and you're like, oh my gosh, my belly is kind of, [SPEAKER_00]: It's the, I need to put something into it.

15:52 [SPEAKER_00]: Cravings, you know, we want the dessert or whatever. [SPEAKER_00]: Food noise is really just, it's this relentless thinking thoughts about food. [SPEAKER_00]: So what they'll describe is that it's not, it could be something healthy, it could be something not healthy, it just in general think about.

16:07 [SPEAKER_00]: is there going to be enough to eat at dinner? [SPEAKER_00]: Am I going to go get seconds? [SPEAKER_00]: Is there going to be dessert afterwards? [SPEAKER_00]: And it's not something specific about it. [SPEAKER_00]: What about the next day? [SPEAKER_00]: It's all it's like in its constant.

16:20 [SPEAKER_00]: They could have just eaten and they still are thinking about food. [SPEAKER_00]: They could be just stuffed and completely satiated. [SPEAKER_00]: But like, still thinking about food. [SPEAKER_00]: And so this is a, it's a completely different concept to people. [SPEAKER_00]: And they didn't realize they had it until they started taking the medicine.

16:37 [SPEAKER_00]: Like, for example, a patient said, yeah, I was able to enjoy my meal out with my wife, because I wasn't thinking about whether my dinner was going to have enough in it. [SPEAKER_00]: I wasn't thinking about the bread that was not here yet. [SPEAKER_00]: It was just like they just actually enjoyed.

16:53 [SPEAKER_00]: Like, they could actually think, and this is maybe why some people, [SPEAKER_00]: feel like they have less anxiety overall, like they feel like they have more brain power to put towards things that matter more in their life, as opposed to just always thinking about food. [SPEAKER_00]: Really interesting concept, and there's some new validated questionnaires.

17:16 [SPEAKER_00]: But in general, I just ask my patients, you think about food when you're not hungry? [SPEAKER_00]: Yes. [SPEAKER_00]: And you just, you can just ask them almost objectively to talk about it. [SPEAKER_02]: Yeah, there's like a running joke in like, a bunch of bodybuilder, like physique type focus people that are like, you look, I'm eating one meal and then I'm actually thinking about the next meal.

17:38 [SPEAKER_02]: And on some of it, it is, it's kind of humorous because it's like, yeah, we're losing weight. [SPEAKER_02]: And so it's almost like an expected part of the journey. [SPEAKER_02]: But for them, it's not, it's transient. [SPEAKER_02]: like context specific because they're actively trying to lose weight to get very, very lean for a show or something like that.

17:53 [SPEAKER_02]: And then also it's not, like, they don't perseverate on this indefinitely. [SPEAKER_02]: Whereas I do, I do to disagree that people who have this maybe aren't even aware that it is a separate entity that's going on until it's gone. [SPEAKER_02]: And they're like, [SPEAKER_02]: What was that that I was always thinking about food one way or another and again, not something specific or not like I'm actually hungry, but just, you know, preoccupied with food and then when it's gone they're like, huh, it's quiet, the day is gone.

18:21 [SPEAKER_00]: It's it's it's really interesting. [SPEAKER_00]: So yeah, that's just there's some there's a Travis masters and there's a few of these. [SPEAKER_00]: Psychiatry, psychology, neurobile, just kind of looking into the mechanisms of it all. [SPEAKER_00]: It's just been studied before for eating disorder, type behavior, kind of ruminating and thinking about food a lot, but like it shouldn't happen in obesity constantly.

18:44 [SPEAKER_00]: They have enough energy stores, so to me it's something pathologic. [SPEAKER_02]: Yeah. [SPEAKER_02]: Yeah. [SPEAKER_02]: That's the thing. [SPEAKER_02]: You would expect that if a person has expanded energy stores, they've developed excess body fat excess at a positive, we'll call that obesity, that the body would subsequently compensate by reducing energy intake and reducing food seeking behaviors and maybe even increasing activity to sort of maintain a normal and ideally healthy for reproductive fitness in the future level of body fat.

19:12 [SPEAKER_02]: But that's not what seems to happen in the modern food environment. [SPEAKER_02]: So anyway, we could do it with another podcast on that. [SPEAKER_02]: But let's transition to some of this clinical efficacy data. [SPEAKER_02]: We've talked about some of the basic science here and kind of how they work by targeting appetite and you know, [SPEAKER_02]: the transit of stuff through the gut, but how well do they work?

19:34 [SPEAKER_02]: So this is to Dr. Baraki. [SPEAKER_02]: So Dr. Baraki, some agulotide, or we'll go to study in a series of studies known as the step and sustain trials. [SPEAKER_02]: Those are just acronyms, among others. [SPEAKER_02]: What were the main findings of these studies in terms of obesity? [SPEAKER_01]: Yeah, really encouraging findings overall without getting, again, too far into the weeds of the statistics and minor, you know, variations and data between the individual studies because each of these were kind of big collections of a series of studies run looking at slightly different outcomes along the way.

20:06 [SPEAKER_01]: in general showed excellent effectiveness of these medicines. [SPEAKER_01]: Good potency on average, you'll hear a lot of kind of average weight loss data cited in these, which is just one metric of efficacy that you can look at. [SPEAKER_01]: So on average, about 15 percent weight loss when these drugs were studied over about 60, eight weeks or so compared to placebo, at least in the earlier studies, as well as the kind of what you would expect to see in terms of reductions in waste measurement, reductions in blood pressure, reductions in blood sugar, hemoglobin A1C, things like that.

20:36 [SPEAKER_01]: Again, some variation around those numbers, but that's kind of like in the commonly cited average weight loss figure, but the other useful metric that I like to look at is [SPEAKER_01]: proportions of patients who achieve the goals that we're looking for, right? [SPEAKER_01]: So it's not just what's the average amount of weight loss because there's going to be a distribution around that, but there's going to be a distribution around any intervention.

20:56 [SPEAKER_01]: So if it's a weight loss intervention that's not related to the use of medicines, just lifestyle, diet, exercise, some other weight loss related medicine, when we talk about what is deemed quote significant to weight loss, at least for health outcomes, what used to be, maybe you're on 5% in some situations.

21:12 [SPEAKER_01]: You'll hear people quote a little bit higher. [SPEAKER_01]: Maybe [SPEAKER_01]: for some medical conditions, it's actually even more beneficial to get larger amounts of weight loss. [SPEAKER_01]: What proportion of patients are achieving that level of weight loss if they were at get placebo over that same course of time compared with if they get the medicine over that course of time?

21:29 [SPEAKER_01]: And when I recently pulled some of this data together across a variety of these semagletide studies and looked at, well, what proportion of patients achieved greater than 5% weight loss when they were on placebo, which was about 30% which is actually a little bit higher than I would expect than higher than we tend to see in practice, but about 86% achieved it on the medicine.

21:51 [SPEAKER_01]: And so we can see that it shifts dramatically like if you imagine a bell curve of, [SPEAKER_01]: People's responses to these interventions, it shifts that whole curve of more people are achieving the target. [SPEAKER_01]: Regardless of what the average amount of weight loss is, but we're getting more people the outcome that we're looking for, which then translates into a lot more downstream benefits on health, which is the main thing that we're talking about here.

22:12 [SPEAKER_01]: So that's my overall take on this magleta data. [SPEAKER_02]: Yeah, not only like a big effect, though, like just in general, greater amount of weight loss, so people achieving that clinically significant weight loss that they go beyond that, but a greater proportion of folks make it there to compare to lifestyle alone.

22:28 [SPEAKER_02]: So yeah, big effects here. [SPEAKER_02]: Uh, Spencer, uh, turns epitide or zepound, mungioro, uh, has been studied into the surmount trials. [SPEAKER_02]: And now what were the findings from these studies that you found, uh, most compelling, and maybe you can contrast those to what we learned from about Samaglutide from the previous data.

22:47 [SPEAKER_00]: Yeah, it's somewhere around like 30 or so percent stronger in terms of total mom weight loss. [SPEAKER_00]: And you can see the responder data, the categorical weight loss is just stronger as well. [SPEAKER_00]: So we see just over like a 20 or so, 21 percent total body weight loss over the course of like 70 to weeks.

23:07 [SPEAKER_00]: And so they've done a head to head in one of these studies [SPEAKER_00]: It's better a little bit better tolerated and anecdotally we notice that as well. [SPEAKER_00]: So a stronger drug that's better tolerated, just a better profile in general. [SPEAKER_00]: We didn't get into like the select trial with the cardiovascular disease reduction with some agglotide, but like patients prefer to his appetite.

23:36 [SPEAKER_00]: So we're anything about 20-21% total body weight loss, [SPEAKER_00]: versus like the 15 or so percent, total body weight less with some magletide, high dose, some magletide. [SPEAKER_00]: Actually, we'll probably talk about they did another study step up. [SPEAKER_00]: They did a very, very high dose week-of-a-be some magletide.

23:53 [SPEAKER_00]: They got a little bit more like 17 or 18%. [SPEAKER_00]: total body weight loss with that. [SPEAKER_00]: But in general, even just the lower doses of even five milligrams of chersepitide, which is the second lowest dose, gets about the same that you would see with 2.4 that the previously highest dose of we go to be some other type, better tolerated is just [SPEAKER_00]: I'm not even paid by Lily, but yeah, I was happy to make it interesting.

24:21 [SPEAKER_00]: I did a, I did a, I did a novo ad ad board, and I just felt back as I'm just like, like, the Lily drugs better, but like if you can make this cheaper. [SPEAKER_00]: So anyway, I like to zip it that much better, just click the data is pretty clear on that. [SPEAKER_02]: Yeah, it does sound like Trezzepotite is generally superior to some agulotite, although it's being equal.

24:39 [SPEAKER_02]: But Dr. Baroque, what does this, what does the pipeline look like? [SPEAKER_02]: Our triple agonist, like Retratertide, going to push this even further, and like, is that what we think the advantage is to Trezzepotite. [SPEAKER_01]: Yeah, I think so, it's interesting to see because I think a general theme in medicine and a lot of other areas is like, when you see a drug or an intervention that has a lot more potency, you might in generally expect, okay, well, more effect in general might also come with more adverse effects in general.

25:07 [SPEAKER_01]: And so seeing the effects of, I guess, bioengineering, really smart people, doing these things to these peptides to achieve simultaneously higher efficacy of the things we want with less, [SPEAKER_01]: adverse effects of the things we don't want is a really unique combination and speaks to the level of, I don't know, expertise and incentives that are at play for them to get this right.

25:29 [SPEAKER_01]: And so that's what we're seeing with the newer agents like the one you just mentioned, what's being termed a quote unquote triple agonist because it hits multiple different receptors. [SPEAKER_01]: And again, setting the details of that basic science aside, hitting multiple receptors, lets us target multiple different pathways to achieve the effects we want and add on additional beneficial [SPEAKER_01]: We've talked about this before for example when we recently did like our blood pressure update and I talked about how a lot of the time when I have a patient who's willing to do it I tend to use multiple lower dose medicines to get the bang for my buck from multiple meds with less side effect risk same thing with lipid or cholesterol lowering therapies

26:06 [SPEAKER_01]: using different medicines at lower doses that work in different ways because we know that hitting different pathways that all kind of converge on a similar outcome, we can get a lot of effectiveness and by keeping the doses on the lower side, if that's feasible for a given patient, then we can mitigate and avoid most of the tolerability type of issues.

26:25 [SPEAKER_01]: And so what we're seeing with these triple agonists and the data coming from RetaturTry is that it is more potent achieving now into the mid-20s on average, like 24 or 25 percent, say weight loss starting to compete with metabolic bariatric surgery, efficacy, and then also having some seemingly unique aspects to it.

26:45 [SPEAKER_01]: The glucogon receptor that it targets, I've seen some discussion that it may be like increases energy expenditure, it may be helps to accelerate. [SPEAKER_01]: You know, the resolution of fatty liver disease as a result of that may be a little bit more lean, lean mass sparing which is would be awesome as well.

27:00 [SPEAKER_01]: And so again, I think the level of expertise and incentives at getting this right are leading to just phenomenal development of these things to get all the things we want with less and less of the things we don't want coming out. [SPEAKER_02]: Yeah, yeah, I found this the development pathway super interesting mainly because as you said the incentives it's like oh look if we can make this work better with less side effects yeah we're we're going to do it and it's like wait if big farm was super evil like that doesn't necessarily seem like the move there, but yeah, it would be interesting to see with if Rhetta gets you know once it gets past all the phase three clinical trials and and there's some better dosing and

27:35 [SPEAKER_02]: and monitoring profiles available for that. [SPEAKER_02]: But yeah, it's out in the wild. [SPEAKER_02]: People are obviously using these research chemicals, which we're gonna talk about shortly, not my favorite thing, but we'll talk about that. [SPEAKER_02]: Before we get there, though, Dr. Nadolsky, because of this pipeline is being just kind of pushed to the end degree, there are some oral options coming down the pipeline.

27:58 [SPEAKER_02]: And I suspect, as I talked about earlier that people are going to prefer an oral option compared to, you know, self-dejecting or whatever, what are you expecting from some of these oral options coming out? [SPEAKER_00]: Yeah, there are two, one, two of them that are going to come out six to 12 months from now.

28:13 [SPEAKER_00]: They just actually just put on a fast track for, or for, or for Glippron, I use to say, or for Glippron, but it's apparently or for Glippron. [SPEAKER_00]: whatever. [SPEAKER_00]: It's a small molecule. [SPEAKER_00]: Let's suppose a big huge peptide that you have to inject or with the semagletide, or you have to put it in a special packaging that changes the pH of your stomach to be able to actually not break it down and absorb it, which I'll talk about in a second more.

28:41 [SPEAKER_00]: Or for Glippron is a small molecule, so you can actually take it orally with food. [SPEAKER_00]: You don't have to worry about [SPEAKER_00]: drinking tons of water or anything other medicines interfering that I know of. [SPEAKER_00]: And it has, you know, around like 10 to 11% total body weight loss.

28:59 [SPEAKER_00]: We don't have all those cardiovascular trial data like we do with the oral semagletide, which I'll talk about in a second. [SPEAKER_00]: But yeah, some are around like a 10 to 11% total body weight loss. [SPEAKER_00]: There's it's supposed to be cheaper because it's easier to make because it's just a regular.

29:17 [SPEAKER_00]: molecule instead of a peptide that needs all this special transporting and things like that. [SPEAKER_00]: So I'm kind of excited to see that because if it's cheaper and we'll talk about the prices and stuff about people trying to maintain their weight loss and having to come off the medicine because of price, this might be something that would be of use there.

29:36 [SPEAKER_00]: And hopefully they do cardiovascular, I think they're going to do some cardiovascular trials to make sure. [SPEAKER_00]: uh... as we've seen before other drugs were thought we're going to be really good you know in the end there might have been some bad things happening that we just didn't know about and some of the oral drugs oral small molecule glp one drugs that didn't come to the market they found some of these through the phase uh... to uh... phase one phase two trials which is a testament to why we do the whole these phase three trials and even further [SPEAKER_00]: post-market surveillance.

30:07 [SPEAKER_00]: So that's or for Glippron, small molecule, not a large peptide. [SPEAKER_00]: They can make it easier to make cheaper to do. [SPEAKER_00]: They have a ton of it stockpiled that they're ready to launch here. [SPEAKER_00]: Again, I'm not getting paid by Lily, but it's excited. [SPEAKER_00]: That's a Lily drug.

30:23 [SPEAKER_00]: Yeah. [SPEAKER_00]: The other one is high dose oral semagletide. [SPEAKER_00]: So we already have this available in the form of [SPEAKER_00]: a Type II diabetes branded drug, which is right, Bellsis, if anybody's heard of that, that's been out for quite a number of years now. [SPEAKER_00]: Not super popular though, it goes up to 14 milligrams, this new higher dose version.

30:42 [SPEAKER_00]: They're going to call allegedly call it like, or will we go via? [SPEAKER_00]: That's what I've heard through the pipeline. [SPEAKER_00]: which I don't know, but whatever, or will we go be this what they're going to call it. [SPEAKER_00]: So it's high dose. [SPEAKER_00]: They actually studied it first at 50 milligrams, that's 5, 0, 50 milligrams.

30:57 [SPEAKER_00]: So it's about a 10, 10-fold difference in absorption. [SPEAKER_00]: I talked to a farm D on my podcast all about it. [SPEAKER_00]: So they put it in 50, but then they found that the 25 worked pretty, pretty well. [SPEAKER_00]: And it's a brown, you know, summer around 14, 15% total body weight loss.

31:14 [SPEAKER_00]: It's not bad. [SPEAKER_00]: Not a bad option. [SPEAKER_00]: And they have that cardiovascular disease and data that we can discuss here. [SPEAKER_00]: But. [SPEAKER_00]: Not a bad option, but it is, it has to be packaged in the snack package that allows your stomach to absorb it, because otherwise if you take an oral peptide, it gets degraded by your own stomach acids.

31:39 [SPEAKER_00]: and won't be absorbed and be broken up and everything. [SPEAKER_00]: So they have to put it in the special thing. [SPEAKER_00]: You have to take it with a tiny little bit of water in the morning, no food for a while. [SPEAKER_00]: Now, the question of whether people would prefer it. [SPEAKER_00]: So what's interesting is that my patients almost love the weekly injection.

31:55 [SPEAKER_00]: It's because I thought the same thing. [SPEAKER_00]: Maybe people would love taken just a pill. [SPEAKER_00]: They love just because the needles are so small. [SPEAKER_00]: They're teeny tiny and some people are afraid of needles and just do it and you'll see what happens. [SPEAKER_00]: And they're like, I didn't even feel anything.

32:11 [SPEAKER_00]: So a lot of patients actually love the weekly injection, but I don't know. [SPEAKER_00]: We'll see. [SPEAKER_00]: I think really what it comes down to is price. [SPEAKER_00]: If you can make these things cheaper, and that's gonna take the cake. [SPEAKER_00]: Well, whatever is the most powerful, but then the expense really takes to neck.

32:29 [SPEAKER_02]: Yeah, not that, not that anybody's asking me to name drugs, but like oral zempics seems like a way better thing than like oral wigovie. [SPEAKER_02]: Yeah. [SPEAKER_02]: Yeah, look, I'm available. [SPEAKER_02]: If you guys need me to consult on drug name, I'm here. [SPEAKER_02]: All right, well, look, we've talked about some of the efficacy very, very effective, but there are some cool other benefits to these medications that have been coming out.

32:53 [SPEAKER_02]: And I think there's some interesting stuff here, not only [SPEAKER_02]: weight loss associated benefits and things like heart disease, that's certain type of cancer and so on and so forth, but also weight independent effects. [SPEAKER_02]: So like maybe these medications do something on their own to reduce the risk of either disease development or disease progression that's independent of weight loss.

33:13 [SPEAKER_02]: So Dr. Nadolsky, what have trials shown so far in terms of like the impact on heart health or cardiovascular health from these from these drugs? [SPEAKER_00]: Yeah, so the semagletite is the big one that we saw a couple of years ago, actually it's pretty much two years ago the select a trial at least the top line results came out I believe the full study came out but select a trial was we go via those with a history of obesity and cardiovascular disease and not type two diabetes so we've seen benefit in the past my brother always talks about the leader trial with the lagletite now that was like whatever it was ten years ago.

33:51 [SPEAKER_00]: So that was the first drug to show cardiovascular benefit. [SPEAKER_00]: And those with type 2 diabetes at high risk cardiovascular disease. [SPEAKER_00]: This was the first one that I know of that people did not have type 2 diabetes, but had a history baseline cardiovascular disease. [SPEAKER_00]: And what they showed is a redic reduction in a cardiovascular cardiovascular events.

34:14 [SPEAKER_00]: And they've done further analyses to show like it doesn't look like it's, it looks like it's mostly [SPEAKER_00]: Maybe at least two thirds of it. [SPEAKER_00]: unrelated or independent of the weight loss. [SPEAKER_00]: And when you look back at studies, we thought that around a 10% total body weight loss, whether it's from lifestyle, bariatric surgery, would lead to reductions in cardiovascular events.

34:38 [SPEAKER_00]: So that's kind of what they were thinking. [SPEAKER_00]: But now, with some of these other drugs, they've had older GLP-1 receptor agonists. [SPEAKER_00]: Alba Glutide was one of them. [SPEAKER_00]: There was a, that was for type 2 diabetes. [SPEAKER_00]: But people didn't lose any weight, [SPEAKER_00]: uh... their cardiovascular event reduction like there's improvement there so there are receptors all over the myocardian there are receptors in our endothelial uh... tissue there's there's receptors uh... changes in our immune system something's going on with this glp1 receptor agonism that goes beyond just the weight loss of course we're going to see blood pressure improvements we're going to see lipid improvements

35:19 [SPEAKER_00]: and just overall mass in general, which may be a less strain on the heart, but like there's something else going on just from taking a GOP1 receptor Agnes. [SPEAKER_00]: So for the heart, I think that's what's really exciting. [SPEAKER_00]: We're waiting on [SPEAKER_00]: similar, but they're actually doing in primary prevention as well.

35:41 [SPEAKER_00]: I don't know, primary, so I'm sure you've all talked about differences between primary and secondary prevention, so primary would be preventing that first heart attack. [SPEAKER_00]: Secondary is somebody's head at heart attack or part event, and you're preventing another one. [SPEAKER_00]: So the tursepotide, the surmount MMO, they're looking at like, it's going to be really interesting.

36:02 [SPEAKER_00]: I think it's going to be positive though, and good. [SPEAKER_02]: Yeah, no, this is just a brief aside. [SPEAKER_02]: You're hearing Dr. Barackie, Dr. Nadolsky, and sometimes myself talk about all these various studies that are very specific to a particular intervention in this case of medication, in a particular population to come up with a particular outcome to see if that changes.

36:23 [SPEAKER_02]: Contrast this to mechanistic data in exercise science, where it's like, look, if you fast, then your growth hormone level goes up. [SPEAKER_02]: some percentage and people are like, yeah, that'll probably lead to more muscle mass. [SPEAKER_02]: And it's like, do you know how many steps you've skipped in the middle to get to that point?

36:41 [SPEAKER_02]: And medical research particularly in agents that have a lot of evidence and data behind them, you can feel quite confident in saying, look, if you are in this population, you have a high probability of seeing some level of this effect, and it's relatively well characterized, which I find very reassuring just [SPEAKER_02]: if you're advising somebody on taking these medications or to not take these medications or other medications that can all be useful there compared to.

37:07 [SPEAKER_02]: It's mostly vibes like we have like a mechanistic like plausibility but we don't have like good outcome data or the outcome data we do have is not good in that case you're like I don't even know why we're talking about this but just a brief insight anyway. [SPEAKER_00]: Awesome. [SPEAKER_00]: I see this on threads.

37:21 [SPEAKER_00]: They're just, they're talking about, this is a very quick tangent. [SPEAKER_00]: People do this with drugs and doctors. [SPEAKER_00]: I think it's because they don't understand study design and how to design trials to look at outcomes. [SPEAKER_00]: So menopausal hormonal therapy, they're saying reduces cardiovascular events.

37:38 [SPEAKER_00]: It's like, it's a whole thing. [SPEAKER_00]: We could do a whole podcast on that. [SPEAKER_00]: And so Austin and I were gone. [SPEAKER_00]: I'm threads. [SPEAKER_00]: I saw I noticed he jumped in and it's just, but it's not just exercise. [SPEAKER_00]: It's unfortunately a lot of other places, too.

37:50 [SPEAKER_02]: Yeah, Austin and I have, I think turned into Clippy from Microsoft Word, the little guy. [SPEAKER_02]: So we're like, hi there. [SPEAKER_02]: What do you think the best direct human evidence is to show that this actually of, you know, I should show up in my feet and I always like it because it's always so funny.

38:06 [SPEAKER_00]: I'm always like, oh my gosh. [SPEAKER_02]: Yeah, you and your brother are we like we like seeing your likes because it makes us feel good about So to Austin, you know, what about other major organ diseases like that of the kidney and that other liver. [SPEAKER_02]: I know there's evidence coming out here So what do we know on that front with respect to these anti obesity medications?

38:25 [SPEAKER_01]: Yeah, several years back, there were just a broad policy about medicines that were being looked at for use and diabetes that they were essentially all being required to look at cardiovascular outcomes, these things like heart attacks and strokes and things like that. [SPEAKER_01]: But interestingly, we're also accumulating evidence in other very, very common organ system diseases.

38:45 [SPEAKER_01]: Obviously, as I mentioned, I'm sitting here speaking to you from the hospital where I have a ward full of patients with all of these things. [SPEAKER_01]: cardiovascular issues, heart attack and heart failure, which have been looked at with these medicines, as well as various levels, degrees of chronic kidney disease, all the way up to dialysis patients, and then my least favorite and the most horrific is advanced liver disease, which is something that we see more and more of these days.

39:09 [SPEAKER_01]: So when I went through, [SPEAKER_01]: training, I saw boatloads of, for example, hepatitis C related cirrhosis now that we can cure that condition, seeing less and less of that, but much more fatty liver disease that has progressed to stiato hepatitis and then cirrhosis as a result and then the complications of that.

39:27 [SPEAKER_01]: And so when this has been examined so far, for example, in the flow trial, look at GLP1 Agnist and what they called kind of this kidney events to borrow a term from the cardiovascular literature, things like progression of chronic kidney disease or death related to kidney related causes.

39:42 [SPEAKER_01]: these medicines are showing benefit in that realm, and then similarly when we look at, for example, the rates of fatty liver disease or resolution or improvement in fatty liver disease, improvement in inflammatory markers around fatty liver disease, which would all lead to a reduction in the risk of progression to cirrhosis and all of those really horrific complications that I have the pleasure of dealing with in the hospital.

40:07 [SPEAKER_01]: the more potent these medicines get the more benefit we're seeing on fatty liver disease and that's what I mentioned earlier the interesting kind of maybe unique aspect of redda that you mentioned as one that can maybe increase some energy expenditure maybe has some unique benefits on the liver whether or not that ends up panning out and being fully accurate just the sheer amount of weight loss that these things can induce you know once you get well beyond seven to half to ten percent [SPEAKER_01]: of weight loss, we can see essentially curing a fatty liver disease, which would be great to reduce the burden of chronic liver disease worldwide.

40:40 [SPEAKER_01]: So not only heart, but also kidney and liver, like three of the major chronic organ system type of conditions that are often also comorbid, they have led to this development of a new term that they're calling CKM syndrome or cardiovascular kidney metabolic syndrome. [SPEAKER_01]: that kind of encompasses all of these things, people having heart disease and liver disease from fatty liver and kidney disease, as very frequently overlapping in patients.

41:04 [SPEAKER_01]: And we have increasingly potent and increasingly well tolerated agents in these medication classes that can somehow simultaneously benefit all of them, not only because they have a shared mechanism, but also because of some of these weight independent effects that Spencer alluded to earlier.

41:20 [SPEAKER_02]: Yeah, maybe we can re-brand CKM as type 3 diabetes, so people don't inadvertently refer to that as like dementia, which is definitively not the case. [SPEAKER_02]: That's another like quack watch red flag, if somebody calls dementia of any kind type 3 diabetes, just use just block, just block and move on.

41:37 [SPEAKER_00]: Sorry, thanks. [SPEAKER_02]: Yeah, it's right. [SPEAKER_02]: Before moving on to some of the side effects we're going to talk about, there is another areas of emerging evidence coming out for everything from like sleep apnea to addiction, some forms of cancer, so on and so forth. [SPEAKER_02]: So I'll have both the way in on this start with you Spencer.

41:54 [SPEAKER_02]: What are some of these areas, these other areas would these medications could be effective based on emerging evidence? [SPEAKER_00]: Yeah, so obstructive sleep apnea is pretty well established. [SPEAKER_00]: There's a surmount OSA trial. [SPEAKER_00]: That's why they've actually made it FDA approved for those with obesity and obstructive sleep apnea, medicare, even allows for it.

42:15 [SPEAKER_00]: We see sometimes a resolution in obstructive sleep apnea people stop needing their CPAPs. [SPEAKER_00]: It's not all the time weight loss doesn't always [SPEAKER_00]: improve a truck to sleep apnea or resolve it, as there can be some anatomical differences, but when you start getting that 10, 15% whole body weight loss, we see it start seeing reductions.

42:37 [SPEAKER_00]: and the apnic events from obstructive sleep apnea. [SPEAKER_00]: So pretty good, pretty good data there. [SPEAKER_00]: There's another drug called QCME that actually, it's not FDA approved for a but it's a venture mean to appear in may combo. [SPEAKER_00]: So we do know that a lot of weight loss can result in improvements in obstructive sleep apnea.

42:53 [SPEAKER_00]: I do believe most of that is weight dependent. [SPEAKER_00]: However, some argue there may be some other weight independent effects. [SPEAKER_00]: I just, it would be hard to tease that out exactly, but kind of interesting there. [SPEAKER_00]: from addiction, so there is a, there's a new, another little, I swear I'm not getting paid by the little, but they just, we should get paid, you know, honestly, I'm gonna text them after this, because I got a direct line as part of my, and I'm like, look, you guys, like, you guys, gotta start putting me on your ad boards.

43:23 [SPEAKER_00]: We'll see what happens there, but there's starting to try to find drugs that are made for alcohol cessation. [SPEAKER_00]: I had a, so funny, so stupid, but I had a viral TikTok a few years ago. [SPEAKER_00]: When I started using a lot of mungeros, it was the type 2 diabetes version of Ture's appetite when that first came out, I was using a lot of it off label and people right away were like, oh, this is so weird.

43:45 [SPEAKER_00]: I don't really want to drink alcohol, and I was like, really, so I actually published some retrospective data of all of the changes in alcohol intake from our patient population of like tens of thousands of patients kind of kind of cool to see that. [SPEAKER_00]: We're going to see other addictive like behaviors, people not biting their nails anymore.

44:06 [SPEAKER_00]: Maybe even some gambling sex addiction type of stuff, opioid addiction type of things that the drugs have a strong response in the reward center of our brains and really stuff. [SPEAKER_00]: So I think we're going to see addictive like behavior improvements there, other things. [SPEAKER_00]: So anti-inflammatory thing.

44:25 [SPEAKER_00]: So sorry, I got a car, right? [SPEAKER_00]: It's rheumatoid arthritis, some of my patients notice, wow. [SPEAKER_00]: I was on my biologic and it kind of helped me with my psoriotic arthritis, but it wasn't until I started trusepathy. [SPEAKER_00]: Again, this is anecdotal, but when you go to Eli Lilly's research page of what they're looking at, the trials are doing.

44:42 [SPEAKER_00]: They are looking into this. [SPEAKER_00]: So big farmers not stupid, they're not going to pay good Gillian's amount of dollars to look into some silly anecdote. [SPEAKER_00]: They're clearly seeing the signal too. [SPEAKER_00]: So I think we're going to see a lot of really just interesting stuff there.

44:56 [SPEAKER_00]: I see kind of [SPEAKER_00]: menstrual cycles. [SPEAKER_00]: There's GLP1 receptors and the the uterus over reason in the type of thelamic but to a terri region. [SPEAKER_00]: I don't know. [SPEAKER_00]: There's some interesting stuff. [SPEAKER_02]: Yep, some of those interesting stuff I've seen come out has to do with like cancer risk reduction and it almost seems like, you know, not to get to technical or jargony, you know, pleotropic effects of these medications.

45:24 [SPEAKER_02]: They're just affecting multiple different areas. [SPEAKER_02]: Look, if there's a receptor there or like something that these things can bind to, it seems to have a decent effect, a Dr. Baroque. [SPEAKER_02]: What's your take on this like cancer risk reduction? [SPEAKER_02]: What's up with that?

45:36 [SPEAKER_01]: Yeah, I think that it's really difficult to study in the way it has been studied so far, you know, cancer is a very heterogeneous disease. [SPEAKER_01]: There's so many different types of cancers. [SPEAKER_01]: They develop by way of so many different types of exposures and things like that.

45:50 [SPEAKER_01]: So like looking at acute leukemia, for example, in comparing that to estrogen-sensitive breast cancer, they're like completely different pathologies. [SPEAKER_01]: And so lumping these things into big buckets and looking at it in an observational way, which also lumps in a whole lot of other variables that are not being equally distributed in a randomized trial, makes it kind of tricky.

46:11 [SPEAKER_01]: I find it plausible that there could be some impact on cancer incidents, particularly among the adiposity associated cancers and things like that, but that's something that I would want, I think, higher quality data to try to tease apart to what Spencer mentioned earlier. [SPEAKER_01]: We already have, for example, some of that in sleep apnea.

46:27 [SPEAKER_01]: We already have that in osteoarthritis. [SPEAKER_01]: We're looking or expecting that, hopefully coming soon in some of the addiction space. [SPEAKER_01]: And I have some concerns around, you know, [SPEAKER_01]: The judicious use of those medicines in the addiction space, knowing that, hey, well, a lot of the patients that I see because I see tons of alcohol related issues in the hospital setting and I have [SPEAKER_01]: a few, as we speak, who are not very well-nourished, for example, and so then what's going to be the impact?

46:51 [SPEAKER_01]: They're not very well-mustled, they're not very well-nourished, they don't have high-quality diets, they're not exercising. [SPEAKER_01]: If I induce 20% weight loss in this person whose diet is comprised mostly alcohol, what's the impact going to be. [SPEAKER_01]: So there's some thoughts and which is the lesser harm there, right?

47:04 [SPEAKER_01]: And in general, I'm trying to get people to drink less, and I will tend to accept a fair amount of risk in other ways, because alcohol is like the most harmful thing that they might be doing. [SPEAKER_01]: share some of his observations around PCOS. [SPEAKER_01]: There's also conversations around like a maybe neuroprotection dementia risk, things like that that will also be super interesting because you know we've seen cardiovascular disease remained the number one killer but on a per capita basis rates of death from cardiovascular disease can have been declining for decades now we're making a lot of progress there with all the tools that we have at our disposal.

47:38 [SPEAKER_01]: Now we seem to have one that's going to be helpful for obesity and the obesity associated comorbidities. [SPEAKER_01]: the longer we live without dying of things like cardiovascular disease or kidney disease or liver disease, the longer our life spans extend, it's going to be more and more cancer and more and more neurodegenerative disease.

47:54 [SPEAKER_01]: And so if these have a favorable impact on those things, that would be a win on those fronts as well. [SPEAKER_01]: So super interested to see how it plays out. [SPEAKER_02]: Yeah, what I'm hearing you say is that if we just take a terzepotide or semaguatide and you stack it with the creatine effectively, you're going to live forever, 10 grams deal.

48:10 [SPEAKER_00]: Yeah. [SPEAKER_00]: No, 30 grams. [SPEAKER_00]: 30 more grams. [SPEAKER_00]: All the grams. [SPEAKER_02]: All the grams. [SPEAKER_02]: All the yeah, so many grams. [SPEAKER_02]: All right, well, let's transition to some of the side effects because with any effective medication, there are no biological free lunches here.

48:23 [SPEAKER_02]: There are risks and side effects. [SPEAKER_02]: So let's discuss some of the common side effects and some of the rare but serious ones. [SPEAKER_02]: So Spencer, what are the most frequent side effects that people should be prepared for and, you know, how do you go about dealing with them in your in your practice?

48:38 [SPEAKER_00]: Yeah, by far, number one is nausea, very common. [SPEAKER_00]: We saw this very early on with the examinator by Edda and all the GLP-1 receptor agonists. [SPEAKER_00]: In fact, many of the haters would say, look, people just lose weight because they're nauseous all the time and thrown up.

48:53 [SPEAKER_00]: Which is plausible, I suppose, if you, you know, if people are, you know, he gets sick from a GI bug and you don't want to eat, you lose some weight. [SPEAKER_00]: And if you feel like that all the time that it can make sense, but [SPEAKER_00]: When you look at the data, it's pretty clear that the nausea is the highest in the beginning and in the longer you run the medicine, it tends to go away for pretty much everybody.

49:12 [SPEAKER_00]: For most people, it's mild to moderate at first. [SPEAKER_00]: Barry, once in a while, it's more moderate to severe where you have to intervene with an anti-naugest medicine. [SPEAKER_00]: We try to minimize it with our diet, I have dietitians and we try to promote kind of a lower fat diet.

49:30 [SPEAKER_00]: Now there's reasons why this may be the higher fatty, so like chips, fries, pizza burgers, wings, that type of thing may be increasing. [SPEAKER_00]: that knowledge and beginning it could be because the gastric emptying, slowing, so you put more fat in the gut and then it's more in having [SPEAKER_00]: and increase in other things like CCK and other hormones that from the fat intake that can also increase nauseous.

49:54 [SPEAKER_00]: So potentially, I don't know what, but lower fat diets tend to help minimize this and maybe smaller, maybe more frequent meals, not the booster metabolism or everything like that, but to help with the nausea. [SPEAKER_00]: And you don't have to do that long term. [SPEAKER_00]: This is again, the nausea's high in the beginning.

50:10 [SPEAKER_00]: And you look at the trial data, it doesn't matter what trial it is, some agglotite resuppotite, they show the trial data that's all peaked up in the beginning, and then as the trial goes on, the nausea goes down. [SPEAKER_00]: Sometimes we have to do zo-frander and dance to help with the nausea, in general though, most people don't have to do that.

50:28 [SPEAKER_00]: So that's number one, I do see a lot of constipation. [SPEAKER_00]: From unlike nausea, it's constant. [SPEAKER_00]: So you have to get in front of it early. [SPEAKER_00]: Lots of fiber, lots of fluid, physical activity. [SPEAKER_00]: The very standard things we do for a constipation. [SPEAKER_00]: Sometimes we add a laxative and we're adding some fiber supplements and things like that.

50:49 [SPEAKER_00]: But constipation's pretty common. [SPEAKER_00]: Try to get in front of it to minimize that. [SPEAKER_00]: reflux, if you're slowing down the gastric emptying in your stomach, there's more of a chance for food and stuff to come back up to a suffocous cause reflux. [SPEAKER_00]: So we do see that.

51:07 [SPEAKER_00]: So people with a history of reflux were like, all right, we got to be careful here. [SPEAKER_00]: You might get some worsening. [SPEAKER_00]: Don't stop your represol or whatever right now. [SPEAKER_00]: Sometimes they need to add it back in for a little bit. [SPEAKER_00]: hopefully over time that improves and generally we see that improve because that gastric emptying is higher in the beginning and then veins were even goes down a lot at the end of or while you're on the drug longer.

51:30 [SPEAKER_00]: We do see diarrhea usually self-limited. [SPEAKER_00]: Generally we try to help people bulk up their stools if happy but it's usually self-limited. [SPEAKER_00]: Sometimes I do pep those. [SPEAKER_00]: Sometimes I do a [SPEAKER_00]: something that goes away over time. [SPEAKER_00]: We see fatigue.

51:47 [SPEAKER_00]: A lot of people that, well, yeah, you're not eating. [SPEAKER_00]: You're going to be tired. [SPEAKER_00]: There's something about the drug and it's likely has to do with the brain effects of the drug, the receptor agonism and the drug where we're talking about the dopamine or people. [SPEAKER_00]: feel like not as addictive, but sometimes it's got a pretty strong effect up there, almost they feel like like an anhedonia, like just kind of like they feel unmotivated and tired.

52:10 [SPEAKER_00]: That happens. [SPEAKER_00]: Sometimes you're going to adjust the dose, sometimes it's just that the beginning, the fatigue generally goes the way by itself though, and you know, a lot of people argue over the cause of it, but it's likely in the brain. [SPEAKER_00]: Some of them may be because you're not eating as much, but [SPEAKER_00]: It's you'll feel like a couple days after your shot and it goes away after a few more days kind of interesting.

52:34 [SPEAKER_00]: We're side effects, gallstones probably. [SPEAKER_00]: We see that because of weight loss likely. [SPEAKER_00]: There may be an effect of GLP1 on the actual gallbladder and changes of how it's moving. [SPEAKER_00]: we can see golf don't precipitate, but we see that within any type of weight loss bariatric surgery.

52:50 [SPEAKER_00]: And from that, we can see, you know, the closest dinosaur golf letter attacks, rarely painted tightest when you look at the, [SPEAKER_00]: When you compare a placebo to the active drug, and these big, huge trials, they put them together in a meta-analysis. [SPEAKER_00]: There hasn't seem to be a statistical difference between the drug and a placebo.

53:08 [SPEAKER_00]: But patients like these are causes. [SPEAKER_00]: Ain't crititis, so it's not different from placebo. [SPEAKER_00]: So those are the common thing. [SPEAKER_00]: Yeah, I don't know if you want to hit awesome ones to talk about the black box warning of thyroid cancer and all the scary things people talk about, but those are kind of the common thing.

53:28 [SPEAKER_01]: Yeah, I was going to echo much of what you said. [SPEAKER_01]: And the, the Packer Titus one is interesting for several reasons, because Packer Titus is a relatively common condition. [SPEAKER_01]: Like it's a, it's something that also just happens to people. [SPEAKER_01]: Sometimes in general, it happens relating to alcohol use pretty often.

53:45 [SPEAKER_01]: It can happen relating to gallstone related causes. [SPEAKER_01]: very often as well and I see it right very regularly in the hospital setting and so Given that there's a relatively high what will call like base rate of people experiencing Pancreatitis that also increases the risk of like well also there's a high base rate of people getting put on these medicines And so there's going to be a scenario where somebody gets put on one of these medicines and because they were just Existing they were gonna get Pancreatitis [SPEAKER_01]: Anyway, and humans that what we do in our brains is we tend to, you know, observe patterns and assume causation between them.

54:19 [SPEAKER_01]: Well, I started this medicine afterwards. [SPEAKER_01]: I got pancreatitis, so it needs, it must be that one caused the other, and that is a reasonable hypothesis to have, but that's also why we benefit from having control trials. [SPEAKER_01]: And that's where this interesting observation comes from in the control trials that when we compare people on drug versus on placebo, we don't actually see a significant difference in that pancreatitis risk.

54:39 [SPEAKER_01]: even though there is a higher risk of developing gallstones relating to the rapid weight loss. [SPEAKER_01]: It's like all the signs you would expect there to be a signal, but there doesn't actually it doesn't actually lead to the outcome that you would expect, which is again, why we benefit from these kind of studies and why all three of us get in arguments on threads all the time, because people make arguments based on vibes or observations or just assuming patterns exist whereas when we actually control the data to account for our own flawed assumptions and [SPEAKER_01]: we actually can get to the truth of the matter.

55:10 [SPEAKER_01]: So pancreatitis ends up being something that I don't tend to like routinely counsel on because what are you going to do aside from, well, I already advise that you probably shouldn't be drinking very much. [SPEAKER_01]: We're advising weight loss regardless here, and so there's a risk of gallstone development with rapid weight loss no matter how we we go about it, and that's something that we can, you know, be attentive to and intervene on if we need to.

55:31 [SPEAKER_01]: So that's just an interesting aspect of the data that [SPEAKER_01]: You know, although things that you might observe or anecdotally hear or expect based on some of these things don't actually tend to pan out the way that we thought. [SPEAKER_02]: Yeah. [SPEAKER_02]: And just lastly, before we get into some of the body composition of performance stuff, Dr. Ndolsky, there's been some concern about this non-artoretic anterior ischemic optic neuropathy or NAION.

55:54 [SPEAKER_02]: It's irreversible eye condition causes partial or complete. [SPEAKER_02]: Vision loss and one of both eyes and a major lawsuit against a novel notice right now like for that You know, you see that all of a place. [SPEAKER_02]: There's a $2 billion lawsuit against the manufacturers because these drugs who they don't want you to know They're they're taking your vision that's any merit to that.

56:13 [SPEAKER_00]: Yeah notice it's not against Eli Lilly I'm Someone from those departments that they're gonna come get me. [SPEAKER_00]: I'm actually friends with a lot of those people so and they're always switching teams all the time So it doesn't really matter, but [SPEAKER_00]: It is true. [SPEAKER_00]: There are some lawsuits out there.

56:27 [SPEAKER_00]: It's a rare risk. [SPEAKER_00]: We had my buddy, um, and ophthalmologist retina of specialist on there is a jamma article last year that's looked at a group of people on Samagutite with Type II diabetes that showed a maybe a small maybe one in like 10,000 people increase risk of people on the medicine.

56:50 [SPEAKER_00]: Maybe an increased risk of this. [SPEAKER_00]: type of blindness, but then more recently this year in Journal of Ophthalmology, they showed maybe a trend towards a decreased risk, at least not statistically significant, just no statistical significant risk. [SPEAKER_00]: compared to people not taking the medicine in a similar population.

57:13 [SPEAKER_00]: So if it is a risk and what my friend told me is that we see it from people's blood pressure going down and usually in the middle of the night so I could see it where the medicine it's just so powerful and people are still on their blood pressure medicine. [SPEAKER_00]: They may have sleep apnea where they're going apnic and it's not getting as much blood flow and oxygen into their blood where there may be maybe there's some sort of risk there but like [SPEAKER_00]: The most recent data doesn't show the signal.

57:41 [SPEAKER_00]: If it is there, it's extremely rare. [SPEAKER_00]: It hasn't been seen in any of the weight loss data. [SPEAKER_00]: It's only in these patients with type 2 diabetes, where maybe there's an increased risk anyway. [SPEAKER_00]: I'm not super concerned, but patients are concerned. [SPEAKER_00]: I wouldn't want to go blind.

57:55 [SPEAKER_00]: So we try to talk about these, try to talk about the data. [SPEAKER_00]: I would just say, look, the signal's not there in the most recent analysis. [SPEAKER_00]: It's in some aguletite only and those with type 2 diabetes, potentially maybe there's some plausibility there, but I would just if it's there, it's extremely rare.

58:12 [SPEAKER_02]: Yeah. [SPEAKER_02]: All right. [SPEAKER_02]: I feel satisfied there. [SPEAKER_02]: We can now move on to some of the other risk risks and potential side effects that would maybe be pertinent to our listenership because we're talking about gains, talking about body composition and performance.

58:25 [SPEAKER_02]: So, Austin, you know, a lot of people talk about the potential risk of losing [SPEAKER_02]: all of your muscle when you go on these agents, you know, um, maybe speak more broadly about little look. [SPEAKER_02]: Why is losing lean body mass a problem with weight loss in general? [SPEAKER_02]: And then what is the long-term consequence of that, you know, for for health and performance?

58:45 [SPEAKER_01]: Yeah, before we get into that, I do think it's worth pointing out because a lot of these terms can get conflated and definitions can get baked into one another in ways where one audience might hear and interpret this term [SPEAKER_01]: Body composition science is complicated and I know Spencer will get into this a little bit as well but what is lean body mass mean, what is fat free mass mean, what is muscle mass mean, you know, all these things have very specific definitions and so it's important to be clear on what you're talking about.

59:17 [SPEAKER_01]: So the the haters as Spencer for them described them earlier use this kind of terminology and they they seem to imply that these drugs have a unique [SPEAKER_01]: effect on reducing or impairing your muscle mass in particular. [SPEAKER_01]: Potentially baking in bone bone into that as well.

59:36 [SPEAKER_01]: and that's a strong claim that would require direct evidence showing that when these medicines are used, that there is a substantially greater degree of specifically muscle mass and or bone mass compared with equivalent amounts of weight loss by other means. [SPEAKER_01]: When we look at this, we'll get into the specifics of what's observed, but it is a valid concern just to address your [SPEAKER_01]: If people are losing significant amounts of muscle mass and bone mass, yeah, I would have some concerns about that.

1:00:09 [SPEAKER_01]: I see the end stages of frailty, Kekexia, people who have severe sarcopenia, osteopeneia, osteoporosis, people who fall, they lose their physical independence, they have fractures, they need to go to nursing homes, things like that. [SPEAKER_01]: I've been seeing that my entire medical career so far in the hospital setting, and it's not like I have seen, for example, over the course of the past decade.

1:00:29 [SPEAKER_01]: Oh, gosh, I'm admitting these people left and right for [SPEAKER_01]: GLP-1 induced arste osteosarcopenia and they're all needed to go to nursing homes because they can't stand up out of a chair anymore. [SPEAKER_01]: Right. [SPEAKER_01]: And so that's kind of where a strong claim is going to need some strong evidence to support it or, you know, we need to look at it more directly.

1:00:46 [SPEAKER_01]: So those are some of the reasons why we care about lean body mass is that risk of [SPEAKER_01]: long-term musculoskeletal health, physical function, independence, things like that. [SPEAKER_01]: And so that would be the question, is do we see higher rates of those things specifically being impaired from the use of these medicines compared with, if you lost 15%, 20%, 25% whatever amount of weight loss through diet or through metabolic bariatric surgery?

1:01:06 [SPEAKER_01]: Do you see that more? [SPEAKER_01]: Do you see it less? [SPEAKER_01]: Does it seem to be about the same? [SPEAKER_01]: Are there ways if it's a real thing? [SPEAKER_01]: can we mitigate it and what exactly are we talking about? [SPEAKER_01]: Is it muscle? [SPEAKER_01]: Is it bone? [SPEAKER_01]: Is it just lean body mass?

1:01:17 [SPEAKER_01]: Which includes body water? [SPEAKER_01]: All sorts of other, you know tissue compartments and things like that organ mass stuff like that. [SPEAKER_01]: So that's kind of my broad take on it [SPEAKER_02]: Yeah, just to summarize for the listenership, the claim is, you know, by again, the haters, is that these particular drugs, the anti-obc medications at large, have a unique effect on the skeletal muscle tissue.

1:01:41 [SPEAKER_02]: that results in more proportional muscle loss per unit weight loss. [SPEAKER_02]: And what's widely quoted in literature for just like diet-induced weight loss is that about 75% of the weight you lose is going to be fat mass, and 25% is going to be not fat mass. [SPEAKER_02]: And some of that is going to be actual scale to muscle fibers, but to Austin's point, some of it's just going to be other things that aren't muscle, but are also not fat.

1:02:07 [SPEAKER_02]: And so, [SPEAKER_02]: literature than would show you that per pound people lose when they take these medications, that more than 25 percent would be not fat mass that people were losing. [SPEAKER_02]: So the question to you, Dr. Nidolsky is, what do you think about their actual risk of losing skeletal muscle mass in relationship to this drugs?

1:02:27 [SPEAKER_02]: I mean, again, there's been a problem that's been a lot of concern over this on social media, especially in the fitness space. [SPEAKER_02]: Is this a real risk? [SPEAKER_02]: Like, is that is this real? [SPEAKER_00]: Yeah, some history around it really is the Peter Teev, which my brother and I call our podcast, the Peter Teev, a hate or podcast in not because he's generally okay, it's just the some hyperbolic statements.

1:02:47 [SPEAKER_00]: He was on the Megan Kelly show a couple of years ago and said that, you know, his patient got fatter. [SPEAKER_00]: quote, fatter on this medicine, they lost more muscle than they did fat, it's kind of interesting, nice anecdote there. [SPEAKER_00]: But then he has pulled up that the the step trials, there was a subgroup analysis, they did a subgroup dexa of some of these patients that used [SPEAKER_00]: the step trials, which was the obesity trials with some agthide, high dose of agthide, and it looked like somewhere around 38 or 39 percent fat-free mass loss.

1:03:21 [SPEAKER_00]: So it's kind of like, well, that is more than we'd expect, but Dr. Brocky said, fat-free mass loss isn't necessarily muscle. [SPEAKER_00]: So when you look at a dexist scan, and this is why I have chief science officer Grant Tinsley, he's literally a body composition expert. [SPEAKER_00]: He would talk circles around me in terms of how to look [SPEAKER_00]: these different compartment models where they look at body composition because a Texas game like, oh yeah, you got your body fat percentage there, but it's it's because it looks at fat free mass and fat mass.

1:03:57 [SPEAKER_00]: And so like, pretty much everything that's not fat mass. [SPEAKER_00]: Like, oh, they lost this much fat free mass, but a lot of that includes glycogen. [SPEAKER_00]: in the in the surmount data that turns out that data is around 25% so a longer drug that that resulted in more weight loss actually resulted in about what we would expect amount of fat remas loss which we assume if we're just making assumptions has a similar composition of that fat remas loss with with muscle so similar to what we'd see with just dieting alone [SPEAKER_00]: or bariatric surgery alone.

1:04:35 [SPEAKER_00]: So then the claim would have to be something about some magletide specifically is extracatabolic beyond its ability to help people. [SPEAKER_00]: uh... lose weight beyond this calorie deficit and there's nothing biologically plausible to make that accurate what i personally think is that there's some sort of fluid shift because of the glp one receptors we've uh... doctor brachie talked about the kidney's in the flow trial i don't know if there's some diet that resists affect there's some fluid shifting [SPEAKER_00]: But it's very possible what looks like an increased fat-free mass loss is literally glycogen or fluid changes.

1:05:12 [SPEAKER_00]: That's what I think. [SPEAKER_00]: Because otherwise, it doesn't really make sense. [SPEAKER_00]: And having said that, we are doing studies in our online clinic, so we're partying with Dexafit. [SPEAKER_00]: Dr. Tinsley is doing all this where he actually looks at lean soft tissue, so trying to nail it down to closer to the muscle tissue.

1:05:36 [SPEAKER_00]: And we did a case series, but we have a whole cohort going on. [SPEAKER_00]: We don't have the data from that yet. [SPEAKER_00]: And it looks like if you just lift some weights and we're not talking about barbell medicine style, you're freaking obsessed with it. [SPEAKER_00]: Even if you're just kind of like doing one like basic two days a week of like what would be recommended and eating sufficient amounts of protein.

1:05:57 [SPEAKER_00]: You're not loading up your each plate with protein and eating a gram per pound of body weight. [SPEAKER_00]: We're talking like, [SPEAKER_00]: 1 to 1.2 grams per kilogram of body weight even some around there with just a couple to two to three days a week of resistance trading full body or splits, you pretty much mitigated all or minimize it all.

1:06:19 [SPEAKER_00]: So I'm not worried. [SPEAKER_00]: I think [SPEAKER_00]: I think it's good that it's brought this whole thing to the forefront, but I think the whole concern is overblown. [SPEAKER_00]: And I think it's just a reason for what we call wheat stigma where it's like, no, we don't want people to lose weight.

1:06:35 [SPEAKER_00]: They reduce their risk of heart attacks. [SPEAKER_00]: They have less liver disease and kidney disease and fewer strokes. [SPEAKER_00]: But oh my god, they lost some extra fat free mass in there. [SPEAKER_00]: So watch out, these drugs are bad. [SPEAKER_00]: I think it's just, um, people are looking for a smoking gun to say, [SPEAKER_00]: And that's my, that's my, probably my bias opinion, but I'm just from a clinical standpoint.

1:06:56 [SPEAKER_00]: I'm not, I'm not concerned. [SPEAKER_00]: I want people to lift weights and he protein, but like, I'm not concerned if like they don't. [SPEAKER_00]: And, and they lose this amount of that free mass percentage wise. [SPEAKER_02]: Yeah. [SPEAKER_02]: Yeah, two additional points. [SPEAKER_02]: If you actually look at that subgroup analysis in the step trial and you look at the placebo group, uh, who was just doing lifestyle stuff alone, they also lost more proportional lean mass than you'd expect.

1:07:19 [SPEAKER_02]: So to me, it almost is like perhaps there's an artifact of the measurement, uh, technique, at least that's a positive possibility. [SPEAKER_02]: But even the latest trial, the semolina study, where they had folks on max dose [SPEAKER_02]: And I was like, oh, that's interesting. [SPEAKER_02]: Is there a muscle preservation effect?

1:07:44 [SPEAKER_02]: Perhaps even, and there's some animal models to support that. [SPEAKER_02]: I don't think that's true to me that seems like within the realm of what's expected, but I just find these concerns about losing so much muscle mass that now you have sarcopenia because I've reduced muscle function from all that muscle loss due to these medications.

1:08:01 [SPEAKER_02]: That seems like an overblown risk. [SPEAKER_02]: compared to the potential benefits everywhere else across the board. [SPEAKER_02]: Yes, if you have somebody where you have concerns about frailty initially, they're probably not a great candidate for a GLP one or other anti-obc medication, although that does you get a little more tricky when you talk about like sarcopenic obesity, because that was also assessed in the semolina study where they, you know, 49% of the starting population had.

1:08:27 [SPEAKER_02]: I'm sarcopenia as diagnosed by, I think it was a hand grip strength in the appendicular skeletal muscle mass, and then at the end of the year, only 33% had it, so it seemed like even though they lost maybe some lean mass, their actual function or muscle quality improved. [SPEAKER_02]: So I don't know.

1:08:42 [SPEAKER_02]: It seems pretty interesting to me. [SPEAKER_01]: Yeah, this is just not fundamentally a major concern that I have, I agree with Spencer's take in general and just look at the major outcomes that we care about. [SPEAKER_01]: And if somebody says, well, the outcome that I care about is my lean, is my lean mass, and I don't actually care about cardiovascular iskin, kidney risk, and fatty liver risk.

1:09:03 [SPEAKER_01]: diabetes risk and I'm unconcerned with the amount of fat mass the person carries this is my like myopic focus is just only math okay don't don't take the drug like nobody knows what I'm going to make it but every other area of health and like what will call hard outcomes [SPEAKER_01]: things that we really care about the most seem to be benefited, and if we were seeing, you know, because we know that sarcopenia, for example, in osteopeenia and osteopeenia and osteoporosis, they increase the risk of certain things.

1:09:26 [SPEAKER_01]: And so if those risks paned out, we would expect to see those signals in the data. [SPEAKER_01]: I would expect to see, oh gosh, we're seeing way more hip fractures in these patients. [SPEAKER_01]: So we're seeing way more falls, or we're seeing, you know, all sort of, and it's like, if that doesn't show up, then this is an unsub, this remains in the realm of hypothesis, but not something that's going to impact my clinical decision making.

1:09:44 [SPEAKER_01]: So yeah, I agree. [SPEAKER_01]: It doesn't take a ton of training and it doesn't actually take a ton of protein to, you know, mitigate lean mass loss to the extent it's going to happen here, especially in undertrained or insufficiently active people at the start. [SPEAKER_01]: And the training is the thing that I emphasize even more than the protein, like if if somebody is willing to do a bit of exercise, I'm going to put even not that I'm less emphasis on protein, but it's not my like major lever that I care about getting people active in general, not just for the lean mass, but for all sorts of other health benefits as my like.

1:10:14 [SPEAKER_01]: strongest heaviest emphasis for people and and always has been even before these drugs ever existed. [SPEAKER_02]: Yeah, if you looked at like an equalizer, like you got a seven band equalizer, and these are all the variables that affect like the proportion of of mass compartments that are lost and so you have, you know, things like sleep, you have protein intake, you have, you know, these medication use whatever.

1:10:38 [SPEAKER_02]: all well and good, all can certainly affect that, but exercise specifically resistance training is the volume knob. [SPEAKER_02]: Like that, that is the main controller here and so without resistance training, you know, all of these other things are the effects are so much smaller and so, you know.

1:10:54 [SPEAKER_02]: Eventually, we're going to get a study where people are using these agents and actually lifting weights, like no shit, they're actually lifting weights and then we're going to see either the results. [SPEAKER_02]: I suspect they'll be very positive. [SPEAKER_02]: And then at that point, we should follow up with the T with some other folks who have expressed strong concerns about this and be like, what now, you know, there's a study that's it's, um, [SPEAKER_00]: They presented it.

1:11:19 [SPEAKER_00]: It's not published. [SPEAKER_00]: It's called the T-Rex study. [SPEAKER_00]: So funny story with my brother and I with Brad Schoenfeld. [SPEAKER_00]: If you know who that is, went to Lily again. [SPEAKER_00]: I'm like, come on. [SPEAKER_00]: I'm the biggest Lily, Lily lover. [SPEAKER_00]: But they decided to go with a different study.

1:11:34 [SPEAKER_00]: Apparently, they probably, probably a good choice. [SPEAKER_00]: They're like, what the hell is this guy on podcast? [SPEAKER_00]: He doesn't know what the hell he's doing. [SPEAKER_00]: They chose a different team. [SPEAKER_00]: They, they showed it. [SPEAKER_00]: I saw the slides from the [SPEAKER_00]: from the conference where they showed a decrease compared to, I believe, the standard of care group, a decrease in fat free mass loss.

1:11:54 [SPEAKER_00]: So as we'd expect, as though it was pretty, they'd cut it in half and that's kind of what I'm seeing. [SPEAKER_00]: I'm seeing cutting in half versus like none at all. [SPEAKER_00]: uh, when people are, are lifting weights. [SPEAKER_00]: So, pretty cool. [SPEAKER_02]: Yeah. [SPEAKER_02]: So, basically, again, what I'm hearing you say is that if you take to zip a tide, put creatine plus resistance training and a little bit of TRT, it's basically a PED cocktail.

1:12:14 [SPEAKER_02]: Is that what we're talking about here? [SPEAKER_00]: Yeah. [SPEAKER_00]: I mean, I'm sure you, I've talked about all the miles that in inhibitors yet. [SPEAKER_00]: Oh, yeah. [SPEAKER_00]: I'd guess. [SPEAKER_00]: I mean, they're, they're studying it. [SPEAKER_00]: The thing is, [SPEAKER_00]: It might be overblown, like we're, of course, barbell medicine, or, you know, I'm obsessed with muscle on that type of thing.

1:12:30 [SPEAKER_00]: It's, is it possible that we're overstating the benefit. [SPEAKER_00]: We don't want people to get frail, but like, is it possible that we're overemphasizing it? [SPEAKER_00]: I don't know, we'll see, because if people live longer and live better with his, uh, milestone inhibited, [SPEAKER_00]: drugs, then everybody's going to be jacked, ripped and just like it's going to be an interesting.

1:12:51 [SPEAKER_00]: I don't know. [SPEAKER_02]: Yeah, just walk around at that point. [SPEAKER_02]: At that point, we will have to reject BMI. [SPEAKER_02]: There'll just be too many jacked people just walking around or like, all right, well, we need another scale here. [SPEAKER_00]: So yeah, forget BMI. [SPEAKER_00]: I mean, yeah, so actually, that was a big part of the conference and not another tangent, but like [SPEAKER_00]: going way past the BMI at this point.

1:13:07 [SPEAKER_00]: I'm sure you've talked about this, but we know that the BMI is actually, it does a decent job. [SPEAKER_00]: We're not everybody's NFL linebacker. [SPEAKER_00]: Most people are not out of NFL linebacker walking into the clinic, not everybody's Jordan and Austin walking into the clinic. [SPEAKER_00]: And if they were, I would look at them and be like, it cares what their BMI is.

1:13:26 [SPEAKER_00]: Somebody should do that, but pretty cool that we are looking at body composition. [SPEAKER_00]: I think it's [SPEAKER_02]: Yeah, all right. [SPEAKER_02]: Well, let's wrap this up with maybe one of the more controversial parts of this podcast. [SPEAKER_02]: We save it for last because if people tune out, then they won't send us hate mail.

1:13:41 [SPEAKER_02]: how hard is it to get these medications? [SPEAKER_02]: You know, we've got some new government policies potentially coming down the pike. [SPEAKER_02]: It's going to make these more accessible, but to you, Spencer, what is the biggest hurdle for people to gain access and maintain access to these sort of medications?

1:13:57 [SPEAKER_00]: Yeah, it's cost, the cost, server-daculous. [SPEAKER_00]: You see it over here in the United States, there's these middlemen, these farms eat benefit managers and because of rebates in the way they structure it. [SPEAKER_00]: with the manufacturers and go to the insurances and the pharmacies instead of being like five hundred six hundred bucks net price they see this list price of twelve hundred dollars of the pharmacy twenty to thirty percent of commercial insurance is prove it actually is probably going to go down here because of the cost of these medicines so that is probably the biggest thing we see we're going to see that improved over over this this next [SPEAKER_00]: Few years though, they just announced lowering the prices if you go directly with the manufacturer.

1:14:38 [SPEAKER_00]: There's some new prices with Medicare that we weren't seeing before that just were announced to price by far price. [SPEAKER_00]: It used to be, well, price and then access, there's a lot of weight stigma, but now everybody's asking about them. [SPEAKER_00]: Primary care doctors are feeling more comfortable with them.

1:14:54 [SPEAKER_00]: So like they're the excess isn't as big of a deal with finding a doctor who's comfortable doing it. [SPEAKER_00]: It's really the cost. [SPEAKER_00]: And I think it's I think we're going to see in five to ten years just the prices are going to be very low, but it's not so much right now.

1:15:10 [SPEAKER_02]: What's the what is the role of vineyard like what is how does vineyard fit into to to all of this for access and and maybe. [SPEAKER_02]: Making sure that people are getting the lowest available cost is that something that vineyard. [UNKNOWN]: Yeah. [SPEAKER_00]: Yeah, so our big thing is like, look, because primary care offices aren't equipped with prior authorization specialists, they don't even, I mean, we get referrals from primary care because they, they're back office simply cannot handle the amount of prior authorization.

1:15:36 [SPEAKER_00]: So if anybody knows what that is, you're basically asking insurance permission, can I write this drug that I recommend for my patient? [SPEAKER_00]: And they have to jump through these hoops of answering all these questions. [SPEAKER_00]: They make it tougher and tougher because they don't want to pay.

1:15:48 [SPEAKER_00]: And so I was like, all right, that's just one of the biggest pain points. [SPEAKER_00]: I have to hire a prior authorization specialist to handhold the process of going to that. [SPEAKER_00]: So that's one thing. [SPEAKER_00]: Obviously, we're special in the... [SPEAKER_00]: feel to where like we know the dosing better.

1:16:04 [SPEAKER_00]: We know the interactions and how to adjust other medications with losing weight. [SPEAKER_00]: We're going to focus on resistance training. [SPEAKER_00]: We have dietitians to minimize side effects and optimize your whole journey. [SPEAKER_00]: So that's a big thing. [SPEAKER_00]: We're going to try to get at the lowest cost possible for you, but we're also going to hand hold you.

1:16:21 [SPEAKER_00]: through the process to make sure your side effects are minimized, your body composition is optimized and you just have the best time and you can chat with us online texting us as opposed to waiting a whole month ago see your primary care doctor. [SPEAKER_00]: That's just it's very quick replies but also expertise is unparalleled.

1:16:42 [SPEAKER_02]: This is actually a little tangent to that topic about cost and the way I view it and the way I kind of explain it is that you have these not only brand name but just prescription medications and those are the highest cost tier and then you have compounded versions which you still need a prescription to obtain but much lower cost and then you have research chemicals which are even lower cost and you don't need a prescription for.

1:17:07 [SPEAKER_02]: How do you kind of view the risk benefit analysis across that continuum, you know, and do you have these conversations regularly with patients? [SPEAKER_02]: Because they're like, look, I like what you're saying. [SPEAKER_02]: I like the benefits, but that cost that price point is just too much.

1:17:24 [SPEAKER_02]: So is there ever like a scenario where you think of like permissive use? [SPEAKER_02]: So you're like, oh, look, man, I don't love these compounded versions, but I actually think the benefits outweigh the potential risks like, [SPEAKER_00]: Yeah, the problem with the compounded versions is that they haven't been studied for safety or efficacy.

1:17:41 [SPEAKER_00]: Now, if you look at the, you can see Reddit and I've had patients come from the compounded versions, they've lost plenty of weight, but because of the nature of the compounded industry, you'll never have safety data. [SPEAKER_00]: You can't do an FDA, you can't do a trial because the ethics committee would be like, no, you gotta use an FDA branded version.

1:18:01 [SPEAKER_00]: there's concerns over where they're getting the source to active pharmaceutical ingredient, and if they're making it in a certain way that's making immunogenicity, immunogenic material that wasn't detected, it's a lot of different things and that might be big pharma, fear mongering against the compound version.

1:18:19 [SPEAKER_00]: So I usually just say look, [SPEAKER_00]: If you cannot get, if you can't afford the FDA approved versions and you can't get it direct. [SPEAKER_00]: Like it's getting a lot cheaper now and it's getting similar, almost similar costs of the compound, it's still more expensive. [SPEAKER_00]: I can't personally attest to the safety of the compounded versions.

1:18:40 [SPEAKER_00]: I sure as heck can't attest to the research grade peptides. [SPEAKER_00]: Now the thing is you'll see there will be some analysis where it's like 99.5% pure. [SPEAKER_00]: as pure as a pharmaceutical grade version, and then they'll do it analysis on the next batch, and there's nothing in it.

1:18:57 [SPEAKER_00]: It's it's actually insane. [SPEAKER_00]: So like you would have to verify every single batch that you got. [SPEAKER_00]: I wouldn't mess around. [SPEAKER_00]: I would never have a family member mess around with [SPEAKER_00]: research grade. [SPEAKER_00]: I wouldn't recommend compounded versions, but you know, I'm in a, you know, if you want to call it a privileged position to wear like, you know, we could get them the FDA approved versions.

1:19:17 [SPEAKER_00]: So I don't, I don't get mad at people for going to the compounded versions because of affordability. [SPEAKER_00]: What I do say is that the the pain of that in the next few years, I think it's going to be so we're going to look back and be like, oh, wow, those are crazy [SPEAKER_00]: not to get the FDA approved version because they're going to be so much cheaper.

1:19:38 [SPEAKER_00]: Again, we're just going to go through the pain in the next few years, unfortunately, to get there. [SPEAKER_02]: All right. [SPEAKER_02]: Final question to Dr. Barackie. [SPEAKER_02]: Well, like we've been talking about some aglytide, Giuseppe Tide, and the future. [SPEAKER_02]: What about older anti-obesity medications and, you know, what about microdosing?

1:19:55 [SPEAKER_02]: Because people talk about that too. [SPEAKER_02]: So, yeah, I thought some of these older medications and also microdosing because we want to be fashionable. [SPEAKER_01]: Yeah, I think the question about older meds fits in nicely with the conversation that you just had around, you know, balancing risks and benefits of, you know, the non FDA Proversions if you're either going for considering a compounded version or you're going like Chinese bathtub level peptides or something like that.

1:20:17 [SPEAKER_01]: Because we have at least as much arguably much even more experience with some of the older anti-obesity medicines now What are the downsides of them? [SPEAKER_01]: Many of them are not quite as potent in terms of their efficacy Some of them come close and but the upside is that in general they are way cheaper They have maybe some of their own inconveniences.

1:20:36 [SPEAKER_01]: I've had plenty of patience for example [SPEAKER_01]: You know, the brand name Cusimia or Fentermintoperemate is one that is probably the most potent and has the best efficacy among the older ones. [SPEAKER_01]: It's an oral agent when it comes in the combination form that's branded. [SPEAKER_01]: It might be a little bit less accessible for some folks, but it's also something that for somebody who's willing to go through with it and deal with a little bit more inconvenience prescribed that meds separately in generic form and, you know, it can do its thing.

1:21:00 [SPEAKER_01]: potentially as a way to get people through this like temporary ideally period of discomfort or pain that spends or described until the cost and the price has come down. [SPEAKER_01]: So I think they do still have a role for now. [SPEAKER_01]: They can be used in conjunction with GLP ones.

1:21:15 [SPEAKER_01]: They can be used on their own. [SPEAKER_01]: They can be a bridge on or a bridge off. [SPEAKER_01]: There's all sorts of different creative strategies that we can use when using things like again, Benjamin Topier Mate. [SPEAKER_01]: Less favorite is going to be appropriate on Naltrexone, but I've had plenty of patients who've used it with varying levels of success Some who did great some who didn't do as well some who didn't get as much of a who kind of fell somewhere in between And which is going to be the case for most interventions and then some patients who have very interesting Maybe disproportionate responses to certain things to Fentermine monotherapy just by itself, which is not something that many of us use too often anymore, but you know once in a while A patient will respond really well to that or to appear a major to some

1:21:51 [SPEAKER_01]: you know, antidepressant category type medicines that for some patients have appetite modifying type effects and things like that. [SPEAKER_01]: So bottom line is they do still have a role. [SPEAKER_01]: They tend to be less expensive. [SPEAKER_01]: They have their own unique pros and cons that you need somebody who has expertise and experience with them to be able to discuss with the patient.

1:22:06 [SPEAKER_01]: And then be able to monitor their therapy and things like that over time and hopefully to keep kind of poking at this and engaging with this process to see when does the cost benefit become, you know, within reach for you or become accessible or do you Maybe unfortunately develop a condition that would qualify you for one of these things in a different way these are all things that would be paying attention to [SPEAKER_01]: So that's my take on the older meds and then lastly the micro dosing topic that's another thing that you'll see popularly on social media It's not something that I don't think either of us is gonna routinely be recommending for people mainly because we don't have the quality of evidence behind those strategies for the types of outcomes that we're looking for in terms of be at weight loss

1:22:46 [SPEAKER_01]: blood sugar control, cardiovascular risk, kidney liver, all these other sorts of things. [SPEAKER_01]: I can't say with confidence that using those levels of doses is going to get you those outcomes that you might be interested in. [SPEAKER_01]: Now, the caveat there is that when you are an independent practicing clinician who feels confident with your practice, because I end up doing this with a lot of other things, you can do stuff off label all the time if you are comfortable with it, if you have a sense of the potential benefits, the potential risks.

1:23:11 [SPEAKER_01]: You're able to discuss this with your patient, and so where that might come more into play, and probably does more regularly come into play, is dosing for tolerability, right? [SPEAKER_01]: And so we know that tolerance, the side effect risks that we talked about earlier, the overwhelming majority of it is going to relate to dosage.

1:23:28 [SPEAKER_01]: And so tinkering with dosages is probably the way that we end up dealing with most of the side effect kind of profiles, whether going to, you know, even tiny or tiny or doses, [SPEAKER_01]: process to be even longer, you know, a lot of the traditional dosing regimens that's going on this dose for four weeks and then you bump it up from there, etc.

1:23:47 [SPEAKER_01]: I could stretch that out longer if I wanted to. [SPEAKER_01]: I could keep you on a lower dose for longer or increment you in a smaller way. [SPEAKER_01]: If you're comfortable with these things, you can use those types of strategies. [SPEAKER_01]: But it's not going to be a standard recommendation for us at this time until or unless we have [SPEAKER_01]: better quality data.

1:24:02 [SPEAKER_01]: I'm not going to go out making grandiose claims about if you just micro dose, you'll get these like life-changing benefits with no side effects or risk or something like that. [SPEAKER_01]: I don't have concerns about risks at the very low doses and that's why we would use those potentially as a strategy for tolerability but not really so much outside of that.

1:24:17 [SPEAKER_01]: So that's my take there. [SPEAKER_02]: Excellent. [SPEAKER_02]: All right, well, to sum up. [SPEAKER_02]: The data is clear. [SPEAKER_02]: The new Anti-OBC medications, especially those targeting multiple receptor pathways, while they're offering efficacy that rivals metabolic and bariatric surgery with improved tolerability and their showing clear benefits for cardiovascular kidney and liver health, with additional potential in the future.

1:24:41 [SPEAKER_02]: If you'd like to have a discussion with professionals about this, you can click on the link in our description below in the show notes. [SPEAKER_02]: You can connect [SPEAKER_02]: That's Dr. Dittolsky's company, and Austin will be starting there, shortly so if you want to work with Dr. Baracky, there is not just weight loss.

1:24:58 [SPEAKER_02]: Spencer, can you talk to some about some of the other stuff that you guys deal with? [SPEAKER_02]: I know you mentioned Cardio Metabolic Health at the onset, but yeah, what can people expect if they end up heading to vineyard? [SPEAKER_00]: Yeah, so think about obesity, but also obesity, Jason, Cardio Metabolic Health.

1:25:14 [SPEAKER_00]: Lip is cholesterol. [SPEAKER_00]: We also help with things like [SPEAKER_00]: easy things like hair loss. [SPEAKER_00]: If you're losing your hair from [SPEAKER_00]: from the weight loss, we can jump in with monoxidil. [SPEAKER_00]: If you're a guy and you just have an endogenic hair loss, we can do a little finaster.

1:25:31 [SPEAKER_00]: We can't call ourselves primary care. [SPEAKER_00]: We like to stick to the card or metabolic, but we can do some of these other things that places these pill mills that you see. [SPEAKER_00]: We pay $50 a month. [SPEAKER_00]: We can send it to places like Mark Cuban, if you're insurance doesn't cover it.

1:25:45 [SPEAKER_00]: So even skin care, like Trent no one, but think about blood pressure, lipid, [SPEAKER_00]: and uh, weight loss is in general and anything kind of adjacent to that. [SPEAKER_02]: There you go. [SPEAKER_02]: And for all your training and nutrition needs, you can check out Barbell Medicine, but before you guys go anywhere, please leave us a five-star rating and uh review.

1:26:02 [SPEAKER_02]: It really helps drive traffic to our podcast so we can keep bringing you all the latest nuance and health and fitness, special shout out to Dr. Niddolski and Dr. Barackie for joining me, Dr. Jordan Fagginbaum. [SPEAKER_02]: On the Barbell Medicine podcast, we'll catch you next week and every week right here on the Barbell Medicine podcast.