GLP-1s and Muscle Loss: Where Are the Strength Trials?

All right, a question that's going to annoy both of us not because we're sick of talking about it cuz we aren't obviously but just like we're not in control. Where are the GLP-1 strength trials? The question is, I've recently been re-listening to your podcast about lean mass loss on GLP-1 medications. You stress the confounders that include water, glycogen, etc. It would seem that the most obvious trial should then be on strength. Person puts in capitalized letters. Medications versus placebo, training versus not. Are any of those coming down the pipe? Look, we agree. This would be awesome. Strength to both in both of our opinions is the right primary endpoint to sort of resolve this debate of whether GLP-1s cause excessive muscle mass loss. Now, I want to just back up for a second. This idea that you can lose an excessive amount of muscle. Like, what does that even mean, right? Excessive to what end? Excessive to harming health? Excessive to harming performance? Those are two different questions, for example. And we think about excessive for harming health and an individual with obesity who would be you know, likely benefit from GLP-1 agonists. That's a much bigger range, you know, like a you the person have to lose a lot of muscle mass um in order for that to happen. Um whereas a person would only have to lose maybe a little bit of muscle mass for it to actually uh reduce performance if you were testing something like a one-rep max, particularly in a trained individual. In untrained people, again, the calculus changes. So, little review of the literature. There is the S-Lite trial. We've talked about this on the podcast before. This is uh this was done in Copenhagen and published in the New England Journal of Medicine in 2021. They had uh over 200 adults with uh obesity. Um they were on a calorie-restricted diet um and then uh to drop 12% of their body weight. Then, they were randomized into four groups. They either got liraglutide, it's an older GLP-1 agonist, exercise alone, they got both, or they didn't do any exercise and they got the placebo liraglutide. The exercise in this trial was mostly aerobic. They didn't do any heavy lifting, uh but they did test strength as a secondary outcome using basically a fancy leg extension machine. The combined group, so liraglutide and exercise, uh preserved um and improved actual knee strength, which is kind of what you see when people are like, "Oh, can you aerobic training increase strength? " Like, well, yeah, particularly in an untrained individual cuz they're being more active. The drug alone group did not show any meaningful strength decline compared to placebo despite losing more weight. Uh and then a follow-up analysis, this is more recent in 2024, um showed that exercise groups also uh preserved uh bone density at the level of the hip, whereas the drug alone group lost some measurable bone density at the hip. This is the same thing you see with weight loss generally speaking without any sort of exercise. Uh this is the probably closest trial that's actively been published um looking at what you're asking for. Um there's another study we've talked about a number of times called the Semaglutide study. Um this is by Alesso, and um they took 106 adults with obesity. Average age was 52. Half of them met criteria for sarcopenic obesity at baseline. Um after a year on max dose semaglutide with no prescribed exercise, um fat mass dropped 18% on average. DEXA, so using X-ray technology, measured uh lean mass dropped at around 5% and it stabilized at month seven. Now, interestingly, their hand grip strength increased by an average of 4. 5 kg despite not exercising. Um and so the number of subjects meeting the sarcopenic obesity criteria dropped from half um to 1/3, which uh is pretty good, especially with no real exercise. We think that one of the major mechanisms here is the reduction of intramuscular fat, and that allows the muscle to um function a little bit better. And so again, it's pointing towards what you want, but it's not the study that you want. So, some things that are coming down the pike. The T-Rex trial, I think Dr. Nadolsky when we did our GLP-1 teaching rounds episode alluded to this. It's not published yet, but this study's being done in Australia right now, and basically they're pairing GLP-1s with structured resistance training versus medication alone. And strength end points are being tested. Again, the preliminary results show that resistance training is preserves a significant amount of lean body mass. You know, and typically what we see in non-GLP-1 trials is about half of the lean mass loss that's seen gets preserved with resistance training. This seems to be doing about the same. It's not out yet. We'll see. There's also the lean prep study. I think I sent that link to you earlier. And they're going to have people on GLP-1s doing some legit strength training, and strength outcomes are the primary end point, which is going to be interesting. Couple other studies to know about. One is the BELIEVE trial. This was published earlier this year by Hemsfield. They

tested bimagrumab versus plus semaglutide. Now, bimagrumab is this drug that kind you can think about it as like a myostatin inhibitor sort of drug that targets that's active in two, as I recall. And so the thought would be like, "Well, look, if you turn that off, people are going to be able to grow muscle and lose fat at the same time. " And so the combination lost 22% body weight, but 93% of it was from fat. And when they compared that to semaglutide alone, they lost a similar total amount of weight, but 72% was fat. So, they lost a little bit more lean mass. The grip strength, interestingly, was the same in both groups. So, kind of speaks to this idea that maybe we're picking up a sort of false flag when we look at body composition analyses in these studies, and we've talked about that a number of times on this podcast and also in our article. The quality study is another one to know about. It's an obasarm plus semaglutide. Now this is a selective androgen receptor modulator. So you can think about like a anabolic steroids that studied abroad. It does it a little bit better those effects. It selectively targets the androgen receptors. Um preliminary results uh show that uh stair climb power dropped by 10% or more in half of the semaglutide alone group versus 16% um in the combination group. Uh this is the first industry trial with a functional endpoint showing a positive signal for this drug although an obasarm is not approved yet. So I don't Yeah. Be curious to know if that ever comes down the pipe. We'll see. There's a phase three trial plan so perhaps that that will happen. Also Regeneron is running multiple phase two trials of uh trevogrumab which is another one of these myostatin uh inhibitor type affecting medications plus semaglutide so we'll see. But they're going to use hand grip and stair climb um endpoints as well not They what are they one rep max leg press do? Like that if there was a barbell medicine study it would be like Let me just sketch this out. It'd be semaglutide alone, tirzepatide alone, semaglutide plus resistance training, tirzepatide plus resistance training and then you just test one rep maxes periodically and see what happens. See if there's a difference. Not that I expect there to be one but I'm just more curious and if I could do this study I get I'm going to do it the way I want. Okay. So often here's a clinical situation. When patients ask you about GLP-1s and strength specifically how do you frame where the evidence is and what you sort of predict for their trajectory here? Yeah. Digging into a little bit of where the question is coming from can be helpful because it matters kind of what messages they've already received and internalized what their fears are and helping them kind of properly weigh the potential risks against the potential benefits when it comes to initiating a treatment like this. You know, it's interesting. You were talking as an aside about some of these studies that have recently come out, including the bimagrumab semaglutide combo, and that was not only previously shown like, yeah, insane, you know, almost pure fat loss and even some, you know, accretion of muscle mass in those groups. And then more recently within the past week, there have been a bunch of longer-term trials that have been published and released data on, including So, like, what happens when you either come off or go down in dose or look for maintenance regimens. And unfortunately, when people came off of that combination, as we expect when coming off of a GLP-1, the tendency was towards some weight regain. But also, when those when folks came off of the bimagrumab, there was also a tendency towards losing the mass that had been accrued while receiving that monoclonal antibody. Biology does its thing yet again. It's undefeated in this in this situation. But, [snorts] you know, it's interesting to me I think that over the long term, this is going to end up becoming being way less of an issue than it has been viewed as to date. That's the first kind of hot take. There are, again, potential benefits and risks on both sides. And if we are shifting like wholesale population body mass downward, yes, there's going to be overall net benefit on the population because our population tends to skew towards the obesity end of the spectrum, right? If we were in another situation where we were in famine times, then our population would skew towards the low end, then the risks would dramatically outweigh the benefits on a population level for the use of GLP-1. So, it's just kind of shifting populations and trying to target the use of these medicines to those who are most likely to benefit. That's why once I see somebody who's on a GLP-1 and their BMI starts to creep all the way down, let's say to like 22, we're dropping to 21, I'm like, okay, we're not really, you know, we probably shouldn't be aiming to push things too much lower here from a body weight standpoint just if we're going to go based on BMI alone. The last interesting little thing, and this is a thought that came to mind while you were kind of laying out some of these study data. How interesting it is of where the fears and the messaging comes from the measurement methods in the trials, right? So, the simplest example is just the use of DEXA, and we've beaten that to death. We've been like, "Yeah, DEXA just shows like, {quote} lean versus, you know, non-lean or fat mass. "

But, when people read lean and they assume that is equivalent to muscle, then all these catastrophic headlines come out going all the way back to the early days of GLP-1s when, you know, Peter Attia went out on the news and said some just absolutely idiotic comments like, "My patients are taking this, and some people are actually getting fatter because they they're It's like, bro, no, that is not happening. That was nonsense, right? " And so, the the hysteria was an artifact of the fact that we used DEXA, right? What if we even had some other metric of, yeah, just muscle mass, and that went down a bit, right? There would still be some apprehension, some anxiety around it. What made me trigger this thought is when you mentioned there's this study of like, yeah, the essentially myostatin inhibitor where muscle mass increased, and everybody should be like celebrating it. But, what if the outcome was instead like strength-to-mass ratio or something like that? I mean, you told me that their strength did not actually improve. They get, you know, muscle mass is just like the final kind of common pathway to force generation. But, actually producing force, demonstrating strength requires integration of like the whole neuro neurological signaling, coordination, all those other things that a GLP-1 doesn't train. So, it's not shocking or surprising that just like putting on some slabs of muscle does not necessarily make you stronger in the absence of training or exposure to a particular stimulus. And so, let's say that from the beginning they had, you know, used 1 RM leg press to muscle mass ratio or something like that in these trials. Like, you would likely have come away with a very different set of, you know, conversation, concerns, discussion about these studies compared with these like much more crude metrics that are more prone to misinterpretation, I would say. So, to come back to the original question, like if the patient is concerned about strength, I want to get a sense of like, well, where is their strength now and what are they doing to either maintain it or build it? And then frame the whole conversation around, well, the use of this GLP-1 is intended to maybe improve your metabolic health, maybe improve your fat mass. And as long as you are training and using this muscle, you should do just fine as long as you're you know, following it even mildly reasonable strength training program. If I can get you to do it twice a week, full body, 20 minutes or something like that of something that's like kind of hard, you will likely be just fine on these medications. And if we have an early sign, for example, that things are not going just fine, we can, you know, take a breather, we can pause, we can talk about a strategy, we can adjust the training if we need to. If we need to stop the medicine for a little bit, there's no harm in that, either. We'll we'll figure it out. So, trying to not make this like a catastrophic thing, but really fundamentally hammering on the point that like training is the key here, using the muscle that you have rather than worrying about the absolute quantity of it quite as much. Yeah. Yeah, I mean, and I think you can go down multiple lines of the evidence, you know, muscular power, muscular strength far out perform muscle mass when it's directly met, you know, MRI or CT, you know, much more accurate than DEXA out for longevity prognostics, for example. And to your point, the increase in lean mass as measured by DEXA, you have to be skeptical of that. We saw this in some of the peptide drugs, although MK-677 is not a peptide drug, it's a small molecule drug. It increases lean mass, but people don't get any stronger because the lean mass is not coordinated, it's not contractile, it's probably just water, for example. But we see this in DEXA studies on people not using GLP-1s. Glycogen loading, for example, can shift DEXA up 1 to 2% for muscle mass and is literally just carbs and water. You know, and there's a um minimal minimum detectable change that DEXA has that's certain uh a certain cut point. There's also um analytical variation within the test itself mostly because it assumes a certain hydration level at the tissue and then it's got its own sort of parameters for what it can and cannot detect. And so, a reader or in this case a listener who's skeptical of, you know, GLP-1s cause all this muscle loss, those headlines should also be skeptical of, you know, this program that is 5 lb of muscle mass in in 8 weeks uh particularly if DEXA is the instrument that's being used. So, anyway, well, I'm sure we'll talk about this again, but yeah, if they would have started out using MRI or CT, I suspect this would not be an issue or if they just use a strength proxy, you know, instead. Yeah.