PeterAttiaDrive #398 AMA86 GLP-1 RAs muscle loss FULL

Hey everyone, welcome to the member-only podcast feed for The Drive. I'm your host, Peter Attia. Welcome to Ask Me Anything AMA episode 86. In today's AMA, we're going to look at the effects of GLP-1 receptor agonists. So these are drugs like Ozempic, Wagovi, and Zepbound. But specifically, we're going to look at the impact they have on muscle. We're going to talk about how much lean mass people actually lose on these drugs and how that compares to weight loss by any other means. We're going to define exactly what lean mass is and how loss of lean mass on DEXA can actually mislead us, how these drugs impact bone mass and fracture risk, the all-important effects of these drugs on strength and physical function, which probably should be the most important metric, the effect of these drugs on different fat depots across the body, who's at most risk for lean mass loss, how to maintain muscle and bone strength on these drugs, and the initial insights of the effects of retatrutide, which is a drug I'm sure many of you have heard of as it's making its way through the peptide cesspool at the moment, but nevertheless will be an FDA-approved drug. in the not-too-distant future. And so people have lots of questions about how will retatrutide affect weight loss, but specifically its impact on muscle mass as well. So without further delay, I hope you enjoy AMA number 86. Peter, welcome to another AMA. How are you doing? Very well, thank you. Awesome. So for today, we are going to talk GLP-1 agonists. And we did our first episode on this about five years ago. It was you and Bob, and back then no one was really paying attention and no one really cared about that episode. And then about a year and a half later, we did a second episode on them, and all of a sudden people really started to care. And so thinking back at this, what do you think it was about that second episode that got so many people's attention on this? I mean, if I were to think about it through the arc of the story of these drugs, I think it was. Obviously the impact on weight loss. I mean, my first foray into GLP-1 agonists clinically was in 2014. So 12 years ago, I started experimenting with liraglutide in patients, found it relatively uninspiring. And for that reason, given the cost and the logistics, kind of abandoned it. And I think when we did our first episode, we were already seeing the effects of semaglutide and how different it was. And so I think it was a really good episode. And I think it was a really positive one because this was now the third generation of GLP-1 agonists. And we realized internally, frankly, I think by, I recall it being in the fourth quarter of 2020, that this was a step function change from the first two. And I just suspect in the answer to your question that I think there was just a. There's a tight lag between when the public sort of came to realize that. Of course, the implications of that were that this was a drug that went from being kind of a niche diabetes drug to, you know, it was a drug that was kind of a niche drug to, you know, this was a drug that went from being kind of a niche diabetes drug to, you know, it was a drug that was kind of a niche drug to, you know, it was a drug that was kind of a niche drug to, you know, it was a drug that was kind of a niche drug to, you know, it was a drug that had far more appeal because it was now for the first time being looked at for weight loss in a non-diabetic. And so that, you know, kind of changed everything. And at the time, you know, the FDA was really just looking at weight loss. They weren't looking at body composition. And so, you know, I think that's sort of, that was the beginning of the story. Just to kind of double click on that, when you started to use these a little more, what were you seeing and what kind of jumped out that could have been problematic? Well, you know, what we saw in the early trials, and I think what we were seeing clinically five and a half years ago was that people who were losing a lot of weight seemed to be losing much more lean mass than we normally saw in people who were going about weight loss using the normal variations of caloric restriction. I mean, I don't know if that's the right word, but the normal variations of caloric restriction or dietary restriction or even time restriction, although there's a bit of an asterisk I could put there. And it was almost a one-to-one ratio, which meant that if a person lost 10 pounds, five of them would be fat and five of them would be lean as it's characterized on DEXA. And so that's pretty relevant, right? So if you're going to lose 10 pounds and half of it's lean and half of it's fat, that's very different than if you're going to lose 10 pounds and eight of it is lean. So we were using DEXA scans, but obviously you could even clinically just look at people and see that something wasn't right with this form of weight loss. And it seemed like around that time, that kind of became a large part of the discussion, kind of outside in the media. And there was a lot of stories about these drugs and some of the warnings, correct? Yeah. A lot of scientific papers began to raise that concern. And I think that's very good in terms of raising public awareness. I think there's also been some fear mongering and speculating beyond what the data have shown. And I think I would add to that, that as we learned, the manner in which the drugs are used and the manner in which the patients are counseled around the other modifiable behaviors, particularly with respect to their nutrition and exercise, can change the outcomes. So you also have to be careful that you don't over interpret what you see in clinical trials, which are, you know, average homogenized data when you don't have insight into how those patients were necessarily counseled. So it's, you know, it's valuable to have that information, but you also don't want to be paralyzed by it. And you don't want to discourage other doctors or patients from kind of experimenting with how to get better results than what the clinical trials showed. Yeah. And so now that we're a few years, past that, what updates do we have around the story of GLP-1s and muscle loss? Well, now there's been quite a bit of research on this question. We also, of course, have not just semaglutide, but now terzepatide. And although it's not yet approved, ratatrutide, which likely will be approved. So we've now seen not just one drug, but three drugs that have a profound impact on weight loss. And we'll sort of talk a little bit about these things. So here, I think what we want to do is talk about the effects of these drugs on muscle, and specifically how much do they lose and why. Do these drugs have any specific muscle wasting effects, or is that just kind of an undesirable side effect of rapid weight loss? And when the studies report that people are losing lean mass on these drugs, we want to really understand what lean mass is. So we use DEXA for body composition in our practice, and that's also what's used in the studies. But when DEXA reports lean mass, it's not just reporting muscle, which is the thing that we care about. It's reporting everything that isn't fat: bone, internal organs, connective tissue, hydration status. Of course, much of your water volume is in muscles, but it's everything. On top of that, there's actually evidence that as BMI goes up, DEXA overestimates the amount of muscle in your arms and legs. And then, of course, the flip side of that is that when heavier patients lose weight, the muscle losses may look worse than they actually are. And then on top of all of that, DEXA can't distinguish between the different types of fat depots or where fat gets stored. And we've talked about this, I think, in a previous podcast on DEXA, where we kind of explained how it works. But remember, a DEXA is a very low-dose X-ray, right? It's a low, low-radiation X-ray, and it's basically calibrated to identify what is fat, what is bone, and what is everything else. And so it does a pretty good job of cumulatively identifying fat. But when it comes to trying to identify subcutaneous fat versus visceral fat versus fat within a muscle, it really has to rely on algorithms that are, at best, not that accurate. So why does this matter? Well, subcutaneous fat is metabolically and structurally pretty benign. It's actually where we evolved to safely store excess energy. It's actually the other kinds of fat that are, you know, quote-unquote, bad for you. And these would include intramuscular adipose tissue, or IMAT, which is essentially the marbling inside the muscle. And then you have intramyocellular lipid, which is the fat inside the individual muscle fibers. And then the gap is going to turn out to be important, because if you lose IMAT, DEXA may tell you that you've lost lean mass, when actually the structure and function of your muscle tissue has improved. And again, DEXA really doesn't have the resolution to make that determination. But that's effectively what we care about. So if that lean mass loss is mostly glycogen, IMAT, and extracellular fluid, we don't really have much to worry about. What we really want to know is, are you losing the contractile units, right, the functional aspects of a muscle that are necessary to help you live independently and care for you and carry out all the sports and activities that you want to live with? So, and we'll get into it, but, you know, this is all part of the mix. And, you know, based on lean mass loss, you would expect to see people who are losing a lot of lean mass to lose a lot of strength and mobility on these drugs, but that's not actually what we're seeing. And I think the last thing that we want to really dive into here is the extent to which people are actually losing muscle and contractile tissue. What can people do about that? What can people do to mitigate that? What's known, for example, about the things I alluded to a few moments ago, which is the ability to manipulate resistance training and nutrition, specifically protein intake, to mitigate those losses. How much impact can you have in the real world making those changes on your own? Yeah, so let's start diving into that. So what do we know now about how much lean mass people are actually losing on these drugs? Well, the number that got everyone's attention came out of the STEP1 trial. STEP1 is just the name of the study. It's not like, you know, STEP1 trial. And that was the original trial for weight loss in semiglutide, which is sold as either Ozempic when it was marketed for diabetes or Wegovy when it's marketed for weight loss. And it showed that 40% of the weight loss in the semiglutide group was lean mass. Again, 40%. So if you're hearing that for the first time, that should probably alarm you as it did for all of us hearing it back then. Now, the good news is STEP1 looks to be a relative outlier. To later trials. And it might also be the case that semiglutide as a drug may be more of an issue here and that other drugs might actually have a better job holding on to lean mass. So there's a meta-analysis that we'll include in the show notes that looked at weight loss trials in both GLP-1 receptor agonists and with an intensive diet and exercise program to get a better handle on whether there's really something out of proportion going on with these drugs. And in this meta-analysis, about a quarter of the weight loss in people on diet and exercise was lean mass, which is actually what you would expect under normal conditions for a person losing weight. If you look at terzepatide, that's the one that's marketed as Munjaro for diabetes and Zepbound for weight loss, it's about in line with that. Roughly a quarter of the weight is lean mass. And that's also the same in that older drug that I mentioned earlier, liraglutide. And that's also the same in that older drug that I mentioned earlier, again, magnitude-wise, liraglutide results in much less weight loss. Now, again, for reference, when you look at meta-analyses of programs where they're heavy lifestyle interventions, including resistance training and obviously caloric restriction, people are losing significantly less lean mass, about one-sixth only, right? 16, 17% of total weight loss is lean mass. Again, compare that to what we're seeing with, on average, for semaglutide is about twice that, one-third of the weight loss is lean mass. But there is an important point to keep in mind here, and that is a smaller proportion of weight loss on terzepatide is lean mass. So terzepatide produces more total weight loss than semaglutide, which means it will result in a little bit more lean mass loss, but that's because you're losing more total weight. It's just that people on terzepatide are losing even more weight as fat, so the percentage is lower. If we compare these drugs to something like bariatric surgery, where the weight loss is larger and faster, how does it look in comparison? We see the same basic pattern, which is to say all things equal, so no resistance training, no dietary modification. You get about the same share of lean mass lost, of total weight loss, on the drug as you do in bariatric surgery. So we have a study with retrospective results from over a thousand bariatric surgery patients, and nearly 2,000 people on semaglutide or terzepatide, all treated at the same center. The surgical patients had a higher baseline BMI and more lean mass going in, but after two years of follow-up, the bariatric surgery led to a lot more fat loss and lean loss than the drug did. But the punchline is this, when you compute lean mass loss as a fraction of total weight loss, it's about 18% in both groups in this study. With surgery, you lose more lean mass, but you also lose more fat loss, and it's the same ratio basically seen in these GLP-1s. Completely different magnitudes, just same proportion. So just to clarify, it sounds like while the absolute numbers differ a lot proportionally, the ratio of lean to fat loss is relatively similar. That's correct. A big chunk of what we see with these drugs isn't necessarily some GLP-1 specific assault on muscle. It's just that you're losing more weight, period, full stop. And the more weight you lose, the more lean mass you tend to lose, but the percentage is about the same, whether you got there surgically through diet or drugs. Again, I think where this is a bit nuanced is when you're using diet and exercise to lose weight, you have to mend your diet and exercise. When you're using a drug, you don't necessarily have to pay as much attention to those things, and that's probably why we're seeing more variability there. Now, it does look like people on semaglutide specifically do lose a bit more lean mass than the traditional expectation for diet and exercise-based weight loss programs. But with terzepatide, which is the most popular drug today, and liraglutide, which is a drug as far as I can tell nobody's on today, it's about the same as what you would expect under those lifestyle conditions. And those traditional expectations were probably under-calibrated in the first place, because there were plenty of diet studies where lean mass loss is actually worse than 25%. And what do we know about at which the pace that that happens? So are people losing most of this lean mass right up front? Is it linear or something else? Yeah, that's probably important, because if it's all front-loaded, then you really have to be doing resistance training and getting your protein in from day one on these drugs, if not pre-habbing yourself before you even start. This is another case where we just don't have great data. The majority of these weight loss trials, you have exquisite graphs of the weight loss trajectory with multiple measurements all along the way. We don't have anything like that for lean mass, because they're just using weight. In the trials that measure lean mass at all, it's just a before and after. There's no interim data point to tell us about the trajectory. I would say the evidence we have here is two controlled trials with liraglutide using DEXA that report that a lot of the weight loss is lean mass from the very beginning. And then several observational studies say that people either barely lose lean mass or even gain it on semaglutide or liraglutide. I think we have to admit that we really don't know the answer here based on this very, very limited and coarse data. But as a practical matter, people should assume they're in danger of losing muscle from day one and not put off training and dietary changes until they lose the weight. And it seems like all these studies are people who are losing weight on these drugs. So do we know what happens to lean mass if people stop taking the drugs? Well, the first thing maybe to say here is that the story you often hear, at least so I'm told, on social media, that when people go off GLP-1s, they regain all of the weight. But that does not actually appear to be true according to the data. There's a systemic review and meta-regression of 48 studies of these drugs, and it looks exactly at this question. And it shows that one year after quitting these drugs, people are losing weight. And that's because they're losing weight. And that's because people still held on to about 40% of their maximum weight loss. Now, at that point, people are still slowly regaining weight, but it is leveling off. And even after you extrapolate out beyond what the original studies show, it looks like about one quarter of the loss persists long-term, which can still be a meaningful amount of weight. And I think the next thing to say is that these studies, in these studies, people are taking off the drug cold turkey with no support in terms of learning skills to control their diet without the drug or getting people exercising. So you could potentially argue that what we're seeing in these studies is maybe even a worst-case scenario, and that maybe if patients tapered off the drug and or were given far better instruction, that there could be better results to coming off these drugs in terms of weight management. And so if that's what we understand on the weight regain piece, what do we know about what happens to lean mass when people come off these drugs? Yeah, unfortunately, I think the evidence here is quite slim. There are a couple of trials underway that are intended to address that very question, but they are still ongoing. I would say from the data we have now, people actually seem to disproportionately regain lean mass rather than fat mass when they come off these drugs. And if that turns out to be true, that would be great news. As of now, there are two trials we can look at. So one is a trial of an experimental drug that is intended to help people on GLP-1s maintain or restore lean mass. And in that trial, everyone was on semaglutide for weight loss. And then on top of that, they were randomized to either a placebo or one of three doses of this muscle maintenance drug for 16 weeks. Then everybody came off semaglutide but stayed on the drug or placebo for another 12 weeks. So we're just going to look at the group that was originally on semaglutide plus a placebo for the muscle drug and then were taken off semaglutide. They lost a median of nine pounds of lean mass during the semaglutide phase, which was 34% of total weight loss. And then after they took away the semaglutide, they regained almost seven pounds of lean mass, but this was 72% of the weight they regained. Now there was another trial that was a lot more complicated and involved liraglutide instead of semaglutide. I think for the purpose of this discussion, the most important thing is that people lost 22 pounds during their one year on liraglutide and four of the 22 pounds were lean mass. One year later, after being taken off the drug, they had regained about four and a half pounds of lean mass. And then they were able to regain all of their lean mass. Again, that's not what I would have expected. And remember, that's without any special effort around resistance training or protein modulation in the diet. So again, the caveat here that might be worth adding is that it's certainly possible that a lot of that lean mass regain is things other than muscle, especially hydration. And so that's the effect of the drugs on lean mass. But I think earlier you were saying that lean mass numbers, aren't really what we're after. Do you want to dive into that a little more? Yeah. We've sort of been talking about lean mass in the context of what it means in DEXA, but I think now we need to probably get a little bit more nuanced. And of course, the reason that's the way we spoke about it is that's the only thing we can report on. But if we really want to understand muscle, we need to kind of peel the onion back a little bit. So lean mass does not just include muscle. It includes a lot of things beyond that. It does include muscle, but it includes organs, skin, bone, lots of extracellular water, and basically anything that is not fat. And very few of these trials include functional outcomes, which would probably be a better way to get at the question of muscle, at least through the lens of function. So even when we see that lean mass has gone down on DEXA, it's not really clear to us if it's translating into a real-world weakness or some impairment of physical fitness. So I think that's a really good way to look at it. I think that's a really good way to look at it. I think it's a really good way to look at it. So lean mass is a reasonable proxy. It's better than just looking at the scale, but it's imprecise. And truthfully, it's a little superficial, and it's not really getting at the heart of what we want to know. And so just there, you kind of mentioned that lean mass on a DEXA can also include bone. One of the questions we get asked a lot is, do we know anything about the effects of GLP-1s on bone health? Yeah. Here's the thing. We don't know anything. We don't know anything about the effects of GLP-1s on bone health. Yeah. Here we actually have some evidence, and it's interesting. When you lose weight on a GLP-1 receptor agonist, you also lose bone mass. Now, we already know that when people lose a significant amount of weight through either lifestyle or bariatric surgery, they develop a high turnover from bone loss. So weight loss from GLP-1 receptor agonists also causes bone loss. We have a couple of trials showing that both semaglutide and liraglutide lead to loss of bone mineral density. But the most important finding is probably from the SELECT trial, because it was in people with ASCVD and obesity. SELECT was a much larger trial than either of the BMD loss-specific studies, and it had the power to look at fracture risk. So hip and pelvic fractures were more frequent in people who received semaglutide, than in those who received placebo, 1% versus 0.2%. So that's a 5x difference. And if they were 75 years or beyond, it was a 2.4% versus 0.6% delta, respectively. So that's not just a number on a test, right? This is an actual fracture. Now, the good news is that the resistance training you need to do for your muscles is also going to help you maintain the structure and the mass of your bones. And people can go back and listen to our episode with Belinda Beck to learn more about the data and the protocols around that. But again, this is a very important reason to always be resistance training. And I would argue it's a non-negotiable if you're taking these drugs to not be doing that. And Peter, on that, do we know anything about if these drugs are actually damaging the bones themselves? We don't have any data to that effect. And there's no study that's asking that question specifically. That's a testable question. But I would say my intuition is that that's not the case and that everything I just described is a direct response to carrying less weight. So when you carry less weight, you have less deformation on a bone. The less deformation is on the bone, the less it remodels in a strong way. And so we do see this effect, as I said earlier, in people losing weight by other means. So that's, I suspect, what's happening. But again, that doesn't discount the need to offset that by lifting heavy things. And on the other end of that, what about muscle? So is the muscle loss just a function of eating less, or is there something specific about how these drugs are working that is causing the muscle to break down as well? Well, I think this is the jugular question, and it's probably the most important question that I see here. But I think the honest answer is we don't have a clean study in humans to really settle this. What you'd really have to do is put people in a metabolic ward and pair feed them, right? So you'd have to have one group on the drug, one group eating exactly what the people on the drug eat, but without the drug, and then you directly compare what happens to their body composition and functional analysis. Now, no one's going to run that study for six months or a year, so the best we can do is look at animal studies that have attempted to do that, and there are two of them. Now, both of these studies treated diet-induced obese mice with either semaglutide, a placebo, or pair feeding, where the pair-fed group was matched calorie for calorie to the semaglutide group. And without going into all the details, they find that the semaglutide-treated mice lose about the same amount of protein as the semi-glutide-treated mice lose about the same amount of lean mass and about the same amount of actual muscle mass for four of the six muscles that they measured, though the semaglutide group lost slightly more in two muscles in the legs. And that was even true in a study where they kind of ramped up the pressure on the mice's muscles by immobilizing one leg with a cast to drive muscle wasting on top of the drug's effect. They also lost the same amount of grip strength or maybe, the mice on semaglutide lost a tiny bit more. And so we know that people are losing lean mass on these drugs. Do we know anything about what's actually happening to their physical function? Are they getting weaker or is it something else? Well, again, that's a very important question. And again, the answer is potentially counterintuitive. So despite all the lean mass losses that I've been sort of highlighting here, people's strength seems to be largely preserved and potentially even some cases improved and their real world functioning gets better. So let's walk through some of these data. So let's start with the SEMA lean study. This was a prospective study done with 106 people who followed it through till the end. So they started out very, very heavy. So mean BMI of 46. Again, that's extraordinary. It's extraordinarily heavy just for comparison. And I think that's an important part of this study. Now mean weight loss in this study was almost 11% at seven months and then 13% at the one year mark. And then at those same time points, fat mass had dropped by 14 and 18% respectively. Lean mass surprisingly only fell by six and a half pounds at seven months, but then it stabilized as they continued losing weight for the rest of that year. So again, lean mass as a fraction of total weight loss in this study was high. It was 40%. And again, if you just heard that, that would be probably alarming. But here's what's interesting. Grip strength increased on average by 10 pounds at the 12 month mark. And then they looked at sarcopenia prevalence, which is actually quite complicated because it's defined by some composite metrics that are looking at strength metrics and lean mass metrics that normalize to total body weight. It was 40%. So people got less sarcopenic on the drug, even while losing lean mass in absolute terms, and quite frankly, losing quite a bit of it at on relative terms. So again, I think that sometimes the details on these things are a little subtle at times, but, but you have to sort of see them, I think, to appreciate the full, the full context. And is that a one-off or have other studies showed maintained or improved strength like that? At least four smaller studies found something similar. Grip strength was maintained despite a meaningful weight loss on these drugs. One small study also found no loss of strength on an isometric version of a knee extension. So that's also a consistent signal across multiple studies. Now the last finding is data from just one arm of a controlled trial that compared low dose semaglutide to a very low calorie diet or the combination of both. So very small study, 10 people in each arm, but it is kind of the comparison. That we would like to see to answer this core question. So the investigators will be reporting the strength results for all three groups in an upcoming paper. And we'll, we'll look forward to that. I'm sure we'll turn it into a newsletter. And what about the big semaglutide trials, step one and step two? Yeah, unfortunately they didn't look at muscle strength directly, but they did look at people's self-reported functional outcomes. And in those trials, people on semaglutide improved more on all domains of the test compared to placebo, including physical function, symptoms, psychological functioning, and total score. In step one, a little over half of the patients versus about a third of the placebo patients hit a clinically meaningful improvement on physical function. So that score measured things like trouble bending over, getting winded, doing routine daily activities, the inability to stand comfortably, not being physically active and things like that. Again, not surprising given the benefits of weight loss. In step two, by the way, it was about 43% versus 31% improving. And there was also a trial in heart failure patients, correct? That's correct. In these obese patients with heart failure, one year of semaglutide improved patients' six-minute walk distance by 21 meters versus 1.2 meters on placebo. As you know, I'm not a fan of this test. But it is the data, and it's commonly used in heart failure patients. And then, of course, on a set of self-reported functional tests, more semaglutide patients hit the 5, 10, 15, and 20-point improvement thresholds than on placebo. And that was across all the different test items, including physical limitations, quality of life, and overall summary. And so just to kind of double-click on this, if people are seeing signs of sometimes greater mobility and perceived strain, what are some of the things that you're seeing? What are some of the things that you're seeing? Even though they're losing lean mass, that might be kind of hard for people to understand. So what do you think about that disconnect between those two? Well, I mean, some of it might just come down to physics, right? If you lose weight, you need less strength to do everything, to get out of a chair, to climb stairs, to walk down the block, to walk around a track. Those kinds of changes don't require you to increase your muscle capacity. You just need to reduce the load. Similarly, the exercise tolerance improvements in heart failure patients are probably driven less by anything specifically happening in skeletal muscle and more by reducing the workload and oxygen demand of the heart and losing some of the epicardial fat, which is the fat that's, you know, deposited around the region of the heart and can potentially restrict the organ itself. That said, we consistently do see real functional improvement across these trials. And for obese people, the thing that matters in the real world is whether they can do things they want to do. And by that measure, it's clear that these drugs are helping, not hurting. In fact, it's worth asking whether some amount of muscle loss is not just expected, but maybe even appropriate when a person goes from being very obese to much lighter. Again, if you like, look at that step one trial, people starting out at an average of over two hundred and sixteen pounds, and they had a hundred and fifteen pounds of lean mass, they lost fifteen pounds of that, which, you know, which left them with a hundred pounds of lean mass. Maybe that's enough. A two hundred and sixteen pound person needs more muscle to get them, you know, out of a chair and all of those other things. But they might not need it as much if they weigh, you know, a hundred and seventy five or a hundred and eighty pounds. And so, Peter, on that, do we know anything about who is at most risk? Are there certain people who could be more vulnerable to losing lean mass than others that they should be aware of and be thinking about when it comes to these drugs? Well, I would have thought that older people would have been more likely to lose lean mass than younger people. And that's in part, I think, just based on the fact that we see more anabolic resistance in older people and obviously in people at rest. But that doesn't actually seem to be the case, at least according to the meta-analyses that look at lean mass losses in the GLP-1 users that I talked about earlier. The fraction of weight loss as lean mass was essentially the same between people over the age of sixty five and people, you know, that are younger than that. But there haven't been a lot of older people included in the trials for these drugs. And there are no trials that are specifically dedicated to answering that question. I also wondered if women might be more susceptible to lean mass loss. And there's, again, just no evidence one way or the other on that. There is a meta-analysis that asked if men and women differentially lost their weight. on GLP-1s in RCTs, and it found that women lost more weight than men on these drugs on average. It was less than two pounds of extra weight loss, but women tend to start out smaller in the first place. So half a pound or more could actually be a larger proportion, depending on where they're starting. When we looked at individual drugs, it seems like this differential effect was proportionally larger with retatrutide, which is the newest class of these drugs that's likely to hit the market probably next year. And women on retatrutide lost over nine pounds more weight than men. And again, this disproportionate effect in women was stronger if they were taking the drug for obesity than if they were taking it for diabetes. But again, that's just weight loss. So there's no data on differential lean mass lost by sex. But if women are losing more weight on these drugs than men, then based on what we've seen, it's not an unreasonable assumption to assume that they may disproportionately lose more lean mass as well. And so, Peter, earlier you mentioned something called IMAT and how it might be part of the story on lean mass loss. Can we double click on that? And also, I think it'd be really helpful for people if you can remind them what IMAT is. Yep. So IMAT, or intramuscular adipose tissue, is a fat that physically infiltrates the muscle tissue itself. So it's the marbling. You would actually see it just if you're looking at, you know, a piece of steak. But you have to keep it sort of distinct from a couple of related but distinct things. So subcutaneous fat, this is the one that most people obviously get phosphorylated over. It's the cosmetic thing. It's the fat that's underneath the skin. So it's the one that most people obviously get phosphorylated over. And separates it from the muscle. So the more subcutaneous fat you have, the less defined your muscles are. But it's important to understand that that fat category is quite metabolically inert. And then there's something that's referred to as IMCL, which is intramyocellular lipid. And those are fat storage forms that are inside the actual muscle fibers themselves. Okay. Now, as I alluded to earlier, DEXA can't tell the difference between any of this stuff. At best, it all lumps it together as body fat. But what's worse is because it's a 2D image and because IMAT is spatially layered with muscle, DEXA can actually mistaken IMAT for lean tissue. So DEXA tends to exaggerate the amount of lean mass it reports in people with a lot of IMAT because it tends to treat IMAT as though it were lean. Now, to separate all three of those compartments, the actual muscle, the subcutaneous fat, and then the intramuscular fat, and the intramyocellular lipid, you need an MRI, which is obviously why it's not done clinically. And Peter, what do we know about how many people that are taking GLP-1s are also resistance training? Well, we don't really know much, truthfully. And the data we have is pretty low quality. I would say what we mostly have. Our surveys that are done by a company called VIRU, the survey found that 36% of patients on GLP-1s had a moderate to high level of concern about muscle loss. And up to 55%, they were making some kind of lifestyle change in response. A little over a third said they were following a high-protein diet, and 38% said they were doing resistance training. Now, this company is developing a drug intended to counteract the muscle loss in people with GLP-1 receptor agonists. So they have an MRI. There's an obvious financial interest in making the demand for a solution to this problem look as big as possible, but that's the only data point we've got. And do we know anything about if people are actually eating enough protein while taking these drugs? I don't think we know. But it doesn't appear as such, given that a study using supermarket receipt data found that people on these drugs are buying more yogurt but less meat, seafood, and eggs. And there are a lot of foods right now that are being reformulated with more protein and being marketed as GLP-1 friendly, which can be anything from frozen meals to Pop-Tart proteins. But we don't have good data as to whether or not people on these drugs are using these. So studies that are looking, or looking at the kinds of self-reporting tools that they usually see in nutritional epidemiology, which of course are notoriously flawed as we've discussed many times before, suggest that people are pretty bad at estimating and getting enough protein. And despite that, when you look at one of the studies that looked at people's self-reported diets on these drugs, they were estimating to be consuming 33 grams of protein a day. So if you take the fact that they're. They're reporting 33 grams of protein a day and know that most people under-report total food, you know, you can certainly make a case that people are definitely not getting enough protein. Again, combining that with the supermarket data, I would say that there's a decent chance that on average people are not getting enough protein, which again, we would define probably close to 1.4 or 1.6 grams per kilogram of body weight. And what does the evidence say about how much resistance training and adequate protein intake can minimize the lean mass loss for people who are on these drugs? Well, if we just look at this from the standpoint of people who are losing weight, we have lots of data that show the importance of resistance training and protein intake to help you hold on to lean mass when you're losing weight. Again, when we're not talking about these drugs, just caloric restriction. And I think we can be very confident that those mechanisms apply here. But on the direct question of on drug, I think the data are few and few. And far in between. But in terms of having the features we want, resistance training and higher protein intake, there are a couple of small observational studies that at least give us some evidence that lean mass loss doesn't have to be as large as you see in trials. But again, they're not necessarily big enough or convincing enough to be particularly informative. And so I would just add to that our own clinical data with patients is that, which again is is confounded and has all the sort of usual problems with it because we're highly involved in their care. But again, we see that when patients are counseled thoroughly on how to consume protein at that 1.6 level and how to properly engage in resistance training, we're seeing very little lean mass loss. And I would suspect that our experience is not unique to us and would be replicated with other providers that have the luxury of providing that type of counsel. And do we know anything about other trials coming down the pipeline that might give us better data on some of these questions that we're asking? Yeah, I think there are five trials in the pipeline that are actually designed to answer this question in a better way. And I think the one that's probably going to be the best is called the lean prep trial. So this will be people on semaglutide or trisepatide, and they're going to be randomized into one of four arms, drug only as a control, and then drug with higher protein intake, with resistance training and resistance training plus one. And the primary outcome here is going to be quadricep cross-sectional area on MRI. So they're looking at actual muscle, which is going to be imaged directly and not just a DEXA for lean mass. They're going to be looking at a number of other metrics as well, including some functional metrics. So I think even though this trial, in my opinion, is probably coming along five years after it should have, better late than never. And I think this is going to be a really informative study for clinicians and for the public. Yeah. In the interim, until we have more evidence in those studies done, what do you recommend people do around resistance training? Look, I think you don't have to reinvent the wheel here. We sort of have, we have very clear insight around what matters here. And it frankly, in some ways just depends on what you're doing at a baseline, right? So if a person is overweight or obese and they don't do any resistance training, the good news is they're not going to have to do a whole heck of a lot to maintain lean mass. They're going to respond very favorably and begin to adapt to their training. And as we've discussed in other podcasts, that might simply be two days a week of whole body training for as little as 30 minutes a week. Now again, you do have to progressively overload, regardless of how you come at this. And progressive overload means using more weight, doing more sets, more reps, less rest. There are lots of different ways to progressively overload, obviously at the other end of that spectrum. And again, we're talking about people who are not strangers to exercise. We could be easily talking about three to four sessions per week. And each of those sessions can be divided up where you're targeting body parts such that each body part is getting probably on the order of 10 to 14 sets per week. And again, you're doing that as working sets and a working set then means you're, you're going to somewhere between one to two reps in reserve. So that's one of the things that's going to be very, very important for you to keep in mind. The second thing that I want to talk about here is how is the muscle being loaded? And as we've discussed many times on other episodes, if you're in the three or greater rep in reserve camp, you're not putting enough stress on the muscle, unless you are that individual who's never touched a weight in their life, but then you're going to quickly get out of that phase. So again, this means you're doing a set such that you, when you stop, you could have at most done two more reps. I think one is the sweet spot. Personally, I'm always trying to titrate to one rep in reserve and if I'm getting, if I can titrate that to be within eight to 12 reps that fails. So I pick a weight that allows me to get to that level within eight to 12 reps and I'm doing somewhere in the order of 10 to 14 sets per muscle group once a week, that tends to be the sweet spot. And is there anything in particular for people who are on these drugs to keep in mind when they're resistance training? Well, obviously one of the big issues that is, I think we're seeing less of now because physicians have a little more experience with how to use the drugs. And I think as we shift from more semaglutide to more triseptide, we just see less of the side effects. But I think nausea, dehydration, fatigue are not uncommon side effects in the first two to three months. And again, it's frankly not unlike what we saw with metformin. Right? Remember metformin was a drug that sort of took a while for people to get used to how to dose it. And if you just put somebody straight on the party dose right away, they felt horrible and they lost a ton of weight and people thought, wow, metformin is a great weight loss drug. And it was like, well, yeah, because it makes you sick. But I think starting at very low doses and obviously using triseptide more than semaglutide reduces that. But I would just say that the key is going as low as possible, getting the effect and slowly titrating up. When it comes to nutrition, the way we counsel our patients is not to spend any effort tracking total calories. But to track protein. And so earlier we talked about how in the self-reporting study, people were eating 33 grams a day. Well, my guess is if you give a patient a target and say, look, you know, Susie, you weigh so and so, and you need to be consuming 120 grams of protein today. And that is the only thing I want you to think about. I don't care how many grams of fat or carbohydrate or anything you eat, but I do want you to track how many grams of protein you're eating. That becomes a little bit of an easier thing to do, and it sort of becomes an easier way to drive adherence. Before we wrap up, we have to talk about something that we get asked a lot about in the GLP-1 space, which is the new drug, retatrutide. So what do we know about its effects on lean mass and muscle function? Well, as you noted, this is a new drug, so it's not yet on the market other than of course illegally when it's sold as a peptide. So this is an important PSA, right? A lot of people listening to this may be on retatrutide or may know people who are talking about being on retatrutide. And retatrutide, just understand that that's being done illegally because this drug is not yet on the market. So Eli Lilly, which is the manufacturer of this drug, is still going through the FDA approval process. Anything that you're consuming that is retatrutide is being stolen because the formula for what amino acids make up the drug is just being replicated on the black market. So with that said, we did see a very recent press release for the Triumph-1 trial in May. And this is one of the large trials that Eli Lilly will take to the FDA to seek approval. It found that retatrutide achieves substantially more weight loss than anything on the market right now to the tune of 28.3% of a person's starting weight when they take the highest dose, which is, quite frankly, getting into bariatric surgery territory. And of course, with all that weight loss, we're definitely going to want to know what the effect is on lean mass and ultimately muscle function. We're going to have to wait and see. I would say the only two things we know so far are from one of their phase two trials. And this was a study in people with type two diabetes, and they didn't have to be overweight or obese. And they were testing a wide range of doses, which includes the doses that were lower than likely, than what's likely to be the minimum dose when the drug gets approved. At the highest dose, people on retatrutide lost 34 pounds more than those in the placebo group of which about 13 pounds was lean mass. weight loss. And the percentages were a bit lower in the lower dose groups. And how does that data compare to the other data on the GLP-1s that are currently on the market? Well, as a percentage of total weight loss, lean mass loss is similar to what was seen with semaglutide, though more than what's seen with terzepatide. But remember, people are losing up to twice the amount of total weight on retatrutide that they were losing on semaglutide. And when you see that 30 to nearly 40% of total weight loss from lean mass is potentially more problematic when you double the total amount of weight loss. So again, if you do some math, imagine you start out at a weight of 220 pounds. If on semaglutide you lose 33 pounds, 38% of that is 12 and a half pounds, that's the lean mass loss. But on retatrutide, that same person would lose 62 pounds. In that case, 23 pounds of that could be lean mass, which is obviously potentially more worrisome. But we just have to keep in mind that I think it's a bit soon to say that because we're dealing with the limitations of relying on DEXA and its measurement of lean mass or imputation of lean mass as a proxy for muscle loss. More lean mass results will come out in another one of their phase three trials, which is going to be called Triumph 3. And they're going to assess self-reported physical function scores in some of their other trials. But I don't believe there are any plans to do any objective strength testing or performance-based functional tests, or to even collect hard data on bone health. Which, you know, if I'm being honest, I find quite frustrating because here we are, we're now on the generation of these drugs, we're seeing ever increasing weight loss. We know what the issues are that we should be concerned with. Quite frankly, I'm surprised the FDA is not demanding this. But you know, that's just me on my soapbox. Speaking of you on your soapbox, you hinted at this earlier, but I think it's worth double clicking on because it's a question we get asked a lot about, which is, there's a lot of people hearing the amazing weight loss around retatrutide, and they're thinking, you know what, I'd rather have it now than wait. So they're going online, finding a vendor to sell it for quote-unquote research purposes only. So just with how much we get asked about this, what advice would you give that person? I certainly understand the appeal. It's very rational. The phase three data look really good, but I think ordering it off the gray market is a mistake. I'm also a little concerned because I think most of the people that are doing this don't understand what they're doing, right? So I think most of the people that are doing this don't know what they're doing. So I think many of the people ordering retatrutide think that it's no different than going on Amazon and ordering vitamin D or melatonin, or it's just another supplement. Like it's an over-the-counter transaction. Like I don't think they understand that what they're actually doing. But you know, if someone wants more insight on that, I think they should go back and listen to the AMA we did all about peptides, which was AMA 83. I think it's unwise to just impute the results from the retatrutide clinical trials to what's being sold on the gray market as retatrutide. The results that you're seeing in clinical trials imply a pure drug that is manufactured under GMP, good manufacturing practices. And we know that these counterfeit versions, some of them are probably good. Some of them are not. And batch to batch, there's going to be variation. There are reports of people getting very sick from some of these, and that's almost assuredly due to contaminants that are making their way in. I don't think this is ever happening deliberately, of course, but when a company doesn't have to hold itself, they're going to have to do it. And I think that's a good thing. The GMP manufacturing standards, it's very easy to imagine scenarios where endotoxin testing is not being done, and therefore you're getting LPS and sepsis and all sorts of things. So for me, it just doesn't make any sense because the alternative is very good, right? You can get terzepatide in a completely legitimate way. I just don't understand why we wouldn't do this. It'd be a very different story, I suppose, if retatrutide popped along and there was no other drug on the horizon that had been used. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. And even there, I would still say it would be crazy to do this without seeing the breadth of the clinical trial data. So yeah, that's sort of my view on this. And so as we wrap this AMA episode up, how do you want to land the plane and leave people on kind of your overall takeaway of everything we talked about? Well, I say this both through my own clinical experience over the last five and a half years of prescribing these drugs and also, frankly, from all of the research that our team has done to prepare for this episode. And what I will say is my view today is that I believe that these drugs are not actively doing something that is harming muscle. I think that the loss of weight, mass, and function that we see really just is derived from the weight loss itself. I think there's a signal in the idea that trisepatide might let you hold onto a little bit more lean mass for a given amount of weight loss compared to semiglutide. And that may also end up being the case with respect to betatrutide. But we could test that question better. Again, I think the question as we have access to data is, do people lose more lean mass? But what I hope we've been able to do in this discussion today is get people to understand that that's probably the less germane question. And the more relevant question is not, are they losing more lean mass? It's, are they losing clinically meaningful contractile tissue in a way that affects strength, function, aging, and resilience? And honestly, the good news is the answer to that question does not appear to be yes. The answer to that question appears to be no. They might actually be able to maintain the thing that matters most. And the caveat here is, provided that they're making a couple of adjustments, along the way, with respect to their nutrition and their training. So I don't think that you get this for free, but I think you get it by adhering to, truthfully, what's probably a bit of common sense. And if this AMA seems like a long, long way it took to get here, I think it was necessary because this wasn't obvious. So what I can say with confidence at this point is, these drugs are really powerful. They are really remarkable. They're life-changing, game-changing, and they're for people with type 2 diabetes, and especially with obesity. I think we're going to learn over time that they may even have pretty impressive geroprotective effects. We've already alluded to this on a couple of other podcasts, and everywhere we look, the data seem to be pointing us in that direction, including with conditions that we don't think of as a huge challenge to your lifespan, but are a challenge to your health span, such as osteoarthritis, where we see an improvement in weight loss, or even once correcting for the weight loss, suggesting anti-inflammatory mechanisms and things of that nature. So really what it comes down to is nothing in life is free, and in exchange for the privilege of living in the year 2026 and having access to this wonderful, remarkable class of drugs, we have to take a little bit of responsibility around how we consume them and what other behaviors we put in place around them to make sure that we get the best of both worlds. We get the metabolic benefits. We get the weight loss benefits. We get the weight loss benefits, but we also preserve the function that we so desperately need to live a long and healthy life. Perfect. I think that wraps it up well, Peter. So until next time, have a good one. Thank you, sir. Thank you for listening to this week's episode of The Drive. Head over to peterottiamd.com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle peterottiamd. You can also leave us a review on Apple Podcasts or whatever podcast player you use. 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