Episode 384: The Paralyzed Personal Trainer (Mystery Case)

23:34Next, we move to the needle EMG or electromyography. This is where they stick a small electrode directly into the muscle to look at its electrical activity. Now, normal resting muscles are pretty quiet. But if a muscle has lost its nerve supply, the fibers can become kind of irritable. They start firing on their own. Now, this is a sign that the muscle has lost its nerve supply, which is also called denervation. In this patient, the tibialis anterior and the peroneal muscles showed heavy denervation. This is obvious from the atrophy that we saw in physical exam, but there's also an electrical signature called fibrillation potentials, which are these small little waves that you can pick up on EMG, another sign that the muscles have been denervated.

24:14Interestingly, when the short head of the biceps femoris, that's part of your hamstrings muscle, was tested, something strange was found. This is the only muscle supplied by the peroneal nerve that branches off above the knee. And in this patient, that muscle was stone cold normal. So Austin, let's look at the map we've drawn. We got a 24-year-old male with a clean MRI. We got a nerve that can still carry sensory information, but its muscle division isn't working. The electrical block has been precisely localized. Everything above the knee is working, but everything below the knee is electrically silent from that nerve.

24:48Given that this apparently started right after his weight loss and high-intensity exercise program, do you have a final diagnosis for what the heck happened to this patient? Yeah, this has only further supported my suspicion so far. And one curiosity here, I mean, he did seem to mention that he had a little bit of some maybe subjective numbness on the dorsum of the foot, which could also fit with some of the sensory distribution of these nerves. Maybe it wasn't enough of a sensory dysfunction to be detected by the study. But yeah, a lot of that is, I would say, not necessarily above my pay grade, but adjacent to it because the details of those studies are not really in my field.

25:27But yeah, this really heavily localizes it to the level of the knee. And so my suspicion is that there was either some unknown, unrecognized, unappreciated trauma with his high-intensity exercise at the time that affected the nerve at his knee during that time. or this is a case of, again, rapid weight loss-induced so-called slimmer's paralysis, where the rapid fat loss in that area leads to functional kind of compression of the nerve. And again, if his weight dropped and has remained low, or he never regained body fat to kind of restore padding in that area, the nerve would not really have an ability to kind of recover its function, innervate that muscle, and lead to him to be able to lift his foot again.

26:05So that's kind of where I'm at. Color me impressed. The diagnosis is Slimmer's paralysis, historically known as dieting palsy. It is a nerve entrapment of the common peroneal nerve at the fibular head. It was once a historical rarity associated with prisoners of war and individuals with severe anorexia nervosa. But there's some concern that there could be a modern spike or uptick in cases with the increased popularity of GLP-1s. Now, the pathophysiology you did describe is mostly a functional compression, but there's some thought there's a second hit. So this sort of two-hit model. As you talked about, hit number one is the depletion of that internal armor of fat.

26:44The common peroneal nerve is pretty vulnerable because it is tethered as it winds around the neck of the fibula. That's the outside smaller bone in your lower limb. In a healthy state, it's enveloped by the structural fat pad. The fat pad acts as a mechanical shock absorber, and it physically increases the space in the fibular tunnel so the nerve isn't pinched against the bone. Now, when this guy lost 11 kilos, 22 pounds in two weeks, the body presumably mobilized fat stores so rapidly that it stripped away the structural fat pad. And so without that cushion, the nerve was left sitting directly on the bone, leaving the margin of safety for compression at zero.

27:21Now, the second hit is the mechanical provocation. So he was doing the high-intensity sprints, squats, aggressive stretching, whatever that means, while his fat pad was progressively getting thinner. And so when active, that nerve needs the fat pad to dissipate pressure. Otherwise, the pressure on the nerve can get too high and disrupt blood flow to the nerve. The nerve do have a blood supply. It's pretty delicate. It's called the vasovasorum. Now, when this blood supply is compromised, nerve conduction temporarily stops. We call that neuropraxia. If it's prolonged, though, the nerve can die, and it must regrow from the site of injury.

27:54And this process is slow. There's Wallerian regeneration, like a millimeter a day. It's slow and it can be incomplete. That's what apparently happened to this patient. By the time he got to the emergency room, the damage was done. He had spent 12 months with basically zero motor signal reaching those muscles. The receivers, the motor end plates in the muscles of his shin, the side of his leg, had undergone some fibrosis. They were no longer capable of receiving a signal, even if the nerve did manage to grow back. So at that point, his treatment plan shifted from neurological recovery to orthopedic salvage.

28:26He underwent a posterior tibialis tendon transfer. Essentially, the surgeons took a functioning muscle from the back of his leg and anchored it to the top of his foot. Kind of had to retrain himself how to walk and pull his foot up with his new hardware. So there's a thought that this might be coming more common, like a pharmaceutical slimmer. The GLP-1 agonists like terzepatide and ritatratide can induce weight loss velocities that mimic bariatric surgery. And while the weight loss isn't necessarily a problem when it's appropriately monitored, inappropriate use, and specifically facilities that are like pill mills, could be increasing the risk of this.

29:02Now, the incidence of general peripheral neuropathy following metabolic bariatric surgery is reported to be somewhere between 5 % to 15%. Now, that's after surgery. And within this broad category, the peroneal mononeuropathy, so single nerve issue, is one of the most frequently cited presentations. Historically, again, as prisoners of war, the incidence was about 10 % in these individuals. I assume that would happen over a longer period of time just due to kind of what was happening. But in surgical cohorts, the latest evidence we have on this suggests a higher percentage than 10%, maybe closer to 15%, mostly at high-volume centers.

29:40And the incidence is probably underappreciated because it's underreported and potentially mild transient cases could be missed as like temporary numbness. so the condition is overwhelmingly unilateral or one-sided 96 % of cases are on one side rather than being bilateral which kind of speaks to this systemic sort of thought you're like well you're losing weight all over the place why does it happen in one side versus the other I don't have probably some yeah just chance chance and maybe some sort of you know subtle side-to-side difference or the way you use your body or the way this guy was doing his exercise may be favored you know not in a bad way, but just the way he tends to move to your point about having a second hit.

30:20But I think mostly it's probably just going to be chance. Yeah. Yeah. Originally, when this was first described, it was like cross-legged palsy or cross-leg paralysis because that would be the inciting event, the mechanical sort of thing that put it over the top. When studied, the most critical marker or risk factor is the velocity of weight loss. So on average, people that get this are losing about 10 % of their body weight per month, which ends up being about 5.4 kilos in this particular cohort. And there's also some additional risk factors that kind of uniquely affect this population. So first off, the population that generally goes about rapid weight loss or uses metabolic bariatric surgery or GLP-1s, they tend to be more commonly individuals with a history of metabolic syndrome or type 2 diabetes.

31:04So there's already perhaps some baseline metabolic neuropathy going on. And then these individuals can undergo rapid weight loss, which mobilizes the fat from those structural fat pads at this particularly vulnerable area, removing that shock absorber. And then, yeah, there's a biomechanical trigger potentially. So prolonged leg crossing, squatting, kneeling, et cetera. All of this could kind of put it over the edge. And there may be some co-occurring micronutrient deficiencies, specifically for folks who've had metabolic bariatric surgery and are being not monitored as closely nutrition-wise.

31:39so like vitamin b1 which is thiamin b12 or copper deficiency can all like synergistically impair the nerve's ability to repair itself and a nerve starved of these essential vitamins is less resilient to perhaps that ischemic stress you know lack of blood flow caused by the collapse of that fibular tunnel this podcast is brought to you by biggs at barbell medicine we spend a lot of time talking about what it takes to build a body that can handle high level performance but the recovery health side is just as critical. Over the last six years, an incredible team of healthcare professionals did something that most people thought was impossible.

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32:43And of course, the style comes in red, white, and blue. Now, if you want the gear that the medical team behind the world's best athletes are wearing, check out the limited edition Team USA collection. You get 15 % off your first order at wearfigs.com with code FIGSRX. That's wearfigs.com, code FIGSRX. So treatment typically revolves around weight stabilization, perhaps some B vitamin supplementation, orthosis for the foot. So just to keep it in the correct position so you don't get a contracture and so on. If there's no clinical or electrodiagnostic evidence of recovery after about three months, surgical decompression is sometimes indicated because they don't want those motor end plates.

33:23So basically where the nerve attaches to the muscle, that end plate, that interface, they don't want that to fibrose or degenerate because otherwise you're kind of up a creek like our patient. Because after in chronic cases, like what he had, yeah, you're going to have to have a tendon transfer so you can walk without your foot kind of slapping the ground. Yeah. I did not know that that was a thing that could be done to manage this. So I'm glad there are some kind of creative orthopods out there who can put people back together again a different way. But yeah, you have to relearn how to like use that new newly transplanted muscle and presumably has, you know, permanent impact on function.

33:57You have to kind of relearn how to do basic things, I imagine, with the help. But that's what PM &R doctors are great at. Yeah. Now, Austin, there's been a few case reports that have come out of individuals on GLP-1s having this. One case was actually titled the terzepatide drop. Have you seen this with any patients? Is this something that's on your radar? Yeah, I've used these medicines with lots and lots of folks. I've not seen this happen yet, although I'm aware of it as an entity. And, you know, I think it's one of those things that is a known risk. It is one of the potential trade-offs that somebody might experience.

34:29But at the same time, it is one of the downsides of, again, just like unmonitored, overly rapid weight loss. And so having kind of it done in a way that is monitored, that is supported, where doses are being adjusted, where nutrition is being monitored. I mean, I've had also patients who I'm actually concerned that, you know, maybe their appetite is being suppressed too much and they're not actually getting in enough nutrition as they are losing weight. And that sets them up for all sorts of other deficiencies and iron deficiency and things like that. So, you know, we are, I'm quite comfortable using these medicines.

34:59I've been using them for a while now with many, many patients with great, some with most of them, I would say with, with great success and some who have speed bumps along the way that need to be kind of navigated individually. But yeah, that kind of monitoring and guidance along the way, I think is important rather than just like more is better or faster no matter what. Yeah. Yeah. I wanted to bring this case up, not only because it's interesting, I did find it interesting, but because it also raises a fundamental question in our field. Is faster actually better when it comes to weight loss? We often hear the argument that rapid initial weight loss is more motivating for the patient or the client, which theoretically could improve long-term adherence.

35:38But as this case proves, there can be a physiological cost. So I wanted to pivot the discussion towards the actual evidence on weight loss velocity. And we need to look at the trade-off between the speed of the result and the quality of the tissue loss, specifically the preservation of lean body mass and the avoidance of collateral fattening, which is a physiological phenomenon where the body aggressively drives overeating following a period of weight loss to restore the lost lean body mass. And while doing so, the individual actually gains a bunch of fat mass alongside the lean mass. So let's start with the most obvious question.

36:10Does the data support the slow and steady mantra when it comes to weight loss. There's a safety concern. We've kind of talked about that. This slimmers paralysis, mostly related to a weight loss velocity that exceeds 10 % of total body weight per month, which would be quite high for most folks. And you brought up gallstones and nutritional deficiencies. Are there any other risks or safety concerns that you have top of mind when somebody's losing weight relatively quickly? I think you alluded to one of them being that, hey, are we having some unfavorable changes in terms of the lean body mass aspect?

36:46There are certainly many favorable things. So for example, if somebody has fatty liver disease, I would expect that to get better rapidly as people because the liver starts rapidly exporting a bunch of that fat. I think I would have to sit down and think like organ system by organ system to decide, are there concerns from a neurological standpoint? We've really covered the main one of deficiencies or the mechanical neuropathies that can develop. Not much from a pulmonary standpoint, not much from a renal standpoint. I'm sure there can be some things from a cardiovascular side, mainly relating to, is there a hypovolemia, meaning is the person not eating or drinking enough and they end up getting low blood pressure, they get dizziness, they might be more likely to pass out.

37:25That's something that I've actually seen a fair amount of. And people, for example, who are on blood pressure medicines often need those to be adjusted. The other thing with, especially like aggressive crash diets, things like that, where people are more prone to electrolyte abnormalities, you can end up with cardiovascular complications, arrhythmias, things like that, that can develop. Let's see what else. So I mentioned the liver, the gallstones we've talked about, the intra-abdominal fat, which itself, the gallstone risk can, I've not seen like rapid weight loss associated pancreatitis, but that's probably, that may be a thing that can happen whether by way of a gallstone or if you're liberating a lot of free fatty acids into the bloodstream and you get like severe, high triglycerides, I guess that's another way that you could get there.

38:05And then again, not much in terms of the lower GI tract or the kidneys or definitely the genitourinary tracts, not much that comes to mind. And then from there, it's musculoskeletal nature. So the muscle mass loss is the thing that comes to mind. I don't know how much of an impact I would expect with very short-term rapid weight loss on bone health. I'm sure there'd be something detectable. Whether that translates into a negative longer-term outcome, it'd be hard to say. So that's my rapid pass through the organ systems and what I can think of off the top of my head. Yeah, I think that's quite good.

38:35The only other thing that comes to mind is maybe on the back end, right? It's like, great, you lost the weight, you know, if that's the target. But if and when weight regain starts, if it's rapid and you were really restricted for a period of time, the refeeding syndrome type thing, we've had a few cases of like thyrotoxic periodic paralysis and some other just electrolyte abnormality stuff. So yeah, that's a concern. So that's safety. Moving on to what our listeners are probably more interested in, body composition. So the impact of weight loss speed or weight loss velocity on muscle mass differs significantly between athletes, lean individuals, and the general population with obesity.

39:20So for athletes, the data for sure supports slow and steady. Now, there is some nuance here because there are papers out there describing relatively quick, dramatic weight loss to make weight with preserved performance. There are a few different ways to do this. It's not highly reliable or conserved across everybody. It kind of varies significantly. We're going to set that to the side and talk about more just, hey, should you lose weight rapidly or slowly if you're an individual who's really interested in performance or otherwise an athlete? And I think there's a really good study to show the evidence on this and kind of demonstrate our position.

39:58So this is a group of elite Norwegian athletes from a variety of different sports. They were randomized to either slow or fast weight loss groups. Slow weight loss group followed a diet that resulted in losing about 0.7 % of their body weight per week, whereas the fast weight loss group doubled it, 1.4 % body weight per week. So that's almost 6 % per month. Now, the study ran until all athletes reached the desired weight loss, which was a minimum of 4 % decrease in their body weight. So it lasted between 4 to 12 weeks. During the study period, both groups also engaged in resistance training four times a week.

40:36At the end of the study period, body weight decreased by about 5.5 % in both groups, with the slow weight loss group losing a higher percentage of body fat compared to the fast group. Additionally, the slow weight loss groups on increase in their lean body mass by about 2%, which might be a measurement error, but it's still not a loss, which it seems positive. And their one rep max squat and bench press improvements were greater in the slow weight loss group compared to the fast group. About 12 % for the squat in the slow group versus 9 % for the fast group. And 13.6 % for the bench press group who was using a slow weight loss approach compared to 6.4 % in the fast group.

41:15Overall, to me, this suggests like, look, if you're already relatively lean, you know, and you're trying to get even leaner, probably slower is better if performance is a concern. But on the other side of the coin, for individuals with obesity, the data really kind of challenges that slow mantra. There's been a few recent meta-analyses that suggest for individuals with obesity, the rate of weight loss does not inherently dictate the amount of muscle loss, provided that protein intake and resistance training are controlled. We know those are two big levers that like preserve muscle mass. And in this particular population, it doesn't seem like going faster produces more lean body mass loss.

41:55Individuals with higher body fat can mobilize fatty acids more effectively and they have more of it to do so. And that can cover some of the energy deficits and preserve some of the muscle loss. This is a lot of the mechanistic stuff that keto advocates tend to cite. But yeah, it actually looks like this plays out for individuals with obesity who do lose weight a little faster. So you might potentially choose that if somebody was interested in doing so, knowing the potential risks and maybe having that top-end velocity ceiling of 10 % per month in mind. The next thing we've got to move on to is metabolic adaptation.

42:30Austin, do you ever talk about metabolic adaptation with your patients? Not using those terms. I think the concepts are kind of baked into my conversation, mainly when I have these conversations all the time now with folks who have many times been struggling with their weight their entire life and feel like they're doing everything right. And yet, despite their best efforts, they either struggle to make progress or they make initial progress and then things tend to rebound. And so it's kind of baked in as part of the explanation of how, quote unquote, the body fights back after your initial weight loss efforts, both in terms of increasing appetite and that kind of question of metabolic adaptation.

43:05I put a lot more emphasis on the appetite aspects here, but that's something that's kind of baked into that conversation implicitly. Yeah. Yeah, people talk about metabolic adaptation or adaptive thermogenesis or, you know, you've broken your metabolism, something like that. You know, they talk about it frequently, but the definition is kind of messy. The way I define it and the way that a lot of researchers that I read define it is that metabolic adaptation is a greater than expected reduction in the amount of calories used in a day in response to weight loss. So, for example, we know as your body mass goes down, you're going to burn less calories because you have less mass.

43:48Now, the proportion of muscle to fat loss, those two things require different amounts of energy per day. And so if you lose way more muscle than fat, you could go down more. this is all predictable. That's not metabolic adaptation. Metabolic adaptation is if there's additional reductions in how many calories that you need per day to keep the lights on in your body that we don't predict by just the tissue loss alone. So it's maybe like a metabolic efficiency increase. Data indicates that rapid weight loss increases the metabolic adaptation more than gradual weight loss. And there's actually a really good meta-analysis that came out, I think, in 2020.

44:27Yeah, there's a deeper suppression or greater suppression of resting metabolic rate. That's basically how many calories you use per day to keep the lights on in your body. In a comparative analysis, rapid weight loss groups who lost about seven and a half kilos reduced their resting metabolic rate by about 137 calories per day compared to only 87 calories per day in a gradual weight loss group who lost about the same weight. They also didn't have significant differences in lean mass that was preserved. So kind of speaking more to that, what we just said that look for individuals with obesity, it doesn't look like they're going to lose that much more muscle mass, if any, if they lose it rapidly, but there might be some more metabolic adaptation.

45:09What's not clear to me is if this is actually meaningful, meaning that, yeah, there's a difference in calories by, you know, 50, 60 calories, but most of these studies or short-term, eight weeks, 12 weeks, 16 weeks, does this end up shaking out in the long run? And does it even matter? For example, we look at even the biggest loser data. The people who lost the most weight and kept it off the longest had the most metabolic adaptation. And so to me, it's almost like individuals who are maybe genetically set up in a way to be obesity sensitive to not only the environment, but then also like resistant to weight loss interventions overall, all, they may just have, you know, this is the lot in life that they've kind of, they've kind of got.

45:53They were dealt a not so great hand genetically and it is what it is. And so I don't know that we should be micromanaging or selecting a particular dietary approach or intervention otherwise that focuses on metabolic adaptation. What do you think about that? Yeah, I fully agree with that. And I think that knowing, or I wouldn't even claim to know, but having a general sense of just the sheer number of variables that can impact these types of outcomes with this concept of metabolic adaptation just being one of them. It's like you're, you know, moving a fraction of a tiny chess piece on like this super complex multivariate board.

46:29Many variables we can't even appreciate, many variables we don't, we can't even modify. So like control the big things that you can, and then the rest may or may not be entirely within your control. And this feels like one of those really tiny ones that is both probably less within our control than we would like it to be, but also less significant of a factor than it is often attributed to be. Yeah. I think it's something you can observe, but to the extent, to the extent you can control it, I don't, I don't think so. I think it's more of like an adaptive response and like mostly, you know, managed or, or influenced by things outside of your control.

47:03And then I almost view it as like a, like a signature of success. Like, look, if you didn't get any metabolic adaptation, I don't know that you lost that much weight. Yeah. Like, yeah, it's kind of, that's fair. So that's, that's the metabolic adaptation arm of this moving on to adherence. There's this thought, well, look, you have to go low and slow because that's the, that's the only way you can keep it off long-term or adhere to this diet long-term or intervention long-term. Well, contrary to that belief that thinks that slow weight loss is more sustainable, the data suggests that rapid initial results can actually be beneficial for adherence.

47:38There's a number of studies on this showing that the amount of weight loss initially within the first few weeks sort of predicts not only achieving that minimally clinically important difference in weight change, so losing at least 5 % of their starting body weight, but also maintaining it. So it can be predictive, and whether this is like a positive feedback loop, like from a behavioral standpoint, like, oh, I was able to succeed, I'm going to keep going. Or if it just identifies those who can be successful, like the people who don't lose a bunch of weight initially, they're like, well, you weren't going to be successful anyway.

48:10So good luck. I can't speak to that, but is this something you see in your practice that people, they start on these medications or, uh, for example, just lifestyle alone, the initial sort of burst kind of predicts how they do long-term. You see that? Um, yeah, it's tough to say. I think that I emphasize with patients just how individual this whole process is, especially with the use of medicines, that different people respond differently to different medicines and to different doses of medicines. If I had to, you know, guess that, yeah, if I start somebody on the lowest dose of trisepatide, for example, and they experience, you know, a dramatic impact on their appetite, they're super sensitive to it and lose a bunch of weight.

48:49In general, those people I would predict to have better outcomes compared with somebody who doesn't feel much of anything. And I'm cranking it all the way up to the max dose of 15 milligrams. However, I have also seen plenty of people, and I recently had some of these conversations, a patient who started on two and a half, and they were like, not responding terribly well to it just yet. And they were starting to get apprehensive. They're like, should I, shouldn't I be feeling more? Am I a hypo responder? And I'm like, cool it. Like we, we don't, we don't know that yet. There are plenty of people who actually don't really tend to respond a ton to the lower doses.

49:18And then we reach some sort of maybe a threshold effect in people. Once we get to seven and a half and something unlocks, and then they start making a ton of progress. So I hesitate based on my own kind of observational experience here to draw any sort of confident conclusion other than I've seen massive amounts of variability between people and how they respond both physiologically and of course, psychologically as well to the process. Some people are like totally open and patient and no concerns. Others are much more impatient and want to see a big result on a low dose and get apprehensive if they're not getting there.

49:47Other people think that they really want to be on the maximum dose. And I'm like, well, if you're responding well to the lower dose, we don't actually have to increase it. And similar in terms of intensities of other interventions, right? When it comes to regular, you know, dietary interventions, exercise interventions, just people are massively different. The sheer number of variables at play, both known and unknown is just enormous here. And again, many of them are things that you did not choose or you were not in control of, right? And so that's kind of part of the challenge that we're trying to deal with, with as good as these tools are that we have still, compared with that level of complexity, relatively crude, I would say.

50:22Yeah. And moving on to the final thought between, look, it's slower, better than faster. What about the potential for weight regain? The prevailing dogma is that slow and steady prevents weight regain. It's not really supported by data as well. Large-scale studies, including this Purcell study we're going to talk about, as well as the National Weight Loss Control Registry, We consistently find no significant difference in the amount of weight regained over the long term between slow and rapid weight loss. Again, it kind of doesn't really matter for individuals with obesity. So this Purcell study is interesting.

50:56It's a randomized trial, 200 participants. One group underwent a rapid weight loss program, 12 weeks, where they went on a very low-calorie diet, like 800 calories a day. The other one went on a gradual program where they reduced their intake by 500 calories per day. The success rate, the rapid weight loss group was far more likely to hit their target weight loss. About 81 % of that group was successful compared to the slow weight loss group. Only 50 % was successful. After three years, both groups regained roughly 70 % of their lost weight. The rapidity of the initial loss did not make the regain worse, and maintenance was equally difficult for both groups, which is kind of how I view this.

51:38I'm like, I don't really care if you go fast or slow. My main concern is that you got there because I think maintaining that is going to be challenging either way. But first we got to get there to even worry about maintenance. Does that make sense for you? Yeah, I mean, I think we've talked about this a lot where it matters how you got there with certain things, but with other areas, it's like we really care about the outcome. And so to the extent we see a lot of people now, especially like kind of moralizing around, did you get there with diet and exercise or did you use the medicines or did you use the surgery and it's like we put a lot more emphasis on like let's get there yeah and then and then uh you know the the details of how you got there and the implications of that and what does maintenance look like we can kind of negotiate along the way this is another super common conversation i'm having with folks who even before we've even started for example the use of a glp1 agonist they're like well what does it look like when it comes to maintenance and it's like well happy to have that conversation of course and i and i lay it out for them but it's like we got we We got to get there first before we can negotiate what does that look like for you.

52:37And we can't even predict. Are you going to be somebody who needs to continue using one of the medicines? Are you somebody who might be able to get away with lowering the dose or using it a little less frequently? Are you one of the, you know, relatively few people, maybe in the order of 15-ish percent of people who can actually come all the way down, potentially even off the medicine and sustain, you know, the majority of your weight loss? There's a lot of variation in how this looks in practice, but let's get there is the primary goal. Yeah. Yeah, the analogy is like with blood pressure, right?

53:05You know, we've talked about on this podcast before that apparently starting with multiple, very low dose antihypertensive seem to work better than like maxing out one particular drug, right? And so imagine you have a patient and you're walking them through this and they're on board. They're like, look, doc, whatever you think is right. And so they're ready to start multiple agents at a low dose. But then immediately right after that, they're like, and when can I come off? And you're like, well, maybe let's get there first and then we'll talk about it. Because, yeah, it directly impacts the risk.

53:33Now, this brings up a new paper that just got released that's getting a lot of traffic. New study from Mass General, Harvard. So you know it's going to get some airplay. The study is titled Weight Regain After Cessation of Medication for Weight Management, a Systematic Review and Meta-Analysis. This was just published. I'll link it in the show notes below. Basically, they did a meta-analysis, a study of studies on people who were on anti-abesia medications. And like, look, what happened? after they got off now uh 37 studies were included about 10 000 patients and they included all sorts of different anti-obesia medications so not just glp-1s but even some of the older agents and invariably there are differences in not only how much weight was lost but the what happens afterwards now the mainstream media and maybe some we'll call them glp-1 skeptics is not the right words, maybe like anti-GLP1 people, whatever.

54:30It seems like that anyway. There's plenty of those out there. We know they're like, look, after you come off the medication, you regain the weight and you regain the weight faster than if you did lifestyle alone. And so in this particular study, they showed that, you know, the systematic review and meta-analysis, they show that, look, people come off these medications, they regain weight four times faster than those who are on lifestyle change alone, so diet and exercise, failing to mention that the people who are on these medications lost way more weight on average. And so yes, the absolute rate of weight regain tends to be faster because they lost more weight in the first place, but also ignores a few other kind of nuances here.

55:08So nuance number one, when we just restrict the analysis to GLP-1s on their own, and we look at like one year data, people come off and they're off for a year, actually seem to preserve more weight loss overall than people on lifestyle alone. Now, whether that, you know, gets back to, you know, null and zero at two years, three years, four, we don't, we don't know, but at least in the first year, it looks like, look, they have some sort of durable effect of these, of these agents. And then two, which is not really a nuanced point, but maybe the, the total point, like any intervention that causes an effect, you'll likely have to continue doing that intervention to preserve that effect, whether it's diet and exercise alone, whether it's medication, whether it's both, you know, whatever.

55:50It's not like you can just do it and be like, okay, I don't have to do it anymore. It's done. Yeah, that's, I mean, honestly, most interventions that we have, here's another interesting hot take that I will have. I have heard rumblings that there are some groups, and I've not confirmed this for myself yet, that looking into, for example, some of the gene-based therapies around GLP-1 signaling. For example, we have existing therapies for this in the context of sickle cell disease, for example. There are some that are being studied for lipid management as well, essentially like a one-time dose of this gene editing treatment that will then lead to a permanent durable lowering of your blood lipid levels or that will edit your sickling hemoglobin genes to essentially cure that condition.

56:42So I'm curious to see for all of these folks who are vehemently against the use of GLP-1s because when you tend to stop the therapy, the effects of the therapy do not persist. I have to assume that they will be vigorously in favor of one-time treatment options for this kind of thing. Yeah, they're not going to be either. And I don't know that I am either because I'm just open to seeing what are the potential benefits, what are the potential downsides, and I will evaluate that evidence like, you know, on its own when it comes to pass. But it's kind of disingenuous and it's going to be very predictable how that ends up playing out, I think, on their part.

57:21Yeah, if you agree that the sort of root cause of obesity is a genetic mismatch with the modern environment, and then if you secondarily agree that, look, it's going to take some time to change the environment to a satisfactory level that really sort of reverses course here, it's going to take some years. So then you're like, well, I guess our actual target is genetics. And then we somehow identify this genetic target and we can, you know, create a treatment that directly does that one-time dose gene editing, CRISPR, whatever. And it does actually change their genes. And now they are well-matched for the current environment.

57:59And that's the treatment for obesity. You're cool with that. And further, what does that Venn diagram look like between the COVID vaccine modifies your DNA versus treatment of obesity modifies your DNA. Like, how does that square? With the technology that we have, I mean, identifying like to the way that you've described folks as being kind of more obesity sensitive or obesity resistant in the context of the modern environment, what are the variables that are most predictive of a quote unquote obesity resistant phenotype? What do the genetics look like of somebody who is quote unquote naturally lean?

58:31And then is there a gene therapy that you want to try to institute to folks who struggle to kind of make them more obesity resistant? There's, I'm not even advocating for this because it's just like a whole minefield of a complex topic in terms of, you know, editing people's genetics. And at what point in life do you do that? And what are the implications and, and things like that. But that's kind of the phenomenon that you're, that you're getting at here. Yeah. I don't know. I think it'd be cool. Like a great, if possible, you know, that would be an interesting option for folks. But yeah, TBD.

59:01I just find the argument that you shouldn't use GLP ones because when you come off them, you're going to regain the weight. And it's like, that's like saying you shouldn't exercise because when you stop doing it, you're going to lose the muscle mass or whatever. It's like, yeah, maybe there's a more durable effect of exercise longer term than GLP-1s. Sure. But for a dietary pattern, it's like saying you can only eat healthy for the next year to lose the weight. And then after that, you have to stop because we don't want you to have to keep doing it. Be silly to have to keep persistently doing something.

59:30Yeah. Despite all the other. Yeah. It's nonsense. All right, Austin, any closing thoughts on losing weight rapidly versus slowly for metabolic health, long-term health trajectory, and maybe how you contrast that with active individuals, athletes who are looking to be a little leaner but not necessarily for a health purpose? Yeah, I think it's a good topic. I think you did a good job kind of surveying the evidence and this whole episode, including starting from the very beginning with the mystery case, serves to lay out and describe a fair amount of the potential pros and the potential cons of doing this, just like any intervention has potential benefits of potential downsides.

1:00:06And so then our job, whether as people considering these paths before us or as clinicians guiding folks through it, is helping them weigh those potential benefits and downsides on an individual basis. So somebody who is at extremely high risk of cardiometabolic complications, yeah, I might favor a little bit more rapid if I can, notwithstanding this maybe risk of a little peroneal neuropathy that is likely to be either not noticed or transient or something like that. But for somebody who values high-level performance, then the calculus changes a little bit there. And so these decisions should be made individually.

1:00:41And, you know, if you have a clinician that you're working with, then you have that level of supervision to have these kind of conversations of what does this look like. And, of course, this is all underscored by our unsurprising recommendation that anytime you're losing weight, you ought to be strength training to do your best to maintain the lean body mass and the muscle mass along the way. Agreed. Yeah, just some more clinical logic that you're spouting here. If the benefits outweigh the risks would proceed. If that flips, then maybe slow down a little bit. But yeah, with conditions that you mentioned, there's some strong push towards let's take care of this obesity thing as quickly as possible to reduce your risk, whether it's heart disease, particularly liver disease, for example.

1:01:22Whereas if it's more of like, eh, this isn't really for health, I'm really concerned with performance, well, then the risks of rapid weight loss seem to outweigh the benefits. which is interesting because on our forum, on our AMAs or whatever, we frequently get questions about, should I follow a protein sparing modified fast? Should I do this other rapid weight loss protocol? And I'm like, look, you're not an individual with obesity to a level that is compromising your health. And you are apparently concerned with performance. How do I know that? Because you're on the barbell medicine forum. Otherwise, how did you make it here?

1:01:54So it seems like that's probably not the move for lean mass preservation, for strength development. And overall, like while the adherence may not be different long-term, I do have concerns about rebound, particularly that collateral fattening situation afterwards. Yeah. Yeah. That's where, why there are criteria for patient selection for various interventions. Now these are not hard rules written in stone, no matter what, like I've certainly prescribed and done things kind of quote unquote off label from time to time, But why, for example, you see criteria for GLP-1s in general, say BMI over 30, BMI over 27 with a comorbidity as just like, here is just some like general patient screening guidelines.

1:02:35Now, have I initiated one of these medicines in a patient who did not meet these criteria? For sure I have. But there were specific reasons, justifications, and based on the conversation and the clinical assessment came to the conclusion that, hey, the potential benefits of this medicine outweigh the potential downsides. For example, one recent use had to do with a patient who had a history of pretty significant binge eating disorder. And despite their best efforts, this was a constant daily struggle that they were dealing with. Yet, through daily heroic efforts, they were actually managing to maintain a BMI below 27.

1:03:07And so they would, unfortunately, insurance is like, no, your BMI looks great. This person's every day is like an absolute struggle to deal with that concept of food noise and compulsions and things like that. I'm like, yeah, seems to me like you stand to potentially benefit from this. It's likely to remain a low dose to try to control that kind of give you a sense of control. I'm not going to crank this up to max dose and aim for massive weight loss, but that's not the aim of this intervention in your situation, right? Similar with metabolic bariatric surgery, there are criteria for the type of person who undergoes it.

1:03:37We would not generally be doing metabolic bariatric surgery on somebody who's BMIs 25 or something like that. You don't see scenarios where somebody gets that surgery and then it's like, oh, they're losing way too much weight, we end up needing to put them on, you know, IV nutrition afterwards to keep their weight up or something like that. It's like, if that's the case, I had questions maybe about the initial patient selection criteria, maybe about the way that the surgery was performed, the way it was set up led to, you know, overdramatic weight loss, maybe they need a surgical revision, things like that, like back that off, etc.

1:04:06So you need skilled clinicians doing this kind of patient selection, and then guiding through that process of potential benefits, potential downsides. Are we meeting traditional criteria? Are we going off label? Or are you just like not a great candidate for this? And why? And what are our alternatives instead? Yeah, perhaps the DIY use and pill mill situation would be exacerbating the risks. Yeah, totally. All right. Well, that is a wrap on the Barbell Medicine Podcast. Special shout out to Dr. Austin Baraki for joining us on this mystery case. If you liked this episode or other episodes, please leave us a five-star rating and a review.

1:04:40It really helps drive traffic to our podcast so we can keep bringing you all the latest nuance in health and fitness. For everyone here at Barbell Medicine, I'm Dr. Jordan Feigenbaum. We'll catch you next week and every week right here on the Barbell Medicine Podcast.