Direct Line April 2026: Stopping Ozempic and Lifting With Osteopenia

0:28Welcome back to the Barbell Medicine Podcast. acsm resistance training standards how to train the frail elderly and more and to help us argue with your drunk uncle your orthopedist the environmental working group and sabrina carpenter it's the second most handsome doctor in north america dr austin baraki what's going on man i do not know that i have such a diverse skill set as to take on all of those targets it's actually the same argument for each of them have you tried caring less that'll work all right fair enough. How are things going? Hectic. I've been in the hospital for a couple days and today was a particularly busy day.

1:03Had about I think 16 inpatients that I saw with my team and managed to discharge about half of them. Had an ICU transfer for a relatively rare diagnosis that needed more urgent management. So yeah a lot going on today. You busy. Okay so not enough to keep up with the what's happening with Sabrina Carpenter, the Coachella controversy. My wife and I did couchilla before I started in the hospital. So I just started on Monday. So we did sit on the couch and watch some of the main acts. And that was one of them. Some of the contrast between some of those headliners in terms of, let's call it the effort that they put into their show was amusing to us.

1:36I mean, I just hope that at some point I can just get on stage and play a YouTube playlist, like just our greatest hits maybe, you know, I don't know. Yeah. All right. Well, let's start off here. We're going to start with GLP ones. No surprise. This first question came from, again, and one of our Barbell Medicine Plus subscribers, and it points at something most of the popular coverage on GLP-1s has missed. The question is, what are your thoughts on the new British Medical Journal paper showing that GLP-1 cardiovascular protection fades after stopping? And more broadly, what is the durability of effect of GLP-1s versus lifestyle versus no intervention?

2:10So the number to keep in your head for this one is two thirds. That's how much of the weight someone regains within a year of stopping a GLP-1 on average. All these trials point to a similar response, and let's go through them one by one relatively quickly here. So we don't spend 30 minutes on this answer. First is the Surmount IV trial. So in this trial, everyone ran a course of terzepatide. So that's Zep bound or Monjaro. By week 36, the group had lost an average of about 20 % of their body weight. Now, at that point, the trial randomized patients into two arms that were otherwise identical.

2:41So half continued using terzepatide. The other half switched to placebo. Both arms still had the same lifestyle support and the same counseling, all that entailed. The only variable was the medication at this point. Now, the continuation arm, the people still using the terzepatide, they kept losing weight. About, on average, an additional 5.5 % of body weight over the next year. Again, that's on top of the 20 % or so they already lost. The placebo arm regained about 14 % of the weight they had lost previously. And again, that's over the next year. About two-thirds of what the drug had produced was gone inside of 12 months.

3:15Same people, same counseling. The only difference was the drug exposure. That's the Surmount IV trial. The Step 1 extension trial is a longer-running version of the same type of setup. Now, semaglutide in this study, so Ozempic, produced an average of 17 % weight loss when people were taking the medication. By week 120, the net sustained weight loss was about 5.5%, and roughly half of the previously treated group was still at or below 5 % of their initial starting weight. Step 4 is another useful study in the semaglutide series with similar findings. Now, what you've probably seen more recently is this new headline that people who use these medications use GLP-1s.

3:55They gain the weight back four times faster than those using lifestyle alone. This is based on a new systematic review looking at 48 studies on the use of GLP-1s and what happens when people come off them. Now, how this weight regain goes is that it's more swift earlier on. So there's rapid regain early and slower regain later, usually plateauing around 60 weeks. the trajectories across drugs look pretty similar once the data is normalized to a percentage of weight loss though there is some difference in the amount of absolute weight regain based on the different agents because it's usually small differences now again what you've seen quoted by mainstream media and by we'll just call them glp1 skeptics is that people regain the weight that they lost on glp1s four times faster than lifestyle only now the problem here is while that is true from a mathematical sense, the amount of weight loss from lifestyle only is way, way less than what we see on GLP-1s.

4:52What we see with like semaglutide and trisepatide in particular, it's about a three to four times greater amount of weight loss. And so if you didn't lose that much, it's going to be hard to gain that back relatively quickly. So if there's more weight to give back, the body gives it back a little more swiftly, but on a percentage of loss basis, the amount of regain is about the same, especially when we compare that to lifestyle only interventions, which I think is an interesting comparator. So we have a number of trials that I consider are probably the best sort of lifestyle only intervention studies that we have, where they have intensive sort of dietary counseling, intensive exercise counseling and follow up and monitoring.

5:33And so you know, these are things like the diabetes prevention program, the look ahead study, pounds lost, etc. And just to kind of go through a few of them, the diabetes prevention program randomized over 3 ,000 adults with overweight or obesity and impaired glucose tolerance to either get metformin, placebo, or intensive lifestyle. At one year, 62 % of the lifestyle group had lost at least 5 % of their initial body weight. But by the 10-year follow-up, more than half of that weight was regained despite ongoing program engagement. So it's not like they stopped using GLP-1, for example. They continued doing the lifestyle but still gained the weight back.

6:08In the look ahead trial, there was over 5000 adults with overweight or obesity and type two diabetes. The intensive lifestyle group averaged about an 8.6 % loss at one year, compared to 0.7 % without it. 68 % of those individuals hit the 5 % sort of weight loss threshold, which we call the sort of clinically significant weight loss. The intervention continued on for years, but by year four, fewer than half of those who achieved this clinically significant weight loss had maintained it. So they were under that sort of 5 % threshold. And the last one we'll cover here is the pounds loss trial. This is 811 adults who were basically randomized to four different macronutrient patterns, all at a 700 calorie per day deficit.

6:49Ideas like, oh, is there a specific macronutrient split that these people need to follow to lose weight? The specific diet didn't matter, but only 15 % of the participants in the pounds loss trial lost 10 % or more of their initial body weight. And that's an important comparison because if you compare that to like the step one trial where they used ozampic semaglutide um they hit 69 of those individuals lost 10 or more the surmount one trial where they used her zapatide 83 hit a 10 weight loss or more uh and so you know if you ratchet that threshold up to like 15 of their initial body weight lifestyle alone rarely hits this number but in the step one trial again using some aglutide over half of them hit that threshold and using church appetite 71 percent hit that threshold so i think this reframes the question here the comparison really isn't between like what are the what's the durability of lifestyle only versus uh you know using glp1s and then coming off lifestyle alone produces a more modest loss of of weight that's being pretty charitable to it.

7:56And it seems to also generate, you know, the same sort of response. People regain the weight. The difference is they're not stopping the lifestyle intervention. They're still doing it, but they regain the weight all the same. So Austin, when you're working with somebody who's interested in starting to GLP one, or they're already on one, do you answer a lot of questions regarding like coming off or tapering down or anything like that? And how does that conversation go? Yeah, I have these conversations all the time. It's a very common concern, common set of questions? What does long term look like?

8:26What does maintenance look like? What can I expect? And I don't tend to cite very specific data, but rather I point out that this is most often for the types of people that I'm talking with a lifelong journey. It's often something they've been struggling with for a really long time. And just intuitively as a result, something that you've been struggling with for a really long time, be it since you were a kid in some cases. It's kind of unrealistic to expect there's just going to be, oh, use this medicine for a couple weeks or a couple months and it's just going to cure this thing forever, right?

8:57So it's going to tend to benefit from some form of long-term treatment. It doesn't have to be the same long-term therapy indefinitely. We can change it. We have options. We can adjust dose. This whole space is evolving. There might be different options for maintenance in the future, but some form of long-term treatment is more likely to be effective than doing a short course and then stopping just because everybody pretty much can lose weight up front as is shown pretty commonly in these trials, but relatively few can sustain that weight loss and why is that well the underlying biology of weight loss is is pretty challenging there's an interesting series of papers i think it's in might be in the obesity medicine journal where they they title it something to the effect of like the physiology of the weight reduced state looking at what are all the things that happen physiologically when you lose weight in other words what are all the ways that your body fights back and the way i frame it to patients is that the medicine does not lose the weight for you but rather it helps you battle against your body fighting back when you successfully lose weight in the first place so it tamps down that biology of the rebound that we observe in these lifestyle studies and these lifestyle studies these like high quality randomized intensive lifestyle interventions these are the kind of papers that i wish people would have a better understanding of when they go out on threads or twitter and they're like if only doctors just prescribed more lifestyle And it's like, well, here's what happens when we try in very intensive, high resource fashion.

10:22People lose a bit of weight. And then despite persisting in the program, the biology of the weight reduced state tends to win in the long term in a lot of these folks. And yet we can, you know, arm ourselves with these tools and we can actually win that battle way more often. And that's the way I view them as just tools. So how do things tend to look long term? Yeah, most people benefit from long term therapy. Some patients are able to come down and dose a little bit in maintenance. some patients are able to space out their dosing and maintenance a tiny fraction of people can come off the medicines entirely and maintain their weight loss but I don't set that as a standard expectation and so that's kind of what we what we look for and so I also don't tend to cite very specific figures because there's just so much variation between people so I say here's what we see on average this is kind of what I would generally expect but you are going to respond as an individual and so I'm going to walk with you through this journey and we'll kind of figure it out together and that usually you know lands yeah no no it's true so if the average you know weight regain from a glp1 cessation so coming off is about two-thirds of the weight that people lost will come back within the next year or so the other number that you need to keep in mind is that only about one in ten people doing lifestyle only will not only achieve clinically significant weight loss even with the lower sort of threshold five percent but then keep it off maintain that right and so that kind of speaks to your experience though here as well you're like look a small fraction of folks who come off glp ones we would maintain it um the other you know continued lifestyle uh interventions and that's kind of what we see with lifestyle interventions generally speaking and so yeah we've been championing lifestyle interventions for a long time now the the thing now is we just have better tools to get people where we want them to go and we are sort of agnostic to like how you got there provided you actually get there and it's done through generally healthful means right so like using a tapeworm or getting cancer is not going to be the advisable way to do that yeah we don't recommend dnd tapeworms yeah exactly but but if you think about like the question because a lot of people reflux to like well how soon can i come off the medicine you don't really tend to see very many people going and doing a consultation with a bariatric surgeon for like gastric bypass surgery or ruin wine they're like okay well so how soon can you undo my surgery it's like that's not how this works you know yeah so yeah so so the question is you know if about uh two-thirds of the weight that's lost is regained within you know about the next year after coming off, what does that regain?

12:45What effect does that have on sort of health outcomes? And so this is the paper that the question asker was referring to. So in this particular paper, it was recently published, 37 randomized trials covering just under 10 ,000 adults who had been on one of these weight management or anti-obesity medications. And the question that the researchers asked was simple. Once people stop the drug, what happens to the weight and these sort of cardiometabolic markers, right? And so a few caveats. First, most of these trials followed people for a year or less after they stopped. So the authors used some sort of statistical modeling to basically take the observed weight regain curves and the observed sort of changes in these metrics like blood pressure, cholesterol, fasting, blood sugar, and so on, and plot those out over time.

13:31So they directly measured the rate of regain within about a year and then they kind of modeled it afterwards so across all of these anti-abesia medications that were paired with a behavioral weight management program the average regain was about 0.4 kilos per month for the newer glp1s specifically so somaglutide and terzepatide the regain was actually more 0.8 kilograms per month and so if you just read that you'd be like these are worse they're worse well the thing is they just lost more weight compared to liraglutide in some of the other older agents. Same thing as the comparison to lifestyle.

14:06And I think one of the earliest characterizations that I still like and I still anchor to is that these are really just behavior change agents. Rather, if you don't wanna call it an anti-obesity medication, if you wanna call it a behavior change agent, I like that because it allows people to do the things they've been wanting to do the whole time or knew that they should be doing. So anyway, they projected this forward in time and the return to sort of baseline weight where people started using these medication plans at right around one and a half years for most of the drugs that were included.

14:35Again, these are modeled projections, not necessarily accurately measured or directly measured because most of the studies didn't run out that far. And so they used a similar approach for health metrics. So things like hemoglobin A1C, that's a measurement of how much sugar sticks to your red blood cells over a few months, basically is your blood sugar maintained within a normal range. They track fasting glucose, they track blood pressure, total cholesterol, triglycerides, etc. or they all moved in the same direction. Once the drug was stopped, every one of those markers started to drift back towards baseline at a relatively steady monthly rate.

15:09And that kind of tracked or correlated well with the amount of weight that was regained. And so we've talked at length about various benefits from taking these medications as well. We know some of the effect that we see, blood pressure lowering, for example, blood lipid lowering, blood sugar lowering has to do with weight loss. But there does also appear to be some weight-independent effects, particularly on things like cardiovascular disease and chronic kidney disease. We talked about the SELECT trial, looking at cardiovascular disease, and this sort of health benefit popped up early, before the weight loss even occurred.

15:47Same thing in the FLOW trial for chronic kidney disease. And so what the other thought was like, well, look, if there is some sort of weight-independent effect of these medications, is that durable? Does that stick around when you stop the medication? And it doesn't seem so, although, again, this wasn't tracked out for years and years and years to really know. But I think, or at least the way I think about it, you can weigh in on this. If you see some sort of independent effect of the medication outside of the mechanism by which it works to achieve the observed endpoint, when you stop taking the medication, you're probably going to stop getting that effect.

16:22Does that make sense to you? Yeah, I'm racking my brain trying to think of another example of like a medicine, especially in adult medicine land. If I'm thinking in other contexts, like you could be like, oh, well, giving, I don't know, antenatal steroids or something for fetal lung maturity is like a one-time dose and it like fixes something. But that's not something that we really tend to see in adults outside of short-term acute conditions like an infection where you take a course of antibiotics and clear the infection and then you can stop. But that's not the same as a chronic long-term condition like hypertension, hyperlipidemia, insulin resistance, diabetes.

16:56so i'm having a hard time thinking of examples uh that that where you could be like well why doesn't it work like that it's like no pretty much all these long-term conditions require ongoing exposure to the intervention to deliver a sustained uh benefit um until we get to more of the the gene therapy type stuff which is um you know not really accessible for a lot of these types of conditions and even when it is i suspect that a lot of the people who are big anti-glp1 fans because the weight comes back when you stop it i don't think that they're going to be flocking to gene editing therapy either so no no yeah although they didn't discover a new protein i think it's brp or something if you read anything about that in mice it seems to be like at the level of the brain very very localized compared to glp1 receptors which are everywhere and so you know this is being celebrated oh we found this new molecule we can just attack the obesity cause and and then there's some pushback we're like yeah but do you get these other additional benefits that maybe you get by selecting the glp1 receptors and i guess we'll find out in 25 years Yeah, exactly.

17:55So yeah, I do think the way to frame this is that the drugs work when you take them. And it's similar to kind of what we see in heart disease, where the benefit of say a lipid lowering drug like a statin, the benefit is proportional to how much they lower the lipids and how long they're lowered for. the question isn't really whether the effects persist when you're off the drug the question is about how much cumulative risk factor reduction the patient you know sort of bought during the time they were on glp1s behave the same way austin is that kind of how you think about it yeah i i suppose you could think about it that way in terms of uh well we're reducing your overall exposure while you're on the medicine kind of when you say it that way though it's almost baked in it's like okay well until you come off and that's generally not the expectation that i'm setting especially with a lot of folks who have struggled with their weight management for like lifelong or for very very long periods of time um you know there's like obviously now going to be more conversation around uh people who maybe haven't struggled with their weight for their whole life and they're looking for so-called you know quote-unquote cosmetic weight loss there was like just a question i saw in our facebook group about this recently and you know that's a separate topic a separate conversation those are not necessarily people where it's you know i would necessarily say that you're likely to benefit from needing this uh from this therapy you know long term or even for the rest of your life whereas there are some patients who maybe they've undergone you know they've struggled with their weight since they were a child and maybe they ended up getting metabolic bariatric surgery they maybe they had some some weight loss and then maybe they unfortunately had more substantial weight regain it's like this is a we'll call it a more resistant you know phenotype of obesity to to intervene upon and so yeah those are types of people where i almost sometimes set expectations like you're going to do the best being on the highest dose of this medicine you can tolerate for the rest of your life there are some people where I can say that with more confidence.

19:39And then other people who are going to more likely settle out somewhere in between. And then a smaller fraction will be able to use it for a bit of time and maybe come off. But I don't set that as a default expectation for at least most of the types of patients who I'm seeing these days. I do think that these conversations will evolve as these medicines become more accessible, more available, more popular. And people who maybe don't have, quote unquote, as resistant of an obesity phenotype might dabble in them, then that conversation might change a little bit. But for now, based on cost and accessibility and guideline recommendations for the types of people who are getting them, yeah, most people benefit from longer term therapy for all sorts of risk reduction as well as the weight management itself.

20:14Yeah. Yeah. So to wrap this up, we need to cover what these new trials don't tell us. And the first thing is, you know, how far does the weight regain actually go? So in all of the extension trials and even these new systematic reviews that we've been discussing, you know, the follow up sort of ends, you know, whether it's a year coming off the drug and then just monitoring folks for a year or less. And so what we see in the longest lasting data sets is that it seems like only 75 % on average. That's kind of like the ceiling of the weight regain. And so is there a durable effect, you know, lasting beyond that?

20:52We don't know. We'll have to see five-year data, for example, to really weigh in on that. But we don't really know. Do people gain all of the weight back? The other thing we don't know is what is the body composition like of the weight regain? so we've talked about this at length a few times that on these medications on these glp1s the amount of lean mass loss is about the same as people see when they do a diet only sort of intervention so they don't exercise they don't lift weights but they're using a calorie restriction through a diet only approach and while it is overstated by mainstream media by influencers by again the glp1 skeptics we have good data showing that yeah it is about the same as a diet only group and the risk of losing too much muscle mass or losing a bunch of strength doesn't seem to be well supported unless inappropriate use was kind of like the initial factor here.

21:40Somebody who was already frail, had low levels of muscle mass, probably should have been prescribed these things in the first place. We just don't, we just don't really see that. There is some data out there, like the T-Rex study is going to be published at some point. It's not out there yet. We've heard some pre-publication rumors milling around that, look, these are people taking GLP-1s. They did resistance training while they were taking the GLP-1s and it cut the lean mass losses in half, which is what you see in these sort of, when you take a diet only group with, and you compare them to diet plus resistance training, that's the lean mass loss in half.

22:12So a good signal there that there's not something uniquely sort of catabolic about the GLP-1s. There's also been a recent concern that with this weight loss and because there's maybe some muscle loss there too and if it is excessive it would generally cause a reduction in sort of the the stimulus or stress on the bone so you get bone loss you get osteoporosis here although we already have data showing that look if people lift while they're on these things does seem to preserve bone mineral density which is exactly the same thing you see when people lose weight with diet only i don't i don't see the same pushback like don't lose weight with the diet if you're not lifting weights because as osteoporosis is a risk.

22:50I assume somebody said that, but I don't hear it as loudly as I do with GLP-1s. Yeah, it's a very irritating, very selective sort of criticism that comes out more in social media than anywhere else and in places that let you use more kind of attention grabbing clickbaity headlines, you know? Yeah, yeah. The composition of regained weight was also not measured in any of these cessation trials. So we don't know, is it mostly fat? Is it mostly lean mass? You would expect, just like every other sort of intervention that causes weight loss, diet, diet plus exercise, exercise only, whatever the, when people lose weight, the first thing that gets restored is the fat mass.

23:27So it would be unsurprising to me that, you know, that's the same thing we observed with GLP ones. We just don't know because it wasn't really measured. But again, I would predict it's mostly fat mass. And so this idea of like, well, you should lose the weight and then that's gets you better set up to like bulk to gain muscle. That's something we've debunked a number of times doesn't really play out. So Austin, if you have a patient who's on a GLP-1, what does the first sort of six months look like after they come off of these things? Are there specific steps that you're taking or what are you doing here?

23:57Yeah, I'm trying to, you know, provide some appropriate guidance and expectation setting up front. And I think that that experience is going to vary based on, again, how quote unquote severe or like resistant of an obesity phenotype did they have at the outset. So the more challenging cases, the ones where the obesity was the most severe, say class three obesity or beyond, people who've had prior bariatric surgery, people who've struggled again since they were kids, things like that. Those are gonna be the folks who have the hardest time coming off of these medicines, especially if they were using high doses to achieve their weight loss in the first place.

24:34People with much milder, less resistant obesity phenotypes, they might have a bit of an easier time. But in general, just based on the half-life of the medicine over the course of a few weeks, to say anywhere from like two to six weeks timeframe at varying rates, the person's appetite, hunger, so-called the food noise term that you've heard tossed around a lot of late, that appetite will tend to come back. And it comes back again to varying degrees. Some a little bit more mild, some comes back with a vengeance. And that ends up becoming the main challenge that people have to contend with. They may have to go back to, as we say, white knuckling it through the day just to try to stick to whatever plan they had in place.

25:12people with a less severe obesity phenotype who along with the medication established fantastic lifestyle habits strong dietary quality strong dietary patterns strong exercise habits sleeping well not you know using a lot alcohol low stress like an optimal situation they're gonna be the most likely to either maintain or regain the least those who don't have either those habits in place those who have you know challenges with sleep uh stress all sorts of other things that can further promote uh you know appetite increases and things like that and those who have the most resistant obesity phenotypes those are folks who are going to have the hardest time trying to white knuckle it through the day the people who wake up and they got to go to war every day and feel like they're doing everything they possibly can and if they you know i hear this a lot where they feel their perception their experiences oh if i slip up once then suddenly i gain 10 pounds and obviously it's it's quite a complex sort of phenomenon, but that's what the experience feels like to them.

26:11And so, you know, it's a tough situation. Sometimes, you know, patients have to come off of these medicines, not through their own deliberate choice, but because of insurance coverage or costs, or maybe someone wants to come off in anticipation of an upcoming procedure or a surgery or because they became pregnant. And so all of these things can impact weight trajectories with varying, you know, opportunities to reinitiate therapy on the back end. So, yeah. Yeah. I think, you know, the conversation around, you know, coming off a blood pressure medication just because you're insurance, you know, or something like that, generally not something you have to deal with because generics are available.

26:48Right. Hopefully we get to that point at some point because discontinuation is not really the goal here unless there's some other reason to do so. So, all right. To wrap this, GLP-1 benefits accumulate during exposure to GLP-1s. similar to the way a blood pressure medication does. Regain after stopping, on average, is about two-thirds of the weight that's lost. It's regained within about a year with some of those health benefits, like the metabolic markers, including fasting blood sugar, cholesterol changes, things like that. Those track with the amount of weight that's regained. But coming off isn't the goal of treatment.

27:22A person stays on, and they stay on with as much of the lifestyle change, exercise, healthy eating, sleeping habits, stress management that they can tolerate better if they do come off the treatment window was the window to sort of bolster or build those habits depending on the person so any claim about what a finite course of glp1 exposure does for health benefits down the road is beyond what the evidence currently supports but uh watch this space maybe we'll have some data on that look i ran glp1s for three months and now i have a 10 risk reduction you know of all-cause cardiovascular mortality that'd be interesting We'll see.

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