195. GLP-1 Maintenance: What Do We Actually Know?

Welcome to the obesity doctor podcast where we explore the science and lived reality of health, weight management, and lasting change. I'm your host, Dr. Sasha Hai, an obesity medicine physician and founder of the high metabolic clinic. Here we cover metabolism, mindset, behavior change, and medical treatments for obesity, along with practical ways to nourish and care for your body sustainably. This is general education only. I am a doctor, but I'm not your doctor. Please seek care from a qualified health professional. Let's get into it. Hi, my friends. Welcome back to the podcast. I am in Milan this week for the EASD Annual Meeting, the European Association for the Study of Diabetes Annual Meeting. I am here mainly to listen to all of the talks about Mazzledi and Mashed, which is metabolic associated stato hepatitis, so liver disease, adiposity related liver disease, and obesity, and it's been a really packed week with lots of first announcements of clinical trials that has been really interesting. I just attended a talk this morning on the phase three clinical trial report of the drug red attruthide in adults living with obesity and type two diabetes, really promising data. There is everything from phase one clinical trials being read out and phase two and all the way to phase three and pre clinical trials, animal models. So, so interesting. There is a huge pipeline of obesity and diabetes medications coming out, GLP1, but lots of other molecules and other peptides like glucagon and amelin and GIP. These are other peptides that you are going to be hearing more and more about. The field used to be so simple when I started as an obesity position. Firstly, we had no medications and then we had one and then we had two and I was like, this is so easy. It's a very easy field to be a doctor in because I don't have to know that much. And it was much more about the art of medicine than the science of medicine. And now I feel like there's just this onslaught of science that I need to know. And so I'm going back to my residency days of actually having to really read papers and understand them and understand clinical trials. So anyway, it's really fascinating. And it's kind of been fun to be in the lawn on my own. I miss my kids and my husband. I kind of wish they were here. But at the same time, I've been able to be more spontaneous. I took a train out to Lake Como on one evening and I went for a run by the lake there, which was great. And I have just been finding different patches of green space to run around because downtown Milan is very, very busy, but it's been fun. I think running is the best way to explore the city because I just get to see so much of it on foot. So I've been really enjoying that and I just got back to my hotel room. It's now eight o'clock at night and I picked up the most delicious pizza on the way back. And I'm not actually a huge fan of Italian food to be totally honest, but this pizza, I don't know if it was because I was hungry. Or it was just like so fresh, but it was probably the best pizza I've had in my life and it had like ricotta cheese on it and the ricotta cheese was so smooth and velvety. Anyway, it was delicious and I think maybe part of it was like I was just so hungry and just wanted to eat it and I was by myself in my hotel room so I could be messy and not worry about being really polite, so that made it all very enjoyable. Alright, anyway, not what I want to check about today. What I want to talk about today is GLP1 maintenance and what we actually know about weight maintenance on these therapies. And, you know, right now, I'm still talking a lot about GLP1, but there will come a day where we can't just talk about GLP1 because it's not going to be the only player or the main player. There's going to be so many other molecules and so we're going to have to broaden our understanding of obesity treatment, but anyway, for today, one of the questions I hear all the time from patients who are taking a GLP1 or GLP1 based medication is, all right, I've lost the weight. I wanted to lose. I'm done and the medication is not really working anymore because my appetite's increasing, so I think I'm ready to stop it like what happens now. And I think this is one of the most important conversations we can be having about obesity treatment because we're not doing people a service if they are going on and off therapy and I have conversations about this all the time with my colleagues. In fact, we talked about this last night at a dinner meeting. I was attending about how often we're seeing patients who were initially on sex and then they lost the weight and then they regained the weight and then they stopped and then they regained the weight and now they're coming back asking for is that bound and you know, and each time it doesn't seem as effective the next round. And as physicians, a lot of us have concerns about this. I definitely do. And I think as long as we continue thinking about these as weight loss drugs, we're going to miss, we're just talking about the wrong thing. Yes, these medications cause weight loss, but it's the reduction in adiposity. So if we think about adipose tissue as the problem because adipose tissue is the problem. Access adipose tissue is what leads to the whole inflammatory cascade that leads to the cardiovascular complications, along with a whole host of other metabolic and other complications like obstructive sleep apnea as an example, liver disease as an example. We need to be thinking about these medications as risk reduction and improving health. It's not just so that you can be a certain size or a number on the scale. And I know I say that, but it's like, don't even think people fully grasp it yet because I needed to hear it. And I need to hear it again and again and again. And I'm pretty, you know, established in this field. I've been doing this a long time and I still need to hear it. So coming back to, do you stay on the same dose that you used to lose weight? Can you reduce the dose? Can you eventually stock the medication? Could you take the medication less frequently? And what happens if you do start to regain weight, do you simply restart treatment? Like so many questions that people have. No, let me pause. I will answer them, but let me just pause. Okay, I want you to think about another chronic disease. We're going to use the example of hypertension. It's an easy example. So high blood pressure, right? If you go and you see your family doctor or you see a cardiologist because your blood pressure is super high and you get put on an ACE inhibitor, like parinda pearl, you know, there's a number of medications that you can get put on. And your blood pressure comes down, would you then be saying, okay, when do I get to stop this? No, you'd be like, okay, wow, we found the right medication has brought my blood pressure down. It makes sense. I need to continue this because otherwise my blood pressure is going to go back up. It's like that with any chronic disease. And yet we don't, you know, there's no discussion. There's no like social media posts about while I was able to stop my parinda pearl and I so I wouldn't prize, right? Like there's just this weird like you're winning if you can reduce your dose or be on a lower dose or stop your medication. It's just this weird thing. And it comes back to we don't understand obesity. We don't understand it's a disease. We still think this is just about weight loss and feeling better in your body, right? And that part is valid. You're allowed to feel better in your body, you're allowed to want that, but let's not lose sight of the fact that it will be cities of disease and it's a disease that's associated with over 200 health complications. Okay, grant over. So I wanted to go over some of the more recent clinical trials looking at maintenance because we now do have a couple. So we have surmount maintain looking at turns appetite as well as a teen maintain, which looked at switching people from turns appetite, which is that boundary to an oral molecule. So or for gone. Let's go with what we already know and has been very, very well established and I have this conversations with patients almost every visit and definitely at the beginning when we're starting therapy and it needs to be reinforced. And I think if you are a physician listening or a healthcare provider listening, this would be a take home message is you need to have this conversation about long term therapy early and frequently reinforce the message over and over and over again. That's the only way we can provide good obesity care. So we know in step one extension, we know from surmount four that people who stop semi-glute hide after successful weight loss within a year, two thirds of the weight had been regained. That was step one extension in the surmount four trial with turns appetite, people who received turns appetite for 36 weeks and then they were randomized to either continue with treatment or switch to a placebo. Those who continue to treatment lost additional weight, that makes sense, those who stopped and received placebo regain a substantial amount of weight over the following year. So we have very good evidence that if you stop these medications, the weight will come back on. And I think it's just important to recognize why, okay, why is that because inevitably the question I get asked is, yeah, but I've completely changed my habits. Right, like I have completely turned my eating around, I'm in control, I have a really good plan, I'm exercising now consistently, like I've changed everything since starting the medication. And people don't realize it's the medication that has allowed you to do all of these things. The medications act on those parts of the brain that get really heightened with weight loss. So we know that there are certain key areas of the brain that when you lose weight, so adipose tissue, your brain is defending against that reduction in adipose tissue mass, fat mass. And so hunger will increase thoughts about food will increase the food. The noise will come back right back, the cravings will come right back. All of those things that were addressed with the medication that made it easier to eat on your plan and choose the healthier option, then have the smaller portions and not eat when you're not hungry. All of those things were taken care of and that's what facilitates people being able to feel like they're in control and say they don't realize it's the medication that did it. So if we take the medication away, all of that sense of control goes away too. And it's that return of the hunger, return of the food noise, that then drives increase in food consumption and the weight gain that happens when people come off the medication. But because this is what people want, they want to know, well, does maintenance have to look exactly like weight loss treatment? And honestly, my answer would probably be absolutely yes, like whatever you did to lose the weight, we know is what you have to do to maintain the weight, but researchers are looking into this and that's where the surmount maintain and then a teen maintain came in. So two trials. Surmount maintain gives us information about the ability to reduce your dose of trizapatide. So this is people who had been treated with trizapatide for 60 weeks and we're taking one of the two higher doses. So either 10 or 15 milligrams, that's the maximum dose. So they were on their maximum tolerated dose and they had already achieved meaningful weight loss and then they were randomized to either a, continue their tolerated dose, b, reduce their dose to 5 milligrams or c, switch to placebo for another 52 weeks. All of these people also continue to receive lifestyle counseling, okay? That piece is important. So remember, they're still doing the things as best they can with support. These were people who had already been on trizapatide for a year and then they're either continuing reducing or stopping, right, essentially with placebo. And so the question was, well, once you've achieved substantial weight loss, because remember, at about a year, you're done losing weight. You're in the maintenance phase, you pretty much reached that in a deer of weight loss. So how much medication do you need to maintain that weight loss? And what they found was that people who stayed on their maximum tolerated dose had the greatest overall maintenance of weight loss. This is exactly what I would expect. So people who stayed on the 10 or 15 milligrams, they maintained their weight loss. Their average weight loss was about 21 percent below their original baseline at the end of the study. So they were able to lose weight, maintain that weight. The people who reduced their dose, their weight came back up a little bit and at the end of the trial period at the end of the 52 weeks, their weight loss was at about 16.6 percent. So still down, but they had regained a little bit from around that 20 percent mark. The placebo group, so these are people who actually had a withdrawal of therapy. They were still down as well, but they were at 10 percent weight loss. So significant regain. So if we're thinking like the native of weight loss is about 20 percent with prosepitide, they were now up to 10 percent weight loss. So reducing the dose of five milligrams didn't mean that they all immediately regain their weight. In fact, they did maintain considerably more than those who stopped treating it all together, but there was some regain. And so the higher dose did better on average. And I think that that is clinically relevant. In the real world, I often have patients who maybe they do go up to 10 or 15 milligrams, but they can't stay on it forever because of a number of reasons, often it's financial, the cost of a 15 milligram pen is more than a 10 milligram pen is more than a 5 milligram pen at least in Canada. And so they ask about, well, can I reduce the dose? And of course, we try to find ways of making this cost effective, but this is relevant. This is an important piece of information. So the answer is yes, you can reduce the dose to five milligrams who will regain a little bit of weight, but if you stay on the five milligrams, you will still maintain a considerable weight loss, something around 16.6 percent from your initial starting weight, but if you're able to stay on the higher dose, then you should maintain all of your weight loss somewhere around the 21 percent mark on average, and everyone is going to have some variability. Another way of putting this among the people who stayed on the maximum tolerated dose, they maintained 96.5 percent of the weight they had lost. Of the people who reduced their dose to five milligrams, they maintained about 67 percent of the weight they had lost. Those who switched to placebo, i.e. withdrawal of treatment, maintained 42 percent of the weight they had lost. So I think there is evidence that a lower dose can maintain a meaningful proportion of prior weight loss in some people, although likely if possible, it's better to stay on the higher dose treatment. As a reminder, there's no prize for being on a lower dose. You're not a better person if you're on the five milligrams dose compared to the 15 milligrams. You're not somehow more controlled or you don't have more willpower because you're on a lower dose. It doesn't reflect any of that, and I do think that kind of enters into the psychology around this discussion sometimes, so I just wanted to speak to that. Interestingly in this trial, they did something called rescue therapy. And I am really happy that they did this, and it's really helpful for us as clinicians as well to have some guidance around this. So what rescue therapy is, is in the people who had either the dose reduction or they saw treatment, i.e. the placebo group, if they regained more than 50 percent of their weight lost, they were put on rescue therapy. Of the people who went down to the five milligrams dose, about a quarter, 25 percent of them had to go on rescue therapy because they had regained 50 percent of their weight. Of the people who switched to placebo, 67 percent, like that's a huge number, two thirds of people who switched to placebo, i.e. stopped, had regained 50 percent of their weight, and then went on rescue therapy. So that is important because in real life, often these people get missed. So what classically happens is people think they can "do it on their own now". And so they stop treatment. And maybe you're also lost a follow-up during that period because they think, "Well, I'm not on the medication anymore. I don't really need to see the doctor anymore." And then they start regaining the weight, but don't seek help. Because again, they internalize this as something wrong that they are doing, right? It's their fault again. And then they come back, you know, and if they're seeing me, like they come back a year or two later and they've regained the weight and then some, and now they're looking to go on therapy. And what I know, at least anecdotally, is the earlier we can intervene in that regain period, the better off, because I have seen so many patients now when they've regained and then some that we just don't get the same response the next time. So I like this. This 50 percent mark. If you regain 50 percent of your weight immediately, you should be, you know, considering getting on rescue therapy, that is something that I think is a really important takeaway, both for physicians listening as well as patients listening. I would actually argue that 50 percent may be too high, but that's just the number that they used in this trial. The principle is pay attention. If you are regaining weight, if you're noticing your symptoms of obesity coming back, i.e., the excess hunger or the lack of satiety, the desire for food, the constant food noise, that is evidence that your disease is not being treated and should prompt you to think about rescue therapy. Okay, so that was surmount maintain. Now let's talk about attain maintain. This was slightly different. This was people who were on trizapotide, and then the researchers looked at whether people could then transition from an injectable incretion i.e., trizapotide, okay, is that down to oral or forgletron, which is a non-peptide GLP1 receptor agonist. So it activates the GLP1 receptor, but it's not actually a peptide. So slightly different than what we are familiar with. This was a phase 3B randomized double-blind placebo controlled trial, and this was participants who had already been on 72 weeks of trizapotide in surmount 5 or semiluteide. So they had been on one or the other at the maximum tolerated dose. And then there were two cohorts. One included people who had previously been taking trizapotide at 10 or 15 milligrams. The other was people who had been taking semiluteide at 1.72.4 milligrams, so kind of the higher end doses of both medications. They were then randomized to daily oral or forgletron or placebo for another 52 weeks. So what I find interesting here is that we're no longer just asking, okay, well, what dose of the same injectable drug should we continue for maintenance? We're asking 10-week transition from one Inquitin therapy to another formulation, maybe an oral formulation, and still maintain the benefit. The results were encouraging among patients who had reached a weight plateau. So they had lost their weight, who had previously been on trizapotide. They maintained about 75 percent of their prior weight reduction when they switched to or forgletron. If they stopped therapy, then they maintained only 50 percent, okay? So make sense. We're seeing weight regain when you stop treatment, but if you go on to another medication, there's some weight regain, but you're able to maintain about 75 percent of the weight loss. Compare this to people who had previously been on Samoglutide, 80 percent. maintenance of the weight reduction with or four glopron compared to 37% with placebo. So again, we see the same general pattern. It's not quite as good to switch to or four glopron, but it's pretty good, right? So you maintain 75% of the weight loss, i.e., regain 25%, or you maintain 80% of your weight loss on semi-glutide, i.e., regain 20%. But if you stop, i.e., switch to placebo, then there's a higher likelihood you're going to regain substantially more. So this is an important development because there may be patients where they can't stay on the injectable medication over the long term for, you know, they don't like the needles or they get a reaction, the injection site, whatever. There's many different serious, and they want to know about oral options. And oral or four glopron does not need to be refrigerated, right? It's simple. It's a pill. You just take it once a day. So that is interesting. There is an important limitation to this trial. There wasn't a group that simply continued their original injectable medication. So we can't look at these results and then conclude that oral or four is equivalent to continuing with transapotitis, because they didn't look at that, they didn't test that. It only tested whether switching to or four glopron was better than switching to placebo. So there are some questions still, but I think this is a good start on talking about maintenance. So what I think we're still missing, for me, some of the interesting unanswered questions are actually the ones that these trials were not designed to answer. So for example, what if we slowly taper down treatment, right? I have done this with some of my patients who are really insisting on wanting to reduce, and we kind of slowly taper and we assess their response, we check in on their symptoms, we assess ongoing cardiometabolic parameters, are they regaining weight, how's their hunger, how's their food control, all of that. So I think really close follow up is another important takeaway for any physician listening, follow your patients. Another question that we don't know is what if we extend the interval between doses? So these are once weekly injectables, but I have some patients who are like, oh, I only needed every 10 days or I only needed every 14 days. I would not say that that's the majority knowing what we do know about the half-life of these medications, because appetite being five days, sema a little bit longer, generally people tend to find that the effect, the benefit that the experience on appetite and food control is kind of wearing off by the end of the week, but certainly an option, right? Could someone who's stable maybe stretch it out to 10 or 14 days? We don't have the answers yet. And so there's a little bit of an art to this, right, where OBC physicians have to work with our patients to individualize things, and we don't have really solid diets here. Another question, and this is where the rest of you protocol was so interesting, is, okay, well, could we stop treatment, really closely monitor patients, and also this involves educating. It's not like I'm seeing them every week in clinic or every month, it's more educating them on, this is what you need to look for, here are the symptoms you need to look for that indicate that your disease is coming back, here are the signs, like this is how much weight regain we're going to tolerate it not more, right? Could we then closely watch and then resume therapy with rest of therapy if we see the disease coming back? So I think we have some interesting data on maintenance, we still have a lot of unanswered questions, maintenance I think is generally best if we continue on the medication that is working and this data supports that, at least with surmount maintain, but for a number of reasons, whether patient preference or other reasons, sometimes we do need to make changes, and so we still do have pretty good options for maintenance. I think this is where we have to stay humble and acknowledge that we don't have all the answers yet, we have emerging data, and there's so much ongoing data and research in this space, there's a little bit of an art to this, it's a little bit of like working with our patients and finding what's right for each individual, and I think that's what makes this also very interesting as a field, is that it is kind of still developing so much and we have so many better therapies coming. I think that in my experience, I have to work individually with each patient, there are some patients who I tell them from the outset, like you have had chronic obesity since childhood, look at your family history, like this is ingrained in your biology and your genetics, it's exceedingly unlikely that you're going to be able to manage this disease without addressing that biology, and that means medical therapy and likely indefinite lifetime medical therapy, and I think if we can firstly remove the blame that a lot of patients have, help them to understand, hey, it's just biology, it really is, it's biology, and it's whatever genetic predisposition, and that's why you need this, then it just helps with that long term adherence to medication, and then there's like a subset of patients where I'm more open to exploring whether they could eventually reduce or come off of medication, so this might be a woman who like never had way issues her whole life, but just now she's gone through the post-menopausal period and has gained a significant amount of weight, particularly central adiposity, and maybe she's got some cardiometabolic changes happening as a result of this acute period of weight change, this is where maybe, you know, maybe we can talk about exploring whether she could reduce the dose and see how she's doing, particularly if she has very strong health behaviors, and I mean pre-existing, not like health behaviors that just came along with medication, but pre-existing, strong health behaviors, including like good underlying muscle mass, like this is someone who's trying to train, then we might have a conversation about this, right? It's shared decision-making between the physician and the patient, and it's always individualized. The key is, you know, we need to have good follow-up, we need to more closely and be prepared to act early if we see a sustained upward trend in weight or deterioration of other clinical markers, like cardiometabolic markers on blood work. And I also find that some patients can successfully reduce their trizapatide dose while maintaining much of their benefit. I haven't actually found this as much with SEMA. In my practice, patients who get up to maximal dose, semilutide, it's very rare that we can reduce the dose and still see maintenance with benefit, usually they need to stay on the higher dose. All right, so where does that leave us right now? Well, I think the evidence gives us fairly clear messages. First, for many people, obesity treatment needs to be thought of as long-term treatment, lifetime treatment, rather than something that ends when a goal weight is reached. Second, the dose required for maintenance may not necessarily be identical to the dose that was required to achieve the initial weight loss, but you're likely going to have the best long-term weight reduction and weight maintenance if you do say on your effective dose. You need to reduce that's a better option than stopping altogether. And then, if you need to switch to oral or forklopron, which is coming to Canada, hopefully early 2027, that is also better than stopping therapy altogether. We still have a lot to learn about how flexible maintenance treatment can be. We don't have all the answers. We don't yet know about gradual tapering or extending the interval between doses or stopping and then closely monitoring. So I think it will be very interesting over the long term to see what level of treatment does this individual need to maintain the health benefits they've achieved and how we do we know when those needs change. I think something very interesting that one of the top obesity researchers said yesterday, he was saying patients have, by the time they've lost the weight, they have invested so much money into that. And if you can just help them see that you stopping your treatment at this point is throwing those thousands of dollars in the garbage because of what we know about weight regain. That might be a way to frame it to help people understand like, hey, it's not worth it. So there's the financial argument, I would say, that there's also the health argument, too. Remember, obesity is a disease where adiposity is causing problems, very, very real complications to over 200 different health conditions. And that's what we're treating. That is what we are preventing and treating when we are treating obesity. And so, like, stay on the therapy that's working to maintain those health benefits and reduce the long-term risk. All right. I hope that was helpful. Sorry for the sound quality. I don't have my usual microphone with me here, but I wanted to get this out and thanks so much for listening. I would love it if you could share this with a friend, share this with someone who needs to hear it. If you could help me get the podcast out to more people, I would be very appreciative and I love getting good quality content out to you. So thanks so much, talk to you soon, bye.