#320 – AMA 64: New insights on GLP-1 agonists (Ozempic, Wegovy, Mounjaro) - efficacy, benefits, risks, and considerations in the rapidly evolving weight-loss drug landscape

0:10Hey everyone, welcome to a sneak peek, ask me anything, or AMA episode of the Drive Podcast. I'm your host, Peter Atia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to peteratia MD dot com forward slash subscribe. So without further delay, here's today's sneak peek of the Ask Me Anything episode.

0:39Welcome to Ask Me Anything AMA episode 64. I'm once again joined by my co -host Nick Stenson. In today's episode we cover a topic that we've addressed in the past but has continued to gain significant attention since we last spoke and that of course is the topic of GLP1 agonists. You may have heard of these drugs, ozempic, and mongaro, but we go much deeper into this. Now, given how these drugs have gained popularity and given how our knowledge on them has advanced, probably non -linearly since we last discussed them, we felt it was appropriate to address many of your questions on these topics and what we've learned through our own experience with patients.

1:17In this conversation, we begin with a very quick background on what a GLP -1 molecule is, how these drugs work, and why they are finding so much utility today. We focus on what we now know about their long -term efficacy, which is longer than what we knew in the past, what we know about side effects, and what we know about what happens when you stop taking these drugs. We also talk specifically about their effects on body composition. This is something we couldn't speak to from clinical trial literature before, but we now, in fact, have that data. We talk about the role resistance training plays on these, and we talk about the differences between the specific GLP1 receptor agonist.

1:58For example, is one of the two on the market today better than others. Talk about the role compounding pharmacies are playing in this. We talk about oral versus injectables. What some other health conditions might be that are amenable to treatment with these drugs when we talk about the types of GLP1 agonists or other receptor agonists that are on the market and that appear to be promising and at least in one case potentially more promising. If you're a subscriber and want to watch the full video this podcast, you can find it on the show notes page. And if you're not a subscriber, you can watch the sneak peak of the video on our YouTube page.

2:34So without further delay, I hope you enjoy AMA number 64.

2:43Peter, welcome to another AMA. How you doing? Doing very well. Thank you for having me. I see you're in a new location today. Do you want to let people know why? Well, after some planning, we've decided to expand the look and feel and create a dedicated studio for this. So excited to have our inaugural in studio podcast today. For people who don't know, we used to transform your office, your actual work offers, into a studio every time we recorded. So how much nicer is it to not have that done each week? It's as much nicer as it is when you have to stop having a weekly root canal. That's good.

3:24That's a good much less noise going on from background, from kids or dogs or anything of that nature as well in the new studio, which is always good. For today's AMA, It's actually funny because it's kind of a little inside baseball how we do the podcast is usually There's anywhere from a 10 to 12 week delay from Podcast recording to release just with how we work But this one is gonna be released first and then we're gonna go back to the old studio a little bit in the release schedule But not the recording schedule and the reason why is we're covering a topic today that we want to turn around and get out as quickly as possible because it seems it's a topic that changes more than almost anything else that we talk about, which is GLP ones or a Zempick Trezepotide, you kind of name it as people have heard of them.

4:18And I actually look back because you and Bob first talked about this. November 2021 is when we set up a so we had a follow up March 2023. And I don't think there's been a topic that has had more change in terms of interest in that period of time than this. And I still, I said at the last podcast we did, this one too, is I remember the first time you involved talked about wanting to do a GLP AMA. And I was like, I have no idea why we're doing this. So with the most technical thing, it made no sense. No one was talking about it. And now it seems like it's everywhere. Even since the last 18 months when we did the last one so much has changed.

5:01And so in this one, we're going to cover everything as it relates to these. And we'll just go through piece by piece and we'll do a little recap of how they work. But previous AMAs will be best if people want to go into detail there. We're not going to spend as much time. We're going to spend much more time on what we know about this now and how this works. The difference between the drugs compounded injection, what we know about weight regains, safety profiles, the past few times you talked about this, there just wasn't as much information as there is now. And so I think it'll be really interesting because I think it's also one where you maybe have changed your mind a little bit based on past conversations that we had.

5:40So it will be a really good one. I think it will be really interesting. And with all that said, do you want to add anything before we start rolling into it? Yeah, actually quite a bit of context. So everything you said just to add on to that. But if there's one thing that I get a kick out of it's I'm scrolling on Instagram and I see a video of me talking about semi -glutide from three or four years ago and I frankly don't even necessarily agree with what I was saying at the time and that's just the nature of how things work. Our knowledge changes a lot and so that's part of my motivation for wanting to talk about this yet again today.

6:13It's that we know considerably more today than we did three years ago, but I also want to acknowledge all the things we don't know. So that's one point I'd want to make. The second point I want to make is there's at least earlier generations of these drugs have been around for quite some time. So the very first time I ever prescribed a class of this drug was a drug called Lira Glutide and it's almost exactly 10 years ago. It was in the fall of 2014 that I prescribed that to a patient. Not a particularly effective drug. So it would be another six years before I would prescribe some of Glutide to a patient in the fall of 2020 and that was a totally different experience.

6:47That was of course ozempic before it had been approved for obesity. So, yeah, I think I just have a lot of stuff I want to talk about. But to your point, there's no need to rehash stuff we've gone through before. I think it was AMA 29 where Bob and I did a very deep dive into the physiology of how these things work and we really probably spent maybe more time than we needed to explaining to people how the GI tract works and how GI hormones work. So not going to do that here. Let's cut right to it. So these are a class of drugs that were initially developed for the management of Type two diabetes.

7:21And that was largely on the basis of the fact that these are a class of drugs that mimic a hormone called GLP1, glucagon -like peptide one, that stimulates the release of insulin from the pancreas, which of course, if you have type two diabetes, as opposed to type one diabetes, is one of the routes of trying to get around the disease. When a patient's pancreas is no longer secreting sufficient insulin, that would be one half of what you would try to do. Of course, there's other things you'd try to do. It's what you want to increase insulin sensitivity. And of course, that makes it so that you don't actually need as much insulin to get the glucose into the liver and to the muscles.

8:00So if the story ended there, we probably wouldn't be talking about this. If the story ended with these are great drugs to help people with type two diabetes, which roughly speaking about one in 10 Americans have today, might not be talking much about it. If it was lowering hemoglobin A1c and things like that, I mean, that would be very important. But again, why is this such a topic? The topic is because with semaglutide, something happened that didn't happen before with Lyurglutide, which was not only did patients have an improvement in their hemoglobin A1c, but their weight dropped dramatically.

8:36And so that led to the obvious question, which is, should we be considering these drugs for weight loss and people who do not have type 2 diabetes? And of course, that was the question that was basically posed through a series of trials three years ago, and the answer turned out to be emphatically, yes. I don't think we need to get into the details, but what's the 101 four -sentence version for people as a reminder on how these drugs actually work? Let's start with the most important, which is the pancreas. So as I mentioned a second ago, it's going to stimulate their release of insulin secretion and reduce glucagon secretion.

9:09So both of those are going to have a net effect of lowering blood sugar. And the jajunum and the ilium, which are just parts of the small bowel, it's going to reduce gastric emptying and GI motility. So it slows absorption of glucose from the intestines and keeps the stomach full for longer, which by the way, might partially relate to some of the satiety benefits. In the liver, it reduces hepatic glucose production. So of course, again, probably something like what Metformin is doing there. are most interestingly, potentially, and we'll talk more about this is in the brain, it's probably stimulating pro -satiety circuits, and then decreasing the activity of the circuits that drive appetite.

9:50And again, I would say that a few years ago, when we talked about this, we really had no idea how much that was driving weight loss. I would say today we have a feeling that it's doing quite a bit. Within fat tissue itself, it's increasing glucose uptake from circulation and increasing lipolysis. Let's be counterintuitive, because on the one hand, that's taking glucose out of circulation. That kind of makes sense due to increased insulin sensitivity, but it's also counterintuitive because that should make a fat cell fatter. But of course, by driving lipolysis, it's actually increasing the throughput on the back end.

10:21In the muscle, it's increasing glucose oxidation. So increasing the capacity of the muscles to oxidize glucose will include a really nice figure in the show notes that goes through this in more detail. So folks can see what's happening. There are lots of other things it's doing that I don't think I'll talk about now, I'm going to wait and talk about them when we get to organ specific questions. For example, what is it doing specifically in the heart? What is it doing in the kidney? These are topics of huge interest today. As we kind of mentioned, it's been about almost 18 months, 19 months since the last time we spoke about this topic.

10:51And so back then, there was a lot of unknowns. We were able to speak about certain things, but then there was also just unknowns with how new these drugs were. And so what have we learned? What's like a quick overview of what we know now compared to what we knew last time we did a deep dive on this? Yeah, there's a lot. I mean, I'll start with just the fact that when we last spoke about this, we were talking really just about two drugs. We were talking about a drug called Semaglutide, which again, the brand name for that, the first one that people talked about was ozemic. It was just rebranded as Wigovie for the obesity indication as opposed to just type two diabetes.

11:28And then we spoke about another one called Terzepetide, which is a slightly different drug, as we're going to see in a moment, a slightly better drug, and a drug that works not just on GLP1, but also on GIP, another hormone. It goes by the brand name, Manjaro, but that's the diabetes version. So Manjaro is too ozemic. What its obesity counterpart, which is called Zeppbound, is to Wigovie. Honestly, I can't keep track of all these names. So I just sort of try to remember the actual generic name of it, which is of course, semically tied in Terzaghi. Today, we have another one that we will talk about that is not yet approved, but it's the one I think people are very interested in.

12:07So big picture, what do we have today? Why would we talk about this again today? Well, we have much more safety data. And obviously, one of the things that I think we should be very cautious about with any new drug, especially a drug that has this much penetration in the market is we want to understand what's happening in post -approval surveillance. So just because a drug gets approved during what's called a phase three study, doesn't mean the FDA stops paying attention. It's their job to continue to pay attention and you wanna see more and more trials, phase four trials, much larger trials, where you look to see is there something that's emerging, that's problematic, that wasn't showing up in the smaller phase three trials.

12:46So we're gonna talk about that. We're also gonna talk about just a longer tail on benefits. So what do we know about weight loss over a longer period of time? Does the individual become recalcitrant to the drug at some point? In other words, do they lose weight for 12 months, but then all of a sudden they just regain in the presence of the drug still being there. There's lots of types of drugs where that's the case, not necessarily for weight loss, but where we sort of get resistant to the effect of the drug. I think today we have a much better understanding of how the drugs promote weight loss.

13:17So in addition to the clinical studies that look at this, I think we have better mechanisms to have more insight into what is actually happening. One of the big unknown questions when we reviewed this the last time was we just didn't have real data. There was one study that we were able to look at that looked at weight regain after stopping. So today we have not just those preliminary studies and insights, but we have more data on that. I would also just add, I have, as I'm sure any doctor who's prescribed these, I have more anecdotal evidence about what that might look like. I think another big thing Nick that I spoke about and speculated about in the past was really around the changes in body composition and not just weight.

13:55And I think I mentioned very specifically that in the phase three tiles, the FDA did not require body composition as part of the primary outcomes. So dexascans were not done in those studies and body weight was simply the metric of interest. And of course, because we started doing dexascans on people, we were seeing some pretty different things with respect to body composition. But the good news now is we can speak to that more from the standpoint of the data that are available. I think we can also say more about the role of exercise in both weight loss and weight maintenance. Again, something we didn't necessarily have any hard data on before.

14:31And then of course, we can talk about the differences in the approved drugs. So we can say a lot more about semi -glutide and tersepotide. And we can also we're going to talk about a new drug that's in phase three that's pretty exciting as well. Well, something that wasn't really going on last time, at least to my knowledge, but seems rampant today as the use of compounding pharmacies to formulate these. And we're going to do a bit of a double click on that because people who have listened to the podcaster know doubt familiar with what compounding pharmacies are. And we covered that on a previous AMA.

15:01We obviously made a point to make sure people understand the good, the bad, and the ugly of compounding pharmacies. I certainly don't want to sit here and say the compounding pharmacies are bad. There's a bit of a buyer beware and they're not all created equal. And so understanding what the role of the compounding pharmacy is and these drugs is important. Let me think. I would say, so we talked about a new drug. We're going to talk about that. I think the other thing that I really want to focus on today is understanding the other health benefits associated with it. So if anybody's scrolling through their Google feed, you almost can't go a day, certainly not a week without something popping up as yet another benefit of this class of drug.

15:40So it's like, oh, it's just been discovered that not only are GLP1 agonists and it usually won't say that it'll say not only is ozempic good for weight loss, but it's also good for treating your sleep apnea or it's good for preventing dementia or all these other things. So I kind of want to go through the state of the evidence on that and really get a sense of of the five to ten other indications that people are talking about how robust are the data. So I'm not going to bury the lead on this. The jugular question with all of these indications is going to be, Is there a benefit of the drug above and beyond the two things that we know it's doing, which is reducing weight and improving metabolic health in glycemic control?

16:19It shouldn't be a surprise that these drugs improve other metrics of health because reducing weight and improving glycemic control always improve health. The question is, are they doing them at a level beyond the nameplate effect? Another topic that really we weren't talking about at all three years ago was the role that these drugs had on addictions or addictive behaviors. And finally, I think the last thing I want to touch on today is reports we've heard about where these medications may indeed increase the risk of suicidal ideation. Again, we'll talk about that, but I think it's, I don't have a hard time saying right now, for someone who doesn't want to wait till the very end of this podcast that the answer there might not be satisfactory in terms of the posity of evidence we have to point to that.

17:03So I think with all that said, I think what we'll do is we'll just check off each one one by one and just go through it all in that order. And so I think let's start with the first, which was, what do we know more about the long -term safety? Has there been any new studies, any new data that's given us any insight into that long -term nature of these drugs? Thank you for listening to today's Sneak Peak AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member. It's extremely important to me to provide all of this content without relying on paid ads.

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