#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
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Summary
In today's episode, we cover a topic that we've covered in the past but has continued to gain significant attention since we last spoke about it in November of 2018. And that's GLP-1 agonists. You may have heard of these drugs, Ozempic and Monjaro, but we go much deeper into this topic.
Transcript
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Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.
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I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can access
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the AMA episodes in full, along with a ton of other membership benefits we've created,
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or you can learn more now by going to peteratiyahmd.com forward slash subscribe.
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So without further delay, here's today's sneak peek of the ask me anything episode.
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Welcome to ask me anything AMA episode 64. I'm once again joined by my co-host Nick Stenson.
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In today's episode, we cover a topic that we've addressed in the past, but has continued to gain
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significant attention since we last spoke. And that of course is the topic of GLP-1 agonists.
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You may have heard of these drugs, Ozempic and Monjaro, but we go much deeper into this. Now,
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given how these drugs have gained popularity and given how our knowledge on them has advanced
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probably non-linearly since we last discussed them, we felt it was appropriate to address many
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of your questions on these topics and what we've learned through our own experience with patients.
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In this conversation, we begin with a very quick background on what a GLP-1 molecule is,
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how these drugs work, and why they are finding so much utility today. We focus on what we now know
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about their long-term efficacy, which is longer than what we knew in the past, what we know about
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side effects, and what we know about what happens when you stop taking these drugs. We also talk
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specifically about their effects on body composition. This is something we couldn't speak
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to from clinical trial literature before, but we now in fact have that data. We talk about the role
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resistance training plays on these, and we talk about the differences between the specific GLP-1
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receptor agonists. For example, is one of the two on the market today better than others? Talk about the
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role compounding pharmacies are playing in this. We talk about orals versus injectables, what some other
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health conditions might be that are amenable to treatment with these drugs. And we talk about the
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types of GLP-1 agonists or other receptor agonists that are on the market and that appear to be
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promising, and at least in one case, potentially more promising. If you're a subscriber and want to
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watch the full video of this podcast, you can find it on the show notes page. And if you're not a
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subscriber, you can watch the sneak peek of the video on our YouTube page. So without further delay,
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I hope you enjoy AMA number 64. Peter, welcome to another AMA. How are you doing?
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Doing very well. Thank you for having me. I see you're in a new location today. Do you want to
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let people know why? Well, after some planning, we've decided to expand the look and feel and
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create a dedicated studio for this. So excited to have our inaugural in-studio podcast today.
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For people who don't know, we used to transform your office, your actual work office into a studio
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every time we were recorded. So how much nicer is it to not have that done each week?
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It's as much nicer as it is when you have to stop having a weekly root canal.
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That's good. That's good. Much less noise going on from background from kids or dogs or anything of
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that nature as well in the new studio, which is always good for today's AMA. It's actually funny
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because it's kind of a little inside baseball. How we do the podcast is usually there's anywhere
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from a 10 to 12 week delay from podcast recording to release just with how we work. But this one
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is going to be released first. And then we're going to go back to the old studio a little bit in the
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release schedule, but not the recording schedule. And the reason why is we're covering a topic today
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that we want to turn around and get out as quickly as possible, because it seems it's a topic
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that changes more than almost anything else that we talk about, which is GLP ones or Ozempic,
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Trisepatide, you kind of name it as people have heard of them. And I actually look back because
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you and Bob first talked about this November, 2021 is when we released that episode. We did a
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follow-up March, 2023. And I don't think there's been a topic that has had more change in terms of
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interest in that period of time than this. And I still, I said at the last podcast, we did this one
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too, is I remember the first time you and Bob talked about wanting to do a GLP AMA. And I was like,
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I have no idea why we're doing this. It was the most technical thing. It made no sense. No one
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was talking about it. And now it seems like it's everywhere. Even since the last 18 months,
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when we did the last one, so much has changed. And so in this one, we're going to cover everything as
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it relates to these. And we'll just go through piece by piece and we'll do a little recap of how
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they work. But previous AMAs will be best if people want to go into detail there. We're not going to
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spend as much time. We're going to spend much more time on what we know about this now and how this
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works, the difference between the drugs, compounded injection, what we know about weight regain,
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safety profiles. The past few times you talked about this, there just wasn't as much information
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as there is now. And so I think it'll be really interesting because I think it's also one where
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you maybe have changed your mind a little bit based on past conversations that we had. So
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it will be a really good one. I think it will be really interesting. And with all that said,
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do you want to add anything before we start rolling into it?
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Yeah, actually quite a bit of context. So everything you said, just to add onto that,
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if there's one thing that I get a kick out of, it's I'm scrolling on Instagram and I see a video
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of me talking about some aglutide from three or four years ago. And I frankly don't even necessarily
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agree with what I was saying at the time. And that's just the nature of how things work.
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Our knowledge changes a lot. And so that's part of my motivation for wanting to talk about this yet
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again today. It's that we know considerably more today than we did three years ago. But I also want
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to acknowledge all the things we don't know. So that's one point I'd want to make. Second point
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I want to make is there's at least earlier generations of these drugs have been around
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for quite some time. So the very first time I ever prescribed a class of this drug was a drug
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called liraglutide. And it's almost exactly 10 years ago. It was in the fall of 2014 that I
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prescribed that to a patient. Not a particularly effective drug. So it would be another six years before I
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would prescribe semaglutide to a patient in the fall of 2020. And that was a totally different
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experience. That was of course Ozempic before it had been approved for obesity. So yeah, I think I
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just have a lot of stuff I want to talk about. But to your point, there's no need to rehash stuff we've
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gone through before. I think it was AMA 29 where Bob and I did a very deep dive into the physiology
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of how these things work. And we really probably spent maybe more time than we needed to explaining
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to people how the GI tract works and how GI hormones work. So not going to do that here. Let's cut right
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to it. So these are a class of drugs that were initially developed for the management of type 2
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diabetes. And that was largely on the basis of the fact that these are a class of drugs that mimic a
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hormone called GLP-1, glucagon-like peptide 1, that stimulates the release of insulin from the
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pancreas. Which of course, if you have type 2 diabetes as opposed to type 1 diabetes, is one of
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the routes of trying to get around the disease. When a patient's pancreas is no longer secreting
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sufficient insulin, that would be one half of what you would try to do. Of course, there's other things
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you try to do as well. You want to increase insulin sensitivity. And of course, that makes it so that you
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don't actually need as much insulin to get the glucose into the liver and to the muscles. So if the
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story ended there, we probably wouldn't be talking about this. If the story ended with, these are great
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drugs to help people with type 2 diabetes, which roughly speaking about 1 in 10 Americans have today,
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might not be talking much about it. If it was lowering hemoglobin A1c and things like that, I mean, that would
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be very important. But again, why is this such a topic? The topic is because with semaglutide,
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something happened that didn't happen before with liraglutide, which was not only did patients
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have an improvement in their hemoglobin A1c, but their weight dropped dramatically. And so that led
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to the obvious question, which is, should we be considering these drugs for weight loss in people
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who do not have type 2 diabetes? And of course, that was the question that was basically posed through
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a series of trials three years ago. And the answer turned out to be emphatically yes.
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I don't think we need to get into the details, but what's the 101 four-sentence version for people
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as a reminder on how these drugs actually work?
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Let's start with the most important, which is the pancreas. So as I mentioned a second ago,
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it's going to stimulate the release of insulin secretion and reduce glucagon secretion. So both
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of those are going to have a net effect of lowering blood sugar. And the jejunum and the ileum,
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which are just parts of the small bowel, it's going to reduce gastric emptying and GI motility.
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So it slows absorption of glucose from the intestines and keeps the stomach full for longer,
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which by the way, might partially relate to some of the satiety benefits. In the liver,
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it reduces hepatic glucose production. So of course, again, probably something like what metformin is
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doing there. Most interestingly, potentially, and we'll talk more about this is in the brain,
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it's probably stimulating pro satiety circuits, and then decreasing the activity of the circuits
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that drive appetite. And again, I would say that a few years ago, when we talked about this,
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we really had no idea how much that was driving weight loss. I would say today, we have a feeling
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that it's doing quite a bit. Within fat tissue itself, it's increasing glucose uptake from
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circulation and increasing lipolysis. So that's a bit counterintuitive, because on the one hand,
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that's taking glucose out of circulation, that kind of makes sense due to increased insulin
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sensitivity. But it's also counterintuitive, because that should make a fat cell fatter.
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But of course, by driving lipolysis, it's actually increasing the throughput on the back end. In the
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muscle, it's increasing glucose oxidation. So increasing the capacity of the muscles to oxidize
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glucose. We'll include a really nice figure in the show notes that goes through this in more detail,
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so folks can see what's happening. There are lots of other things it's doing that I don't think
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I'll talk about now. I'm going to wait and talk about them when we get to organ-specific
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questions. For example, what is it doing specifically in the heart? What is it doing in the
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kidney? These are topics of huge interest today.
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As we kind of mentioned, it's been about almost 18 months, 19 months since the last time we spoke
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about this topic. And so back then, there was a lot of unknowns. So we were able to speak about
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certain things, but then there was also just unknowns with how new these drugs were. And so
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what have we learned? What's like a quick overview of what we know now compared to what we knew last time
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we did a deep dive on this? Yeah, there's a lot. I mean, I'll start with just the fact that when we
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last spoke about this, we were talking really just about two drugs. We were talking about a drug called
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semaglutide, which again, the brand name for that. The first one that people talked about was
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Ozempic. It was just rebranded as Wigovi for the obesity indication as opposed to just type 2 diabetes.
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And then we spoke about another one called terzepatide, which is a slightly different drug,
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as we're going to see in a moment, a slightly better drug and a drug that works not just on GLP-1,
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but also on GIP, another hormone. It goes by the brand name Manjaro, but that's the diabetes version.
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So Manjaro is to Ozempic what its obesity counterpart, which is called Zepbound, is to Wigovi. Honestly,
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I can't keep track of all these names. So I just sort of try to remember the actual generic name of it,
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which is of course semaglutide and terzepatide. Today, we have another one that we will talk about that is
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not yet approved, but it's the one I think people are very interested in. So big picture, what do we
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have today? Why would we talk about this again today? Well, we have much more safety data. And
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obviously, one of the things that I think we should be very cautious about with any new drug,
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especially a drug that has this much penetration in the market, is we want to understand what's
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happening in post-approval surveillance. So just because a drug gets approved during what's called
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a phase three study doesn't mean the FDA stops paying attention. It's their job to continue to
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pay attention. And you want to see more and more trials, phase four trials, much larger trials,
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where you look to see, is there something that's emerging that's problematic that wasn't showing up
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in the smaller phase three trials? So we're going to talk about that. We're also going to talk about
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just a longer tail on benefits. So what do we know about weight loss over a longer period of time?
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Does the individual become recalcitrant to the drug at some point? In other words,
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do they lose weight for 12 months, but then all of a sudden they just regain in the presence of the
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drug still being there? There's lots of types of drugs where that's the case, not necessarily for
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weight loss, but where we sort of get resistant to the effect of the drug. I think today we have a
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much better understanding of how the drugs promote weight loss. So in addition to the clinical studies
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that look at this, I think we have better mechanistic studies to have more insight into what is
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actually happening. One of the big unknown questions when we reviewed this the last time was we just
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didn't have real data. There was one study that we were able to look at that looked at weight regain
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after stopping. So today we have not just those preliminary studies and insights, but we have more
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data on that. I would also just add, I have, as I'm sure any doctor who's prescribed these, I have more
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anecdotal evidence about what that might look like. I think another big thing, Nick, that I spoke about
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and speculated about in the past was really around the changes in body composition and not just weight.
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And I think I mentioned very specifically that in the phase three tiles, the FDA did not require
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body composition as part of the primary outcomes. So DEXA scans were not done in those studies and
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body weight was simply the metric of interest. And of course, because we started doing DEXA scans on people,
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we were seeing some pretty different things with respect to body composition. But the good news now is we can
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speak to that more from the standpoint of the data that are available. I think we can also say more
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about the role of exercise in both weight loss and weight maintenance. Again, something we didn't
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necessarily have any hard data on before. And then of course, we can talk about the differences in the
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approved drugs. So we can say a lot more about semaglutide and terzepatide. And we can also, we're going to
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talk about a new drug that's in phase three, that's pretty exciting as well. Something that wasn't really
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going on last time, at least to my knowledge, but seems rampant today is the use of compounding
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pharmacies to formulate these. And we're going to do a bit of a double click on that because
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people who have listened to the podcast are no doubt familiar with what compounding pharmacies
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are. And we've covered that on a previous AMA. We obviously made a point to make sure people
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understand the good, the bad, and the ugly of compounding pharmacies. I certainly don't want to
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sit here and say that compounding pharmacies are bad. There's a bit of a buyer beware and they're
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not all created equal. And so understanding what the role of the compounding pharmacy is in these
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drugs is important. Let me think. I would say, so we talked about a new drug. We're going to talk
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about that. I think the other thing that I really want to focus on today is understanding the other
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health benefits associated with it. So if anybody's scrolling through their Google feed, you almost
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can't go a day, certainly not a week, without something popping up as yet another benefit of this
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class of drug. So it's like, oh, it's just been discovered that not only are GLP-1 agonists,
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and it usually won't say that, it'll say, not only is Ozempic good for weight loss, but it's also good
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for treating your sleep apnea, or it's good for preventing dementia, or all these other things.
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So I kind of want to go through the state of the evidence on that and really get a sense of,
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of the five to 10 other indications that people are talking about, how robust are the data?
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So I'm not going to bury the lead on this. The jugular question with all of these indications
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is going to be, is there a benefit of the drug above and beyond the two things that we know
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it's doing, which is reducing weight and improving metabolic health and glycemic control? It shouldn't
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be a surprise that these drugs improve other metrics of health because reducing weight and
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improving glycemic control always improve health. The question is, are they doing them at a level beyond
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the nameplate effect? Another topic that really we weren't talking about at all three years ago
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was the role that these drugs had on addictions or addictive behaviors. And finally, I think the
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last thing I want to touch on today is reports we've heard about where these medications may indeed
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increase the risk of suicidal ideation. Again, we'll talk about that, but I think it's, I don't have a
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hard time saying right now for someone who doesn't want to wait till the very end of this podcast,
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that the answer there might not be satisfactory in terms of the paucity of evidence we have to point
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to that. So I think with all that said, I think what we'll do is we'll just check off each one,
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one by one, and just go through it all in that order. And so I think let's start with the first,
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which was, what do we know more about the long-term safety? Has there been any new studies,
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any new data that's given us any insight into that long-term nature of these drugs?
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