#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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Welcome 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 GLP-1 agonists. You may have heard of these drugs, Ozempic and Monjaro, 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. In 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. We'll

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 GLP-1 receptor agonists. For example, is one of the two on the market today better than others?

We talk about the role compounding pharmacies are playing in this. We talk about orals versus injectables, what some other health conditions might be that are amenable to treatment with these drugs. And we talk about the types of GLP-1 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 of this podcast, you can find it on the show notes page.

And if you're not a subscriber, you can watch the sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy AMA number 64. Peter, welcome to another AMA. How are 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 office, into a studio every time we were 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. That's 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 going to be released first and then we're going to go back to the old studio a little bit and 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-1s or ozempic, trisepatide, you kind of name it, as people have heard of them. And I actually look back because you and Bob first talked about this November 2021 is when we released that episode.

We did 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 and Bob talked about wanting to do a GLP AMA. And I was like, I have no idea why we're doing this. It was 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. And 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 regain, safety profiles, the

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. So 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, 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 semaglutide 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. It'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. 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 liraglutide, 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 semaglutide to a patient in the fall of 2020. And

That was a totally different experience. That 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 2 diabetes. And that was largely on the basis of the fact that

that these are a class of drugs that mimic a hormone called GLP-1, glucagon-like peptide 1, that stimulates the release of insulin from the pancreas, which of course, if you have type 2 diabetes as opposed to type 1 diabetes, is one of the routes of trying to get around the disease, right?

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 try to do as well. 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. So 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 2 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 liraglutide, which was not only did patients have an improvement in their hemoglobin A1C, but their weight dropped dramatically.

And so that led to the obvious question, which is, should we be considering these drugs for weight loss in 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 the release of insulin secretion and reduce glucagon secretion. So both of those are going to have a net effect of lowering blood sugar.

and the jejunum and the ileum, 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. Most interestingly, potentially, and we'll talk more about this, is in the brain, it's probably stimulating pro-satiate circuits and then decreasing the activity of the circuits that drive appetite. And 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. That's a bit 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. In the muscle, it's increasing glucose oxidation, so increasing the capacity of the muscles to oxidize glucose.

We'll 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. And so back then there was a lot of unknowns. So 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 Ozempic. It was just rebranded as Wigovi for the obesity indication as opposed to just type 2 diabetes. And then we spoke about another one called terzepatide, 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 GLP-1, but also on GIP, another hormone. It goes by the brand name Manjaro, but that's the diabetes version. So Manjaro is to Ozempic what its obesity counterpart, which is called Zepbound, is to Wegovi. 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, semaglutide and terzapotide. 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. So 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 want to 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? So we're going to talk about that. We're also going to 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. So in addition to the clinical studies that look at this, I think we have better mechanistic studies 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. And 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 DEXA scans were not done in

in those studies and body weight was simply the metric of interest. And of course, because we started doing DEXA scans 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. And then of course, we can talk about the differences in the approved drugs. So we can say a lot more about semaglutide and terzepatide. And we can also, we're going to talk about a new drug that's in phase three, that's pretty exciting as well. Something that wasn't really going on last time, at least

to my knowledge, but seems rampant today is 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 podcast are no doubt familiar with what compounding pharmacies are, and we've covered that on a previous AMA. We 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 that 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 in these drugs is important. Let me think. I would say, so we talked about 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. So it's like,

oh, it's just been discovered that not only are GLP-1 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 10 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 and glycemic control? It 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 paucity of evidence we have to point to that.

So 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?

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