The Peter Attia Drive - #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

00:00:00.000 Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.

00:00:15.820 I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can access

00:00:20.280 the AMA episodes in full, along with a ton of other membership benefits we've created,

00:00:24.900 or you can learn more now by going to peteratiyahmd.com forward slash subscribe.

00:00:30.600 So without further delay, here's today's sneak peek of the ask me anything episode.

00:00:39.080 Welcome to ask me anything AMA episode 64. I'm once again joined by my co-host Nick Stenson.

00:00:45.700 In today's episode, we cover a topic that we've addressed in the past, but has continued to gain

00:00:49.900 significant attention since we last spoke. And that of course is the topic of GLP-1 agonists.

00:00:55.380 You may have heard of these drugs, Ozempic and Monjaro, but we go much deeper into this. Now,

00:01:00.320 given how these drugs have gained popularity and given how our knowledge on them has advanced

00:01:05.820 probably non-linearly since we last discussed them, we felt it was appropriate to address many

00:01:12.080 of your questions on these topics and what we've learned through our own experience with patients.

00:01:17.460 In this conversation, we begin with a very quick background on what a GLP-1 molecule is,

00:01:23.900 how these drugs work, and why they are finding so much utility today. We focus on what we now know

00:01:30.400 about their long-term efficacy, which is longer than what we knew in the past, what we know about

00:01:35.980 side effects, and what we know about what happens when you stop taking these drugs. We also talk

00:01:41.880 specifically about their effects on body composition. This is something we couldn't speak

00:01:45.720 to from clinical trial literature before, but we now in fact have that data. We talk about the role

00:01:50.800 resistance training plays on these, and we talk about the differences between the specific GLP-1

00:01:57.080 receptor agonists. For example, is one of the two on the market today better than others? Talk about the

00:02:03.900 role compounding pharmacies are playing in this. We talk about orals versus injectables, what some other

00:02:09.340 health conditions might be that are amenable to treatment with these drugs. And we talk about the

00:02:15.240 types of GLP-1 agonists or other receptor agonists that are on the market and that appear to be

00:02:21.420 promising, and at least in one case, potentially more promising. If you're a subscriber and want to

00:02:26.440 watch the full video of this podcast, you can find it on the show notes page. And if you're not a

00:02:30.760 subscriber, you can watch the sneak peek of the video on our YouTube page. So without further delay,

00:02:35.500 I hope you enjoy AMA number 64. Peter, welcome to another AMA. How are you doing?

00:02:46.220 Doing very well. Thank you for having me. I see you're in a new location today. Do you want to

00:02:51.140 let people know why? Well, after some planning, we've decided to expand the look and feel and

00:02:58.280 create a dedicated studio for this. So excited to have our inaugural in-studio podcast today.

00:03:04.460 For people who don't know, we used to transform your office, your actual work office into a studio

00:03:11.180 every time we were recorded. So how much nicer is it to not have that done each week?

00:03:18.220 It's as much nicer as it is when you have to stop having a weekly root canal.

00:03:22.880 That's good. That's good. Much less noise going on from background from kids or dogs or anything of

00:03:29.980 that nature as well in the new studio, which is always good for today's AMA. It's actually funny

00:03:37.100 because it's kind of a little inside baseball. How we do the podcast is usually there's anywhere

00:03:43.120 from a 10 to 12 week delay from podcast recording to release just with how we work. But this one

00:03:49.880 is going to be released first. And then we're going to go back to the old studio a little bit in the

00:03:55.340 release schedule, but not the recording schedule. And the reason why is we're covering a topic today

00:04:00.720 that we want to turn around and get out as quickly as possible, because it seems it's a topic

00:04:06.400 that changes more than almost anything else that we talk about, which is GLP ones or Ozempic,

00:04:14.620 Trisepatide, you kind of name it as people have heard of them. And I actually look back because

00:04:19.780 you and Bob first talked about this November, 2021 is when we released that episode. We did a

00:04:26.080 follow-up March, 2023. And I don't think there's been a topic that has had more change in terms of

00:04:33.340 interest in that period of time than this. And I still, I said at the last podcast, we did this one

00:04:39.600 too, is I remember the first time you and Bob talked about wanting to do a GLP AMA. And I was like,

00:04:46.160 I have no idea why we're doing this. It was the most technical thing. It made no sense. No one

00:04:51.740 was talking about it. And now it seems like it's everywhere. Even since the last 18 months,

00:04:58.500 when we did the last one, so much has changed. And so in this one, we're going to cover everything as

00:05:04.840 it relates to these. And we'll just go through piece by piece and we'll do a little recap of how

00:05:11.240 they work. But previous AMAs will be best if people want to go into detail there. We're not going to

00:05:15.880 spend as much time. We're going to spend much more time on what we know about this now and how this

00:05:21.280 works, the difference between the drugs, compounded injection, what we know about weight regain,

00:05:26.760 safety profiles. The past few times you talked about this, there just wasn't as much information

00:05:31.620 as there is now. And so I think it'll be really interesting because I think it's also one where

00:05:35.900 you maybe have changed your mind a little bit based on past conversations that we had. So

00:05:40.740 it will be a really good one. I think it will be really interesting. And with all that said,

00:05:45.120 do you want to add anything before we start rolling into it?

00:05:49.360 Yeah, actually quite a bit of context. So everything you said, just to add onto that,

00:05:54.180 if there's one thing that I get a kick out of, it's I'm scrolling on Instagram and I see a video

00:05:58.280 of me talking about some aglutide from three or four years ago. And I frankly don't even necessarily

00:06:04.700 agree with what I was saying at the time. And that's just the nature of how things work.

00:06:08.340 Our knowledge changes a lot. And so that's part of my motivation for wanting to talk about this yet

00:06:12.960 again today. It's that we know considerably more today than we did three years ago. But I also want

00:06:18.740 to acknowledge all the things we don't know. So that's one point I'd want to make. Second point

00:06:22.440 I want to make is there's at least earlier generations of these drugs have been around

00:06:25.620 for quite some time. So the very first time I ever prescribed a class of this drug was a drug

00:06:29.940 called liraglutide. And it's almost exactly 10 years ago. It was in the fall of 2014 that I

00:06:35.360 prescribed that to a patient. Not a particularly effective drug. So it would be another six years before I

00:06:40.380 would prescribe semaglutide to a patient in the fall of 2020. And that was a totally different

00:06:47.020 experience. That was of course Ozempic before it had been approved for obesity. So yeah, I think I

00:06:52.800 just have a lot of stuff I want to talk about. But to your point, there's no need to rehash stuff we've

00:06:57.200 gone through before. I think it was AMA 29 where Bob and I did a very deep dive into the physiology

00:07:03.540 of how these things work. And we really probably spent maybe more time than we needed to explaining

00:07:10.160 to people how the GI tract works and how GI hormones work. So not going to do that here. Let's cut right

00:07:16.040 to it. So these are a class of drugs that were initially developed for the management of type 2

00:07:20.760 diabetes. And that was largely on the basis of the fact that these are a class of drugs that mimic a

00:07:27.700 hormone called GLP-1, glucagon-like peptide 1, that stimulates the release of insulin from the

00:07:35.040 pancreas. Which of course, if you have type 2 diabetes as opposed to type 1 diabetes, is one of

00:07:40.560 the routes of trying to get around the disease. When a patient's pancreas is no longer secreting

00:07:46.720 sufficient insulin, that would be one half of what you would try to do. Of course, there's other things

00:07:50.920 you try to do as well. You want to increase insulin sensitivity. And of course, that makes it so that you

00:07:55.480 don't actually need as much insulin to get the glucose into the liver and to the muscles. So if the

00:08:01.080 story ended there, we probably wouldn't be talking about this. If the story ended with, these are great

00:08:06.600 drugs to help people with type 2 diabetes, which roughly speaking about 1 in 10 Americans have today,

00:08:14.560 might not be talking much about it. If it was lowering hemoglobin A1c and things like that, I mean, that would

00:08:19.760 be very important. But again, why is this such a topic? The topic is because with semaglutide,

00:08:24.880 something happened that didn't happen before with liraglutide, which was not only did patients

00:08:30.620 have an improvement in their hemoglobin A1c, but their weight dropped dramatically. And so that led

00:08:37.860 to the obvious question, which is, should we be considering these drugs for weight loss in people

00:08:42.420 who do not have type 2 diabetes? And of course, that was the question that was basically posed through

00:08:47.080 a series of trials three years ago. And the answer turned out to be emphatically yes.

00:08:50.900 I don't think we need to get into the details, but what's the 101 four-sentence version for people

00:08:57.080 as a reminder on how these drugs actually work?

00:09:00.480 Let's start with the most important, which is the pancreas. So as I mentioned a second ago,

00:09:05.360 it's going to stimulate the release of insulin secretion and reduce glucagon secretion. So both

00:09:10.200 of those are going to have a net effect of lowering blood sugar. And the jejunum and the ileum,

00:09:16.700 which are just parts of the small bowel, it's going to reduce gastric emptying and GI motility. 0.98

00:09:22.400 So it slows absorption of glucose from the intestines and keeps the stomach full for longer,

00:09:27.260 which by the way, might partially relate to some of the satiety benefits. In the liver,

00:09:32.540 it reduces hepatic glucose production. So of course, again, probably something like what metformin is

00:09:38.200 doing there. Most interestingly, potentially, and we'll talk more about this is in the brain,

00:09:43.020 it's probably stimulating pro satiety circuits, and then decreasing the activity of the circuits

00:09:49.040 that drive appetite. And again, I would say that a few years ago, when we talked about this,

00:09:53.220 we really had no idea how much that was driving weight loss. I would say today, we have a feeling

00:09:58.000 that it's doing quite a bit. Within fat tissue itself, it's increasing glucose uptake from

00:10:03.040 circulation and increasing lipolysis. So that's a bit counterintuitive, because on the one hand,

00:10:07.980 that's taking glucose out of circulation, that kind of makes sense due to increased insulin

00:10:11.520 sensitivity. But it's also counterintuitive, because that should make a fat cell fatter.

00:10:15.680 But of course, by driving lipolysis, it's actually increasing the throughput on the back end. In the

00:10:21.140 muscle, it's increasing glucose oxidation. So increasing the capacity of the muscles to oxidize

00:10:26.040 glucose. We'll include a really nice figure in the show notes that goes through this in more detail,

00:10:30.940 so folks can see what's happening. There are lots of other things it's doing that I don't think

00:10:34.520 I'll talk about now. I'm going to wait and talk about them when we get to organ-specific

00:10:37.640 questions. For example, what is it doing specifically in the heart? What is it doing in the

00:10:41.500 kidney? These are topics of huge interest today.

00:10:44.880 As we kind of mentioned, it's been about almost 18 months, 19 months since the last time we spoke

00:10:50.340 about this topic. And so back then, there was a lot of unknowns. So we were able to speak about

00:10:55.700 certain things, but then there was also just unknowns with how new these drugs were. And so

00:11:00.440 what have we learned? What's like a quick overview of what we know now compared to what we knew last time

00:11:07.420 we did a deep dive on this? Yeah, there's a lot. I mean, I'll start with just the fact that when we

00:11:12.140 last spoke about this, we were talking really just about two drugs. We were talking about a drug called

00:11:18.020 semaglutide, which again, the brand name for that. The first one that people talked about was

00:11:23.300 Ozempic. It was just rebranded as Wigovi for the obesity indication as opposed to just type 2 diabetes.

00:11:29.520 And then we spoke about another one called terzepatide, which is a slightly different drug,

00:11:33.880 as we're going to see in a moment, a slightly better drug and a drug that works not just on GLP-1,

00:11:39.020 but also on GIP, another hormone. It goes by the brand name Manjaro, but that's the diabetes version.

00:11:46.020 So Manjaro is to Ozempic what its obesity counterpart, which is called Zepbound, is to Wigovi. Honestly,

00:11:54.340 I can't keep track of all these names. So I just sort of try to remember the actual generic name of it,

00:11:59.380 which is of course semaglutide and terzepatide. Today, we have another one that we will talk about that is

00:12:03.500 not yet approved, but it's the one I think people are very interested in. So big picture, what do we

00:12:09.480 have today? Why would we talk about this again today? Well, we have much more safety data. And

00:12:13.620 obviously, one of the things that I think we should be very cautious about with any new drug,

00:12:18.820 especially a drug that has this much penetration in the market, is we want to understand what's

00:12:23.280 happening in post-approval surveillance. So just because a drug gets approved during what's called

00:12:28.860 a phase three study doesn't mean the FDA stops paying attention. It's their job to continue to

00:12:33.320 pay attention. And you want to see more and more trials, phase four trials, much larger trials,

00:12:38.240 where you look to see, is there something that's emerging that's problematic that wasn't showing up

00:12:43.980 in the smaller phase three trials? So we're going to talk about that. We're also going to talk about

00:12:48.640 just a longer tail on benefits. So what do we know about weight loss over a longer period of time?

00:12:55.560 Does the individual become recalcitrant to the drug at some point? In other words,

00:13:00.220 do they lose weight for 12 months, but then all of a sudden they just regain in the presence of the

00:13:04.700 drug still being there? There's lots of types of drugs where that's the case, not necessarily for

00:13:08.920 weight loss, but where we sort of get resistant to the effect of the drug. I think today we have a

00:13:13.180 much better understanding of how the drugs promote weight loss. So in addition to the clinical studies

00:13:19.180 that look at this, I think we have better mechanistic studies to have more insight into what is

00:13:23.120 actually happening. One of the big unknown questions when we reviewed this the last time was we just

00:13:28.660 didn't have real data. There was one study that we were able to look at that looked at weight regain

00:13:34.180 after stopping. So today we have not just those preliminary studies and insights, but we have more

00:13:39.660 data on that. I would also just add, I have, as I'm sure any doctor who's prescribed these, I have more

00:13:44.740 anecdotal evidence about what that might look like. I think another big thing, Nick, that I spoke about

00:13:50.420 and speculated about in the past was really around the changes in body composition and not just weight.

00:13:55.220 And I think I mentioned very specifically that in the phase three tiles, the FDA did not require

00:13:59.980 body composition as part of the primary outcomes. So DEXA scans were not done in those studies and

00:14:08.820 body weight was simply the metric of interest. And of course, because we started doing DEXA scans on people,

00:14:14.260 we were seeing some pretty different things with respect to body composition. But the good news now is we can

00:14:18.400 speak to that more from the standpoint of the data that are available. I think we can also say more

00:14:23.360 about the role of exercise in both weight loss and weight maintenance. Again, something we didn't

00:14:27.980 necessarily have any hard data on before. And then of course, we can talk about the differences in the

00:14:33.600 approved drugs. So we can say a lot more about semaglutide and terzepatide. And we can also, we're going to

00:14:39.980 talk about a new drug that's in phase three, that's pretty exciting as well. Something that wasn't really

00:14:45.240 going on last time, at least to my knowledge, but seems rampant today is the use of compounding

00:14:50.760 pharmacies to formulate these. And we're going to do a bit of a double click on that because

00:14:55.000 people who have listened to the podcast are no doubt familiar with what compounding pharmacies

00:14:58.720 are. And we've covered that on a previous AMA. We obviously made a point to make sure people

00:15:03.860 understand the good, the bad, and the ugly of compounding pharmacies. I certainly don't want to

00:15:07.240 sit here and say that compounding pharmacies are bad. There's a bit of a buyer beware and they're

00:15:10.600 not all created equal. And so understanding what the role of the compounding pharmacy is in these

00:15:15.340 drugs is important. Let me think. I would say, so we talked about a new drug. We're going to talk

00:15:20.280 about that. I think the other thing that I really want to focus on today is understanding the other

00:15:26.320 health benefits associated with it. So if anybody's scrolling through their Google feed, you almost

00:15:32.840 can't go a day, certainly not a week, without something popping up as yet another benefit of this

00:15:39.380 class of drug. So it's like, oh, it's just been discovered that not only are GLP-1 agonists,

00:15:45.720 and it usually won't say that, it'll say, not only is Ozempic good for weight loss, but it's also good

00:15:49.600 for treating your sleep apnea, or it's good for preventing dementia, or all these other things.

00:15:53.740 So I kind of want to go through the state of the evidence on that and really get a sense of,

00:15:57.900 of the five to 10 other indications that people are talking about, how robust are the data?

00:16:03.240 So I'm not going to bury the lead on this. The jugular question with all of these indications

00:16:07.580 is going to be, is there a benefit of the drug above and beyond the two things that we know

00:16:14.080 it's doing, which is reducing weight and improving metabolic health and glycemic control? It shouldn't

00:16:19.460 be a surprise that these drugs improve other metrics of health because reducing weight and

00:16:25.640 improving glycemic control always improve health. The question is, are they doing them at a level beyond

00:16:30.880 the nameplate effect? Another topic that really we weren't talking about at all three years ago

00:16:36.500 was the role that these drugs had on addictions or addictive behaviors. And finally, I think the

00:16:43.080 last thing I want to touch on today is reports we've heard about where these medications may indeed

00:16:49.140 increase the risk of suicidal ideation. Again, we'll talk about that, but I think it's, I don't have a

00:16:54.480 hard time saying right now for someone who doesn't want to wait till the very end of this podcast,

00:16:58.480 that the answer there might not be satisfactory in terms of the paucity of evidence we have to point

00:17:03.040 to that. So I think with all that said, I think what we'll do is we'll just check off each one,

00:17:08.640 one by one, and just go through it all in that order. And so I think let's start with the first,

00:17:13.900 which was, what do we know more about the long-term safety? Has there been any new studies,

00:17:18.900 any new data that's given us any insight into that long-term nature of these drugs?

00:17:24.580 Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested

00:17:30.600 in hearing the complete version of this AMA, you'll want to become a premium member. It's

00:17:35.900 extremely important to me to provide all of this content without relying on paid ads. To do this,

00:17:41.140 our work is made entirely possible by our members. And in return, we offer exclusive member-only

00:17:46.660 content and benefits above and beyond what is available for free. So if you want to take your

00:17:51.860 knowledge of this space to the next level, it's our goal to ensure members get back much more than

00:17:56.620 the price of the subscription. Premium membership includes several benefits. First, comprehensive

00:18:02.440 podcast show notes that detail every topic, paper, person, and thing that we discuss in each episode.

00:18:09.000 And the word on the street is nobody's show notes rival ours. Second, monthly ask me anything or AMA

00:18:16.260 episodes. These episodes are comprised of detailed responses to subscriber questions,

00:18:20.940 typically focused on a single topic and are designed to offer a great deal of clarity and

00:18:26.080 detail on topics of special interest to our members. You'll also get access to the show notes

00:18:30.600 for these episodes, of course. Third, delivery of our premium newsletter, which is put together

00:18:36.360 by our dedicated team of research analysts. This newsletter covers a wide range of topics related

00:18:41.920 to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our

00:18:48.980 private podcast feed that provides you with access to every episode, including AMA's sans the spiel

00:18:54.920 you're listening to now and in your regular podcast feed. Fifth, the qualies, an additional member

00:19:01.700 only podcast we put together that serves as a highlight reel featuring the best excerpts from

00:19:07.480 previous episodes of the drive. This is a great way to catch up on previous episodes without having to go

00:19:12.580 back and listen to each one of them. And finally, other benefits that are added along the way.

00:19:17.100 If you want to learn more and access these member only benefits, you can head over to

00:19:21.940 peteratiamd.com forward slash subscribe. You can also find me on YouTube, Instagram, and Twitter,

00:19:28.640 all with the handle peteratiamd. You can also leave us review on Apple podcasts or whatever podcast

00:19:35.460 player you use. This podcast is for general informational purposes only and does not constitute the practice

00:19:41.560 of medicine, nursing, or other professional healthcare services, including the giving of medical advice.

00:19:46.760 No doctor patient relationship is formed. The use of this information and the materials linked to this

00:19:53.040 podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for

00:19:59.000 professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining

00:20:04.620 medical advice from any medical condition they have, and they should seek the assistance of their

00:20:09.580 healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously.

00:20:15.360 For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com

00:20:22.360 forward slash about where I keep an up-to-date and active list of all disclosures.

The Peter Attia Drive - October 07, 2024

#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

Episode Stats

Summary

Transcript