Pros and cons of GLP-1 weight loss drugs and metformin as a geroprotective agent [AMA 45 sneak peek]

1. 0:00 – 0:08

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive Podcast." I'm your host, Peter Attia.

2. 0:08 – 4:09

   The hype around semaglutide, tirzepatide, and other GLP-1 agonists for weight loss

   1. SPSpeaker0:10

      Peter, how you doing?

   2. PAPeter Attia0:11

      Doing very well.

   3. SPSpeaker0:12

      We got some fun topics, two main ones that I think people are gonna be interested in. But one thing I realized, although n- not at the time of this recording, but by the time this is released, we'll be about two weeks out from the book launch. Did you ever think we would be able to use those words two weeks-

   4. PAPeter Attia0:29

      [chuckles]

   5. SPSpeaker0:29

      ... out from the book launch?

   6. PAPeter Attia0:32

      No. [chuckles] No. I... This, this, this, this, this, uh, book is, uh, is like a cat that died eight times and somehow managed to, to, to, to eke out survival before the ninth and final death.

   7. SPSpeaker0:47

      No turning back now, right? Like, if we're recording this and something went wrong where the book's coming out, like, I just can't imagine what it would be. It's going to print. It's done.

   8. PAPeter Attia0:57

      Right.

   9. SPSpeaker0:57

      C- cover looks good. Cover looks great. Um, we'll have a dedicated book podcast coming up for, um, listeners where we kinda talk about it and, like, let people know what's going on. But yeah, it's kinda mind-blowing if you think about by the time people are listening to this. It's about two weeks out until they get their hands on it.

   10. PAPeter Attia1:14

       Yeah. Well, [chuckles] I, uh, I hope it delivers. [chuckles]

   11. SPSpeaker1:17

       Yeah. So Peter, I think what we're gonna talk about today is really two different subjects, both of which we've covered a little bit in the past, but there's been a lot of new insights that have come out, new studies, new information, and we receive a lot of questions on them. And the first is something you and Bob covered back in AMA 29, which was back, I think, end of 2021. And I remember at the time you guys were talking about, "Hey, we're gonna do an AMA on GLP-1 agonists and these drugs," and it was kind of one of those things where it was really... I hadn't really heard much being talked about. It seemed so new and, you know, I was kinda like, "Are we sure we wanna do this?" And you and Bob were both like, "Yeah, just wait. There's gonna be a lot of talk about this."

   12. PAPeter Attia1:59

       Yeah. We, we were, we were so wrong and so right, so we were way too far ahead of the curve talking about this. In fact, our first real discussion about it was in the spring of 20... Wha... No, no, in the spring of 2020. So in the spring of 2020, we did a journal club internally, got very deep in the rabbit hole. By the fall of 2020, we were putting patients on the f- you know, the, the... one of the drugs we'll be talking about today, semaglutide. Um, a year later, we're doing an AMA on it. It's still very under the radar, and today I would say this is the single most talked about drug, period. There, there cannot be a drug that is getting more attention right now than semaglutide and, and its ilk, right? So that means, you know, branded Ozempic, branded Wegovy, tirzepatide branded, uh, you know, uh, like, all of those drugs which we're gonna talk about today, um, I don't think a day goes by that I'm not getting pinged by somebody about it. So we're, we were way too early on it [chuckles] and so we're gonna come back and talk about it with a much greater clarity. And, and also, you know, I have a much, much stronger point of view on it today than I did two, almost three years ago.

   13. SPSpeaker3:29

       And that's why I think it's gonna be good to touch back on it is because not only do we get so many more questions because of how much it's talked about, but I know you have so much more experience with this in clinic and other things where you have a lot of new insights. So that will be the first piece, and then the other piece that we're gonna cover is gonna be kinda looking at some metformin data and kind of thinking about how you're thinking about that drug in particular, not so much as for people who are diabetics, but more so for those who are in the camp of k- kind of taking it as a geroprotective longevity agent. So all goes according to plan, that's what we will cover today, which I think will be really good. And so

3. 4:09 – 12:20

   Overview of GLP-1 agonists and why these drugs are getting so much attention

   1. SPSpeaker4:09

      I think it will be really important just to kinda catch people up a little bit, and I don't think we have to go into so much detail because we do have AMA 29, and if anyone wants to get in the science, that, in classic Peter/Bob fashion, really dives into the science. But do you wanna just give people a quick overview of, like, the GLP-1 drugs and why people are so excited about them, why they're talked about so much?

   2. PAPeter Attia4:33

      Yeah. So y- you're absolutely right. I... If, if I were to kind of rehash everything Bob and I spoke about, uh, two years ago, we would not get through the content of this podcast. I really do wanna talk about different things today. That said, you have to have at least a modicum of understanding of what these hormones do in the body. So, um, we're really gonna be talking about two hormones today, GLP-1, or glucagon-like peptide 1, and GIP, glucose-dependent insulinotropic polypeptide. Both of these are hormones that are released from the gut. I'm not gonna go into the details right now. One is released from one part of the gut, one is released from the other, but the net net is their effect on insulin. Now, you might be saying, "Well, okay, why, why are we talking about this again?" So pull up the figure, Nick. We have a, we have a figure that I think is, um, kind of an elegant way to put all of this in context. So, um, y- you gotta understand that these drugs really started as drugs to take care of patients with type 2 diabetes. Again, what is type 2 diabetes? Type 2 diabetes is a disorder of carbohydrate metabolism. So blood glucose gets too high, and that is the defining feature of it. Now, you could argue that might not be the right defining feature. Maybe we should be defining it earlier on. But it's basically a very extreme state of insulin resistance. So in a person who is developing type 2 diabetes Their cells, most notably their muscle cells, but also other cells in the body such as the liver, are becoming resistant to the effects of insulin, and as such, their blood glucose levels are rising. The reason for that, of course, is that the muscle is the most important storage depot for glucose. And so if the muscles are resistant to the effect of insulin, glucose will accumulate in the bloodstream. So what are we to do about this? There are lots of things to do about it, but what this figure shows is that an important strategic plan is using things that either stimulate insulin to be released and/or inhibit glucagon release. Both of those things will have the same net increase, which is to lower blood glucose, both directly, because if you stimulate insulin resi- release, you're going to put more insulin into circulation. That's going to overcome, at least transiently, the insulin resistance in the muscle. Now, of course, that turns into a very slippery slope because you can only play this game for so long before you basically exhaust the pancreas's capacity to produce more and more insulin, and at some point you just end up having to use exogenous insulin. The inhibition of glucagon release, conversely, changes the way that the liver puts glucose into circulation. And so as you can see in this figure, without going into all the details, GLP-1 and GIP act through both of these arms. They stimulate insulin resis- release. This is endogenous insulin production, and they inhibit glucagon release. And the net effect of both of these is a reduction of blood glucose. Just for anybody looking at the figure, [lips smack] uh, not relevant to this discussion, but there is a different class of drugs called DPP-4 inhibitors that, um, act further upstream of all that. Okay, so we have this observation which was that people who were taking GLP-1 agonists were not only improving glycemic control, which you would expect, but were also losing weight. And the question was, well, why are they losing weight? And as, as we discussed a few years ago, and as I'm gonna tell you again today, we don't have a really clear explanation for why, right? I mean, virtually everybody who's had any clinical experience with these and who has looked at the literature agrees that it's clearly a central effect, meaning there is something about these hormones that is changing our appetite, uh, namely, of course, reducing our appetite. And so when you take these hormones, your appetite goes down, you eat less, you lose weight. It's relatively straightforward. Um, but the exact why is not clear, meaning it's not exactly clear why GLP-1 is acting centrally in reducing appetite. [lips smack] So, um, let, let's take a look at the next figure as well, just to put in a broader context all of these drugs. Again, um, you know, this is a... This is all through the lens of type 2 diabetes, right? So the goal in type 2 diabetes, at least the, you know, end goal is to lower blood glucose. Uh, I would take some issue with that. I would say that the goal should be to increase insulin sensitivity, which will result in a reduction in blood glucose. But let's put that aside for a moment. What you see here is [clears throat] lots of different drugs, two of which we're gonna talk about today. We're gonna talk about metformin, and metformin really acts primarily to reduce glucose production, so it's, uh, it's gonna reduce what's called hepatic glucose output. Um, maybe it increases glucose utilization in the muscles. I think that's far less of an effect. Uh, so it... You know, you look at a figure like figure two, and you might come to the conclusion that those are equal. I don't think that's the case. Um, there's another class of drug we're not gonna talk about today, but it's a very important class of drug, and it's a class of drug we have spoken about before. We've talked about this on the podcast with Rich Miller, and that's the SGLT2 inhibitors. [lips smack] Uh, specifically, we spoke about one called canagliflozin. So, um, these are drugs that act in the kidneys, and they impair glucose reabsorption, so you end up peeing out more glucose. The reason we've spoken about them before is not in the context of that, but rather in the context of the benefits on longevity as a result of that. So metformin we're gonna talk about today less because of its diabetic effects. We're gonna talk about it through its geroprotective effects, and SGLT2 inhibitors we'll definitely come back to 'cause they're super interesting. Uh, I, I think that canagliflozin and its derivatives are very promising drugs [lips smack] in the geroprotective space. But just so you can see it, this is how they're acting in the diabetes space. Um, you have sulfonylureas, and you have these incretin therapies that we're gonna talk about today. So in a, in a sort of a rather large nutshell, that's, that's the backdrop to what we're talking about here.

   3. SPSpeaker11:11

      I think it's important maybe just to kind of remind people that even though that graph we just looked at was all about, like, anti-diabetic drugs, I'm assuming, and I think you'll confirm, that a lot of people who are reaching out to you to ask questions on these GLP-1 drugs don't have diabetes, correct?

   4. PAPeter Attia11:28

      Oh, yeah. I mean, it goes without saying that everybody who's reaching out to me on this topic, and that's ranging from friends to patients to random people I don't know, are, you know... Virtually none of these are people with type 2 diabetes. These are people that are, um, asking the question solely through the lens of weight loss. And I want to be clear, like, some of these people are in genuine need of weight loss, right? Some of these people are, you know, walking around with 50% of their body weight in body fat or, you know, 40% of their body weight is, is fat. Um, but perhaps more disturbing to me is the people who are reaching out to me who are frankly not overweight remotely, um, but are saying, like, "I really want to lose 10 pounds to look good on my vacation, and I should be taking this, right?" Um, and so, you know, again, those are some of the things that I, that I want to be able to, to

4. 12:20 – 14:08

   Defining the term “geroprotective”

   1. PAPeter Attia12:20

      address

   2. SPSpeaker12:21

      And, um, people who have listened to the podcast for a while will pr- are familiar with this term, but it might be good to just give a super quick definition because we've used it twice now. When we say geroprotective, that's just a fancy way of saying, do you want to explain to people kind of what you mean by that?

   3. PAPeter Attia12:36

      Yeah. Geroprotective is sort of a, I mean, as its name suggests, gero aging protective. Um, it's a class of drug that, that, or it's a, it's a, it's a term we use to describe drugs whose exact mechanisms of aging might not be known, but they appear to act broadly across various different hallmarks of aging. So, you know, I would argue that lipid-lowering drugs, uh, improve longevity, but I don't think I would call them geroprotective because they're kind of just acting not on a hallmark of aging, but rather on one very specific element, which is lipoproteins. And those of course do factor very heavily into ASCVD and to a lesser extent, uh, dementia. But, you know, c- c-contrast that with, say, rapamycin or SGLT2 inhibitors or potentially metformin, where they're probably doing a lot of things that overall improve lifespan and healthspan beyond just kind of whack-a-mole-ing one disease at a time.

   4. SPSpeaker13:41

      You mention it, and I'll just give people a podcast number, but Richard Miller, that episode was number one forty-eight. I think it's such a fascinating episode, and for people who kind of want to understand the science of these drugs, what goes into testing them, what to think about, can't recommend that enough, Richard Miller. Um, just amazing insights and that podcast was great. So anyone who hasn't listened to it, one forty-eight, definitely go back to it.

5. 14:08 – 19:10

   Semaglutide: background, brand names, indications, and more

   1. SPSpeaker14:08

      I think the next question that we get a lot is, you know, when the AMA twenty-nine came out with you and Bob, I think just semaglutide was on the market and being talked about. But two thousand twenty-two, you know, you mentioned it, tirzepatide came out and also is showing some really good results. And I think one of the common, like, questions people have is, what's the difference between these two drugs and kind of how do they compare?

   2. PAPeter Attia14:33

      Yeah, no, that's a, that's a great question. So, um, uh, to be clear, there are other versions of this drugs that, other versions of GLP-1 agonists that came earlier. Not gonna talk about them right now. So the first time this ever popped up onto my radar was like twenty thirteen. Um, but, but... And that, that was a drug that was used for type 2 diabetes and never gained FDA approval for obesity. At least I don't think it ever did. But let's start with semaglutide. So semaglutide is a pure GLP-1 agonist. Um, to be, uh, more clear, it is, um, it has even a, it, it, it has a, I, I would say a sort of comparable, um, affinity to pure, uh, GLP-1. So one way that we do that, there's a, you know, sort of a chemical way that you can look at the concentration of semaglutide and ask the question, how much of it do you need to replicate the effect of, you know, pure GLP-1? And in the case of semaglutide, you know, it's on the order of, you know, half as potent, okay? But it's a-- but nevertheless, it's a pure GLP-1 agonist, meaning it's replicating, as opposed to antagonist. You sometimes hear that in pharmacology. Antagonists block the effect of, uh, a hormone. The branded name for semaglutide in the c- in the use for type 2 diabetes is called Ozempic, and it comes in three doses, I believe, point five, one, and two milligrams. These are auto-injector pens, uh, that need to be refrigerated. They're very expensive. We're gonna talk about that later. And so a patient who's historically been getting this for treatment of their type 2 diabetes, hopefully they're not paying out of pocket for this. You know, they're either giving themselves point five or one or two milligrams of this drug. And, um, they're doing it weekly, which by the way, speaks to something I should have said earlier. Remember how earlier I said that semaglutide is not quite as potent as the actual GLP-1, as the native GLP-1? And you might say, "Well, why didn't they make it that way?" And the reason is it was designed that way. It was designed to have a much longer half-life. So if you're thinking about drug delivery, how long the drug stays in circulation is really important. So if you could make native GLP-1, but it only stuck around your system for six hours and you had to inject yourself four times a day, that's a much worse trade-off than, say, being able to have it slightly less potent and just use a more, you know, a greater dose of it, but only inject yourself once a week. So anyway, uh, little aside there. Um, so basically, Ozempic, as semaglutide, was approved in late twenty seventeen. We'll talk a little bit about the data for why that was the case. Um, I think a higher dose was actually approved, uh, just last year. Okay. Now fast-forward to, I think it was June of twenty-one, spring of twenty-one, thereabouts. I, uh, the study came out, I think, in April of twenty-one that looked at, uh, semaglutide. It was actually using Ozempic, but the indication was in treating obesity without diabetes. That's the study that we, that, that we talked about that at length in the previous AMA, uh, and we will touch on it briefly today. But nevertheless, that led to the approval of a new drug called Wegovy, which is of course the exact same drug. So semaglutide ... is Ozempic, is Wegovy. The difference is basically branding and dosing. So Wegovy is dosed up to 2.4 milligrams per week, and that was approved, uh, as I said, probably in the spring of '21, and it was just recently approved for kids age 12 and up, uh, at the time of this recording last month. So, um, does that... I hope that kinda makes sense before I go on to, uh, uh, before I go on to tirzepatide.

   3. SPSpeaker18:51

      I think it, I think it does, and it's, it's kinda good to just hear, 'cause I, I think anyone who watches TV will have seen commercials, and you see Wegovy, Ozempic. You see stories about semaglutide. So I think it's a good just kinda overview of just different terms, similar things.

6. 19:10 – 27:08

   Tirzepatide: background, brand names, indications, and more

   1. PAPeter Attia19:10

      Cool. Okay. So now we will switch and talk about a newer drug called tirzepatide. Tirzepatide is not the same as semaglutide, and it is, in fact, a drug that is known as a co-agonist. So it is both GIP and GLP-1. And you'll recall I said that, uh, semaglutide is, you know, directionally speaking, about half as potent as native GLP-1. Well, tirzepatide is even less than that, right? Tirzepatide, when you use the same sort of chemical assay, uh, called a KI or an affinity s- um, metric, it's y- you know, like a quarter as, as potent as native GLP-1. However, when you compare the GIP activity, it's virtually identical to native GIP. So you think of semaglutide as, um, a slightly weaker version of GLP-1. You would think of tirzepatide as a much weaker version of GLP-1, but a very potent GIP. It's basically equivalent biologically to GIP. So, um, this is branded as a drug called Mounjaro. Is it worth pointing out our text thread on this topic?

   2. SPSpeaker20:32

      Oh, it's really funny you brought that up-

   3. PAPeter Attia20:35

      [laughs]

   4. SPSpeaker20:35

      ... because one of the things I was gonna say is rumor is that your alias is Johnny Mounjaro-

   5. PAPeter Attia20:44

      [laughs]

   6. SPSpeaker20:44

      ... because of your affinity for this drug. Can you confirm nor deny that?

   7. PAPeter Attia20:48

      I, I will absolutely deny it. I do have an alias, and it is not Johnny Mounjaro, even though there are people within our organization that are trying to make that happen. But no, it is, it is not. I have a much cooler alias than Johnny Mounjaro, although I will admit that's a pretty cool alias.

   8. SPSpeaker21:05

      It's got a good ring to it.

   9. PAPeter Attia21:06

      It does.

   10. SPSpeaker21:06

       It kinda rolls off the t- it's like a man of mystery, Johnny Mounjaro.

   11. PAPeter Attia21:09

       [laughs]

   12. SPSpeaker21:09

       You don't know what he does.

   13. PAPeter Attia21:10

       No, no. He's-

   14. SPSpeaker21:10

       Could be

   15. PAPeter Attia21:11

       ... it's insane. I mean, I hope that somebody listening to this adopts that moniker and is forevermore Johnny Mounjaro. Okay. So, um, Mounjaro, which is the, just the branded name for tirzepatide, comes in, uh, same, same thing, right? It's, it's a preloaded pen that you inject, so you don't have to draw it up or anything like that. It comes in increments. Uh, I believe it's 2.5, 5, 7.5, 10, 12.5, all the way up to 15 milligrams. And, um, it was approved relatively recently for type 2 diabetes. So that approval took place in, I mean, like a year ago, right? A r- relatively new drug. It has not yet gained FDA approval for obesity. However, the New England Journal of Medicine did publish a study in the fall, which is where a lot of the hoopla came from, that demonstrated that this is even a better drug than semaglutide for weight loss. And, um, presumably the, uh, they're in the process of now gaining approval for, um, obesity use. Of course, because a drug is a- approved by the FDA, you can basically use it for anything you want. It's just considered off-label, and it would never be, um, approved by insurance companies. But for people who are willing to pay out of pocket, um, there are lots of people who are both being prescribed and using tirzepatide or Mounjaro for the purposes of obesity. And of course, just to be clear, whatever approval comes for obesity, it's gonna have a new name, right? So just as you have Wegovy for obesity and Ozempic for type 2 diabetes, you have Mounjaro for type 2 diabetes, and you're gonna have some equally bizarre name for, uh, obesity.

   16. SPSpeaker22:55

       This may be a naive question. This is... I don't know the science as well. Will either of these drugs ever be non-injectable? Like, will there ever be a day in which you can take a pill? Or because of what they do in the body, do they always, do we think they'll always have to be injectable?

   17. PAPeter Attia23:13

       Yeah, so, so, so actually there is an oral semaglutide as well. Uh, I'm blanking on the brand name. It begins with an R. It's like R-Y something. Um, it is used somewhat for type 2 diabetes. That's its indication and approval. It's, um, also very expensive, and I'm not exactly sure of what the differences are and why one would prefer it over the injectable. The only thing I can think of is if a person doesn't want to inject, uh, doesn't want to use a needle, and/or refrigeration is a problem, 'cause obviously these things need to be refrigerated. So, so that, that might be kind of an issue there.

   18. SPSpeaker23:54

       I mean, that's what I was kind of figuring. I assumed someone was trying to figure it out just for those people with a fear of needles, as injecting yourself as often as you would have to would be a little tough. Um, so kinda now that we got the overview, the next question we always get is, okay, how do those two drugs, semaglutide, tirzepatide, compare in their effectiveness? So in looking at weight loss, HbA1c, those other things that they're measuring, do we see a difference in the results? And kinda what do we know about that?

   19. PAPeter Attia24:29

       Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a member. We created the membership program to bring you more in-depth exclusive content without relying on paid ads. Membership benefits are many, and beyond the complete episodes of the AMA each month, they include the following. Ridiculously comprehensive podcast show notes that detail every topic, paper, person, and thing we discuss on each episode of The Drive. Access to our private podcast feed. The Qualies, which are a super short podcast, typically less than five minutes, released every Tuesday through Friday, which highlight the best questions, topics, and tactics discussed on previous episodes of The Drive. This is particularly important for those of you who haven't heard all of the back episodes. It becomes a great way to go back and filter and decide which ones you want to listen to in detail. Really steep discount codes for products I use and believe in, but for which I don't get paid to endorse. And benefits that we continue to add over time. If you want to learn more and access these member only benefits, head over to peterattiamd.com/subscribe. Lastly, if you're already a member but you're hearing this, it means you haven't downloaded our member only podcast feed where you can get the full access to the AMA and you don't have to listen to this. You can download that at peterattiamd.com/members. You can find me on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about where I keep an up-to-date and active list of such companies. [outro music]

Episode duration: 27:08