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

Summary

Highlights

• The upcoming book release by Peter Attia is a much-anticipated event, marking a milestone for his expertise sharing 📚.
• Semaglutide and its brand variants (Ozempic, Wegovy) were initially developed for diabetes, but are now popular for weight loss 🌟.
• Tirzepatide (Manjaro), a newer drug, is showing promising weight loss results, potentially even more effective than semaglutide 💊.
• The discussion delves into how these drugs function by mimicking hormones that regulate insulin, irrespective of diabetes presence 📊.
• The podcast questions the usage of these drugs by healthy individuals seeking weight loss for aesthetic reasons ⚖️.

Key Takeaways

• GLP-1 drugs like semaglutide and tirzepatide are trending as weight loss solutions, gaining much attention beyond their diabetic uses 🚀.
• Metformin is being explored for its potential as a geroprotective agent, offering benefits beyond its traditional role in managing diabetes 🧬.
• The episode highlights ethical concerns about the use of weight loss drugs by individuals who are not significantly overweight 🚦.
• Peter Attia talks about how personal and public interest in these medications has grown, even among those without diabetes 🌟.
• New studies and data continue to shape the understanding and recommended uses of these drugs, indicating their evolving landscape 📈.

Overview

Chapters

• 00:00 - 01:00: Introduction and Book Release Discussion The chapter introduces the release of a new book and features a discussion between the host, Peter Attia, and a guest named Vader. Peter welcomes the audience to the Drive podcast and mentions that some interesting topics will be covered in the episode. Although the exact date of recording is not specified, it highlights that by the time of the episode's release, the book launch will be approximately two weeks away. This creates anticipation and sets the stage for the primary content of the podcast.
• 01:00 - 05:00: Introduction to GLP-1 Agonists and Metformin The chapter opens with a discussion on the metaphorical 'nine lives' of a book being akin to a cat. This symbolizes the numerous challenges and close calls the book faced in its journey towards publication. With the assurance that the book's launch is imminent, the speaker reflects on the effort put into finalizing details like the cover, underlining the achievement of bringing the book to print despite obstacles.
• 05:00 - 09:00: GLP-1 and GIP Hormones Explained The chapter begins with a discussion about an upcoming book podcast and the anticipation of its release in two weeks. The main focus is on two subjects: GLP-1 and GIP hormones. While these topics have been addressed before, the chapter highlights that there are new insights, studies, and information available. Many questions have been received on these topics, leading to the decision to explore them further in this chapter.
• 09:00 - 13:00: Mechanism of GLP-1 Drugs in Managing Diabetes In this chapter, the discussion revolves around the anticipation and early conversation about GLP-1 agonists as a treatment for diabetes. The speaker recalls a past AMA session where they, along with Bob, had a foresight about the growing importance and discussion surrounding GLP-1 drugs. At the time, GLP-1 agonists were not widely talked about, and there was some uncertainty about whether it was the right time to focus on them. However, both the speaker and Bob confidently believed that these drugs would soon become a significant topic of interest.
• 13:00 - 17:00: Weight Loss Effects and Appetite Changes of GLP-1 Agonists In the chapter titled 'Weight Loss Effects and Appetite Changes of GLP-1 Agonists', the discussion focuses on the exploration and early adoption of GLP-1 agonists for weight loss and appetite management. The narrative reflects on initial conversations from spring 2020 and details an internal journal club that delved deeply into the subject. By the fall of 2020, the application of GLP-1 agonists in patient treatment had commenced.
• 17:00 - 22:00: Comparison of GLP-1 Agonists and Other Diabetic Drugs The chapter discusses the growing popularity and attention surrounding the diabetic drug semaglutide and its branded versions such as Ozempic and Wegovy, as well as others like tirzepatide. Despite being relatively under the radar initially, semaglutide is now one of the most discussed drugs.
• 22:00 - 31:00: Terzapatide vs. Semaglutide The chapter discusses the topic of Terzapatide versus Semaglutide, which appears to be a highly popular topic as indicated by frequent inquiries. The speaker notes that there is now greater clarity and a more defined perspective on the drugs compared to two or three years ago. This suggests that significant developments or insights have emerged over time, warranting a revisit and deeper exploration of the subject. The anticipation of a detailed discussion implies that this is a subject of considerable interest and importance in its field.
• 31:00 - 37:00: Effects on Non-Diabetic Weight Loss and Geroprotection This chapter explores the effects of non-diabetic weight loss and geroprotection. It begins by addressing common questions and leveraging new insights from clinical experiences. The discussion shifts towards the role of metformin, focusing on its benefits beyond diabetes management, emphasizing its potential for geroprotection and its effects for non-diabetic individuals.
• 37:00 - 40:30: Conclusion The conclusion focuses on summarizing the content covered in the chapter, specifically on the topic of longevity agents and GLP-21 drugs. It mentions that the chapter provided an overview without going into excessive detail, as more information was available in another source (AMA 29) for those interested in the scientific aspects. The chapter concludes by emphasizing the excitement around GLP-21 drugs and their potential impact.

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

• 00:00 - 00:30 hey everyone welcome to the drive podcast I'm your host Peter attia Vader how you doing doing very well we got some fun topics two main ones that I think people are going to be interested in but one thing I realized although not at the time of this recording but by the time this is released will be about two weeks out from the book launch did you ever think we would be able to use those words two weeks out from the
• 00:30 - 01:00 book launch no no I this 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 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 right cover looks good cover looks great
• 01:00 - 01:30 um we'll have a dedicated book podcast coming up for um listeners where we kind of talk about it like let people know what's going on but yeah it's kind of 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 yeah well I hope it delivers yeah so Peter I think what we're going to 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
• 01:30 - 02:00 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 going to 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 kind of like are we sure we want to do this and you and Bob were both like yeah just wait there's going to be a lot of talk about this yeah we were we were
• 02:00 - 02:30 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 wow 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 patience on
• 02:30 - 03:00 the you know the one of the drugs we'll be talking about today semi-glutide 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 semi-glutide and and it's ilk right so that means you know branded ozempic branded wigovy terzapatide branded uh
• 03:00 - 03:30 you know like all of those drugs which we're going to 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 and so we're going to 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 and that's why I think it's going to be
• 03:30 - 04:00 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 going to cover is going to be kind of 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 kind of taking it as a zero protective
• 04:00 - 04:30 longevity agent so all goes according to plan that's what we will cover today which I think will be really good and so I think it would be really important just to kind of 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 want to just give people a quick overview of like the glp 21 drugs and why people are so excited about them
• 04:30 - 05:00 why they're talked about so much yep so you're absolutely right 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 want to 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 we're really going to be talking about two hormones today glp1 or glucagon like peptide one and
• 05:00 - 05:30 Gip glucose dependent insulin otropic polypeptide both of these are hormones that are released from the gut I'm not going to 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 well 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
• 05:30 - 06:00 this in context so um you got to 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
• 06:00 - 06:30 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
• 06:30 - 07:00 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
• 07:00 - 07:30 insulin 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
• 07:30 - 08:00 circulation and so as you can see in this figure without going into all the details glp1 and Gip act through both of these arms they stimulate insulin resist 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 not relevant to this discussion but there is a different class of drugs called dpp4 Inhibitors that [Music] um
• 08:00 - 08:30 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 we're also losing weight and the question was well why are they losing weight and as we discussed a few years ago and as I'm going to tell you again today we don't have a really clear explanation for why right I mean virtually everybody
• 08:30 - 09:00 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 and 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
• 09:00 - 09:30 is acting centrally in reducing appetite so um 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 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 I would take some issue with that I would say that the goal should be to increase insulin sensitivity
• 09:30 - 10:00 which will result in a reduction in blood glucose but let's put that aside for a moment what you see here is lots of different drugs two of which we're going to talk about today we're going to talk about metformin and Metformin really acts primarily to reduce glucose production so it's uh it's going to reduce what's called hepatic glucose output maybe it increases glucose utilization in the muscles I think that's far less of an effect so it you know you look at a
• 10:00 - 10:30 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 going to 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 uh specifically we spoke about one called canaga flowsin so 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
• 10:30 - 11:00 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 going to talk about today less because of its diabetic effects we're going to talk about it through its zero protective effects and sglt2 Inhibitors will definitely come back to because they're super interesting uh I think that can agaflows and its derivatives are very promising drugs in the Jiro protective space but just so you can see it this is how they're acting in the diabetes space um you have sulfona ureas and you have
• 11:00 - 11:30 these incritin therapies that we're going to 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 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 oh yeah I mean it goes without saying that everybody who's
• 11:30 - 12:00 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
• 12:00 - 12:30 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 address and um people who have listened to podcasts for a while 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
• 12:30 - 13:00 geoprotective that's just a fancy way of saying do you want to explain to people kind of what you mean by that yeah jira protective is sort of a I mean as its name such as Giro 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
• 13:00 - 13:30 lowering drugs uh improve longevity but I don't think I would call them Giro protective 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 contrast that would say rapamycin or sglt2 Inhibitors or potentially metformin where they're probably doing a
• 13:30 - 14:00 lot of things that overall improve lifespan and health span Beyond just kind of guacamole one disease at a time you mention it and I'll just give people a podcast number but Richard Miller that episode was number 148. 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 and what to think about can't recommend that enough Richard Miller
• 14:00 - 14:30 um just amazing insights and that podcast was great so anyone who hasn't listened to it 148 definitely go back to it I think the next question that we get a lot is you know when the AMA 29 came out with you and Bob I think just some glue tide was on the market and being talked about but 2022 you know you mentioned it for zepatide 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
• 14:30 - 15:00 between these two drugs and kind of how do they compare yeah that's a great question so um to be clear there are other versions of this drugs that other versions of glp-1 agonists that came earlier not going to talk about them right now so the first time this ever popped up onto my radar was like 2013. 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
• 15:00 - 15:30 start with semi-glutide so semiglutide is a pure glp-1 Agonist um to be more clear it is um it has even a it has a I I would say a sort of comparable um Affinity to Pure uh glp1 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 semi-glutide and
• 15:30 - 16:00 ask the question how much of it do you need to replicate the effect of you know pure glp1 and in the case of semi-glutide you know it's on the order of you know half as potent okay but it's a nevertheless it's a pure glp-1 Agonist meaning it's replicating as opposed to antagonists you sometimes hear that in Pharmacology antagonists block the effect of a hormone the
• 16:00 - 16:30 Branded name for semiglutide in the in the use for type 2 diabetes is called ozempic and it comes in three doses I believe 0.51 and 2 milligrams these are auto injector pens uh that need to be refrigerated they're very expensive we're going to 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 0.5 or 1 or 2
• 16:30 - 17:00 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 semi-glutide is not quite as potent as the actual glp1 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
• 17:00 - 17:30 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 greater dose of it but only inject yourself once a week so anyway a little aside there um so basically ozempic as semi-glutide was approved in late 2017. we'll talk a little bit about
• 17:30 - 18:00 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 21. spring of 21 thereabouts the study came out I think in April of 21 that looked at uh semi-glue tied it was actually using ozempic but the indication was in
• 18:00 - 18:30 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 wigovi which is of course the exact same drug so semiglutide is ozempic is wagovi the difference is basically branding and dosing so agovi is dosed up to 2.4 milligrams per week and that was
• 18:30 - 19:00 approved 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 kind of makes sense before I go on to uh before I go on to teres appetite I think it I think it does and it's it's kind of good to just hear because I think anyone who watches TV well I've seen commercials and you see mcgovi ozembic
• 19:00 - 19:30 you see stories about semi-glutides so I think it's a good just kind of overview of just different terms similar things cool okay so now we will switch and talk about a newer drug called terzapatide Trace appetite is not the same as semi-glutid and it is in fact a drug that is known as a co-agonist so it is both Gip and glp1
• 19:30 - 20:00 and you'll recall I said that semi-glutide is you know directionally speaking about half as potent as native glp1 while teresabatide is even less than that right trizepatide when you use the same sort of chemical assay called a Ki or an affinity metric it's you know like a quarter as as potent as native glp-1 however when you compare the Gip activity it's
• 20:00 - 20:30 virtually identical to Native Gip so you think of semi-glutide as a slightly weaker version of glp-1 you would think of terzapatide 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 Manjaro is it worth pointing out our text thread
• 20:30 - 21:00 on this topic oh it's really funny you brought that up because one of the things I was going to say is rumor is that your Alias is Johnny Manjaro because of your affinity for this drug can you confirm nor deny that I I will absolutely deny it I do have an alias and it is not Johnny munjaro even though there are people within our organization that are trying to make that happen but no it is it is not I
• 21:00 - 21:30 have a much cooler Alias than Johnny Manjaro although I will admit that's a pretty cool Alias it's got a good ring to it it kind of rolls off it's like a Mana mystery Johnny Manjaro you don't know what he does no no it's insane I mean I hope that somebody listening to this adopts that moniker and is forevermore Johnny manzaro okay so um Manjaro which is the just the Branded name for terzapatide comes in uh same same thing right it's a pre-loaded pen that you inject so you
• 21:30 - 22:00 don't have to draw it up or anything like that it comes in increments I believe it's 2.55 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 relatively new drug it has not yet gained FDA approval for obesity however the New England Journal of Medicine did publish
• 22:00 - 22:30 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 semi-glutide for weight loss and um presumably the uh they're in the process of now gaining approval for obesity use of course because a drug is approved by the FDA you can basically use it for anything you want it's just considered off label and it would never be approved by insurance companies but for people who are willing to pay out of pocket
• 22:30 - 23:00 um there are lots of people who are both being prescribed and using Trace appetite or Manjaro for the purposes of obesity and of course just to be clear whatever approval comes for obesity it's going to have a new name right so just as you have wigovi for obesity and ozempic for type 2 diabetes you have jarrow for type 2 diabetes and you're going to have some equally bizarre name for obesity this may be a naive question this is I don't know the science as well well either of these drugs
• 23:00 - 23:30 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 yeah so so so actually there is an oral semi-glutide as well I'm blinking on the brand name it begins with an R it's like Ry something um it is used somewhat for type 2 diabetes that's its indication and approval it's also
• 23:30 - 24:00 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 doesn't want to use a needle and or Refrigeration is a problem because obviously these things need to be refrigerated so so that that might be kind of an issue there 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 is injecting yourself
• 24:00 - 24:30 as often as you would have to would be a little tough um so kind of now that we got the overview the next question we always get is okay how do those two drugs semi-glutide Trace appetite compare in their effectiveness so in looking at Weight Loss hpa1c those other things that they're measuring do we see a difference in the results and kind of what do we know about that thank you for listening to today's sneak
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• 27:00 - 27:30 [Music]