#246 - AMA #45: Pros and cons of GLP-1 weight loss drugs and metformin as a geroprotective agent

Hey everyone. Welcome to a Sneak Peek, Ask Me Anything or AMA episode of the Drive podcast. I'm your host, Peter Attia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created. Or you can learn more now by going to Peteratti md.com subscribe so without further delay, here's today's sneak peek of the Ask Me Anything episode. Welcome to ask me anything ama episode number 45. I'm once again joined by Nick Stenson. In today's episode, we focus on two topics, both of which are getting a lot of questions lately. The first is GLP1 agonists, most notably semaglutide, also known as ozempic and wig govy and tirzepatide. These weight loss drugs are all the rage right now, and there is probably not a day that goes by where someone isn't asking me my thoughts on them. So in the first part of this episode, we dive very deep into these what they are, their differences, how they're marketed, how they came to market, meaning what we learned about them when they were just being used as diabetes drugs, what we know about them clinically because we've been using these drugs sparingly for about three years. Most importantly, I think where my reservations are, and I do have many reservations that I discuss here. If you're thinking about taking these drugs, if you're taking these drugs, if you're curious about them, this episode is for you. The second part of this podcast. We go a little deeper into metformin. This is something I've talked about in the past, but a little more attention has come up lately, just by way of background. Metformin has gathered a lot of interest over the past few years, but a lot of it goes back to a study that came out in 2014 that suggested that diabetics taking metformin actually had better health outcomes, that is Lower mortality than non diabetics not taking metformin. This is a very counterintuitive finding and of course it suggests that metformin is indeed zero protective. Well, in this episode I dive much deeper into that assumption, both going back to the original 2014 study and looking at a more recent study that uses a very similar analysis but on a different population. So if you have any interest in metformin, if you have any interest in GLP1 agonists, this is the episode for you. Now, if you're a subscriber and want to watch the full video of this podcast, you can find it on the Show Notes page. If you're not a subscriber, you can watch a sneak peek of the video on our YouTube page without further delay. I hope you enjoy. AMA number 45.

Peter, how you doing?

Doing very well.

You ready for another ama?

Here I am.

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 book launch?

No, no. This book is. Is like a cat that died eight times and somehow managed to eke out survival before the ninth and final death.

And there's 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. We'll have a dedicated book podcast coming up for 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 this, it's about two weeks out until they get their hands on it.

Yeah. Well, I hope it delivers, 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 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 GLP1 agonists and these drugs. And it was kind of one of those things where I hadn't really heard much being talked about. It seemed so new. And 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.

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 21. 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 one of the drugs we'll be talking about today, semaglutide. 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 cannot be a drug that is getting more attention right now than semaglutide. And it's ilk, right? So that means branded Ozempic, branded wegovy, Tirzepatide, branded. Like all of those drugs which we're gonna talk about today, I don't think a day goes by that I'm not getting pinged by somebody about it. So 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 also 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 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 geoprotective 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 will be really important just to 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 the GLP1 drugs and why people are so excited about them, why they're talked about so.

Much, you're absolutely right. If I were to rehash everything Bob and I spoke about 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 1 and GIP glucose dependent insulinotropic 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, why are we talking about this again? Pull up the figure, Nick. We have a figure that I think is kind of an elegant way to put all of this in context. 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. 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 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 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, GLP1 and Gipsy act through both of these arms. They stimulate insulin, resist. 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 act further upstream of all that. So we have this observation, which was that people who were taking GLP1 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. 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, 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. But the exact why is not clear. Meaning it's not exactly clear why GLP1 is acting centrally and reducing appetite. Let's take a look at the next figure as well. Just to put in a broader context. All of these drugs, again, this is all through the lens of type 2 diabetes. So the goal in type 2 diabetes, at least, the 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, 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. 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. 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. 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 about talked, talked about this on the podcast with Rich Miller, and that's the SGLT2 inhibitors. Specifically, we spoke about one called kanagaflozin. 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 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 will definitely come back to because they're super interesting. I think that kinagaflozin and its derivatives are very promising drugs in the JIRA protective space. But just so you can see it, this is how they're acting in the diabetes space. You have sulfonyureas and you have these incretin therapies that we're going to talk about today. So in a rather large nutshell, that's the backdrop to what we're talking about here.

And I think it's important maybe just to kind of remind people that even though that graph we just looked at was all about 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 GLP1 drugs don't have diabetes, correct?

Oh, yeah. 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, virtually none of these are people with type 2 diabetes. These are people that are asking the question solely through the lens of weight loss. And I want to be clear, some of these people are in genuine need of weight loss. Some of these people are walking around with 50% of their body weight in body fat, or 40% of their body weight is fat. But perhaps more disturbing to me is the people who are reaching out to me who are frankly not overweight remotely, but are saying, I really want to lose 10 pounds to look good on my vacation and I should be taking this, right? And so again, those are some of the things that I want to be able to address.

People who have listened to the podcast 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 geoprotective. That's just a fancy way of saying, do you want to explain to people kind of what you mean by that?

JIRA protective is sort of a, I mean, as its name suggests, zero aging protective. 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 I would argue that lipid lowering drugs improve longevity, but I don't think I would call them zero 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 dementia. But 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 whack a moling one disease at a time.

And you mentioned 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 them, what to think about, can't recommend that enough. Richard Miller Just amazing insights and that podcast was great. So anyone who hasn't listened to it148 definitely go back to it. I think the next question that we get a lot is when the AMA 29 came out with you and Bob, I think just semaglutide was on the market and being talked about. But 2022, you know, you mentioned it, tirzepatide came out and also is showing some really good results. And I think one of the common questions people have is what's the difference between these two drugs? And kind of how do they compare?

To be clear, there are other versions of this drug, other versions of GLP1 agonist that came earlier. Not gonna talk about them right now. So the first time this ever popped up onto my radar was like 2013. 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 GLP1 agonist. To be more clear, it has a comparable affinity to pure GLP1. So one way that we do that, there's 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 pure GLP1? In the case of semaglutide, it's on the order of half as potent, but nevertheless, It's a pure GLP1 agonist, meaning it's replicating as opposed to antagonists. You sometimes hear that in pharmacology, antagonists block the effects of hormone. So the branded name for semaglutide 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 that need to be refrigerated. They're very expensive. We're going to talk about that later. 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. They're either giving themselves 0.5 or 1 or 2 milligrams of this drug and 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 GLP1, as the native GLP1, 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. If you're thinking about drug delivery, how long the drug stays in circulation is really important. So if you could make native GLP1, 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 greater dose of it, but only inject yourself once a week. So, anyway, little aside there. So basically, Ozempic as semaglutide was approved in late 2017. We'll talk a little bit about the data for why that was the case. I think a higher dose was actually approved just last year. Now fast forward to, I think it was June of 21, the study came out, I think in April of 21 that looked at semaglutide. It was actually using Ozempic, but the indication was in treating obesity without diabetes. We talked about that at length in the previous AMA 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. Wegovy is dosed up to 2.4 milligrams per week. And that was approved, as I said, probably in the spring of 21, and it was just recently approved for kids age 12 and up at the time of this recording last month. I hope that kind of makes sense before I go on to Tirzepatide.

I think it does, and it's kind of good to just hear. 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 overview of just different terms, similar things.

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 drugs, GIP and GLP1. And you'll recall I said that semaglutide is, directionally speaking, about half as potent as native GLP1. Well, tirzepatide is even less than that. Tirzepatide, when you use the same sort of chemical assay called a ki or an affinity metric, it's a quarter as potent as native GLP1. However, when you compare the GIP activity, it's virtually identical to native GIP. So you think of Semaglutide as a slightly weaker version of GLP1. You would think of Tirzepatide as a much weaker version of GLP1, but a very potent GIP. It's basically equivalent biologically to GIP. So this is branded as a drug called Manjaro. Is it worth pointing out our text thread on this topic?

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

It's got a good ring to it. It kind of rolls off the top. It's like a man of mystery. Johnny Munjaro. 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 Manjaro. Okay, so Mounjaro, which is just a branded name for Tirzepatide, comes in same thing. 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. I believe it's 2.5, 5, 7.5, 10, 12.5, all the way up to 15 milligrams. It was approved relatively recently. For type 2 diabetes. So that approval took place like a year ago. 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 presumably 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, 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 going to have a new name. So just as you have Wegovy for obesity and ozempic for type 2 diabetes, you have Mounjaro for type 2 diabetes and you're going to have some equally bizarre name for obesity.

This may be a naive question, just 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 we think they'll always have to be injectable?

Oh, not a naive question. In fact, there is an oral semaglutide as well. I'm blinking on the brand name. It begins with an R. It's like R Y something. It is used somewhat for type 2 diabetes. That's its indication and approval. And it's 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, doesn't want to use a needle and or refrigeration is a problem because obviously these things need to be refrigerated. So that might be kind of an issue there.

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 as often as you would have to would be a little tough. Now that we got the overview, the next question we always get is 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 kind of what do we know about that?

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