#246 - AMA #45： Pros and cons of GLP-1 weight loss drugs and metformin as a geroprotective agent
Episode Stats
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Summary
In today's episode, Dr. Nick Stenson joins Dr. Atia to discuss two topics that are getting a lot of questions lately: Glp1 agonists and metformin. In this episode, we cover the differences between these two, how they came to market, what we know about them clinically, and where they fall in the hierarchy of weight loss drugs.
Transcript
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hey everyone welcome to a sneak peek ask me anything or ama episode of the drive podcast
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i'm your host peter atia at the end of this short episode i'll explain how you can access
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the ama episodes in full along with a ton of other membership benefits we've created
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or you can learn more now by going to peter atia md.com forward slash subscribe so without
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further delay here's today's sneak peek of the ask me anything episode
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welcome to ask me anything ama episode number 45 i'm once again joined by nick stenson in today's
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episode we focus on two topics both of which are getting a lot of questions lately the first is
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glp1 agonists most notably semaglutide also known as ozempic and we govi and terzepatide these weight
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loss drugs are all the rage right now and there is probably not a day that goes by where someone
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isn't asking me my thoughts on them so in the first part of this episode we dive very deep into these
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what they are their differences how they're marketed how they came to market meaning what we learned
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about them when they were just being used as diabetes drugs what we know about them clinically
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because we've been using these drugs sparingly for about three years most importantly i think
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where my reservations are and i do have many reservations that i discuss here if you're
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thinking about taking these drugs if you're taking these drugs if you're curious about them
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this episode is for you the second part of this podcast we go a little deeper into metformin this is
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something i've talked about in the past but a little more attention has come up lately just by way
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of background metformin has gathered a lot of interest over the past few years but a lot of it goes
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back to a study that came out in 2014 that suggested that diabetics taking metformin actually had
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better health outcomes i.e lower mortality than non-diabetics not taking metformin this is a very
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counterintuitive finding and of course it suggests that metformin is indeed giro protective well
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in this episode i dive much deeper into that assumption both going back to the original 2014
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study and looking at a more recent study that uses a very similar analysis but on a different
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population so if you have any interest in metformin if you have any interest in glp1 agonists this is
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the episode for you now if you're a subscriber and want to watch the full video of this podcast you
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can find it on the show notes page if you're not a subscriber you can watch a sneak peek of the
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video on our youtube page without further delay i hope you enjoy ama number 45
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vader how you doing doing very well you ready for another ama here i am we got some fun topics
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two main ones that i think people are going to be interested in but one thing i realized although
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not at the time of this recording but by the time this is released we'll be about two weeks out from
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the book launch did you ever think we would be able to use those words two weeks out from the book
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launch no no this uh book is uh is like a cat that died eight times and somehow managed to eke out
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survival before the ninth and final death well and there's no turning back now right like if we're
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recording this and something went wrong where the book's coming out like i just can't imagine what it
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would be it's going to print it's done right cover looks good cover looks great we'll have a dedicated
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book podcast coming up for listeners where we kind of talk about it like let people know what's going
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on but yeah it's kind of mind-blowing if you think about by the time people are listening to this it's
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about two weeks out until they get their hands on it yeah well i hope it delivers um peter i think what
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we're going to talk about today is really two different subjects both of which we've covered a little
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bit in the past but there's been a lot of new insights that have come out new studies new
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information and we receive a lot of questions on them and the first is something you and bob covered
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back in ama 29 which was back i think end of 2021 and i remember at the time you guys were talking about
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hey we're going to do an ama on glp1 agonists and these drugs and it was kind of one of those things
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where i hadn't really heard much being talked about it seems so new and you know i was kind of like are we
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sure we want to do this and you and bob were both like yeah just wait there's going to be a lot of
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talk about this we were so wrong and so right so we were way too far ahead of the curve talking about
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this in fact our first real discussion about it was in the spring of 21 no no in the spring of 2020
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so in the spring of 2020 we did a journal club internally got very deep in the rabbit hole by the
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fall of 2020 we were putting patients on one of the drugs we'll be talking about today semaglutide
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a year later we're doing an ama on it it's still very under the radar and today i would say
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this is the single most talked about drug period there cannot be a drug that is getting more
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attention right now than semaglutide and it's ill right so that means branded ozempic branded we govi
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terzepatide branded like all of those drugs which we're going to talk about today i don't think a day
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goes by that i'm not getting pinged by somebody about it so we were way too early on it and so we're
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going to come back and talk about it with a much greater clarity and also i have a much much
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stronger point of view on it today than i did two almost three years ago and that's why i think
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it's going to be good to touch back on it is because not only do we get so many more questions
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because of how much it's talked about but i know you have so much more experience with this
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in clinic and other things where you have a lot of new insights so that will be the first piece
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and then the other piece that we're going to cover is going to be kind of looking at some
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metformin data and kind of thinking about how you're thinking about that drug in particular
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not so much as for people who are diabetics but more so for those who are in the camp of
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kind of taking it as a gyroprotective longevity agent so all goes according to plan that's what we
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will cover today which i think will be really good and so i think it will be really important just to
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catch people up a little bit and i don't think we have to go into so much detail because we do have
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ama29 and if anyone wants to get in the science that in classic peter bob fashion really dives into
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the science but do you want to just give people a quick overview of the glp1 drugs and why people
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are so excited about them why they're talked about so much you're absolutely right if i were to rehash
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everything bob and i spoke about two years ago we would not get through the content of this podcast i
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really do want to talk about different things today that said you have to have at least a
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modicum of understanding of what these hormones do in the body so we're really going to be talking
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about two hormones today glp1 or glucagon-like peptide 1 and gip glucose dependent insulinotropic
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polypeptide both of these are hormones that are released from the gut i'm not going to go into the
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details right now one is released from one part of the gut one is released from the other but the net
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net is their effect on insulin now you might be saying well why are we talking about this again
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pull up the figure nick we have a figure that i think is kind of an elegant way to put all of this
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in context you got to understand that these drugs really started as drugs to take care of patients
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with type 2 diabetes again what is type 2 diabetes type 2 diabetes is a disorder of carbohydrate
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metabolism blood glucose gets too high and that is the defining feature of it now you could argue
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that might not be the right defining feature maybe we should be defining it earlier on but it's basically
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a very extreme state of insulin resistance so in a person who is developing type 2 diabetes their
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cells most notably their muscle cells but also other cells in the body such as the liver are becoming
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resistant to the effects of insulin and as such their blood glucose levels are rising the reason for
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that of course is that the muscle is the most important storage depot for glucose and so if the muscles
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are resistant to the effect of insulin glucose will accumulate in the bloodstream so what are we to do about
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this there are lots of things to do about it but what this figure shows is that an important strategic
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plan is using things that either stimulate insulin to be released and or inhibit glucagon release both of
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those things will have the same net increase which is to lower blood glucose both directly because if you
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stimulate insulin release you're going to put more insulin into circulation that's going to overcome
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at least transiently the insulin resistance in the muscle now of course that turns into a very slippery slope
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because you can only play this game for so long before you basically exhaust the pancreas's capacity
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to produce more and more insulin and at some point you just end up having to use exogenous insulin
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the inhibition of glucagon release conversely changes the way that the liver puts glucose into
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circulation and so as you can see in this figure without going into all the details glp1 and gip
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act through both of these arms they stimulate insulin release this is endogenous insulin production
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and they inhibit glucagon release and the net effect of both of these is a reduction of blood glucose
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just for anybody looking at the figure not relevant to this discussion but there is a different class of
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drugs called dpp4 inhibitors that act further upstream of all that so we have this observation
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which was that people who were taking glp1 agonists were not only improving glycemic control which you
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would expect but we're also losing weight and the question was well why are they losing weight and
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as we discussed a few years ago and as i'm going to tell you again today we don't have a really clear
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explanation for why virtually everybody who's had any clinical experience with these and who has
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looked at the literature agrees that it's clearly a central effect meaning there is something about
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these hormones that is changing our appetite namely of course reducing our appetite and so when you
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take these hormones your appetite goes down you eat less you lose weight it's relatively
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straightforward but the exact why is not clear meaning it's not exactly clear why glp1 is acting
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centrally and reducing appetite let's take a look at the next figure as well just to put in a broader
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context all of these drugs again this is all through the lens of type 2 diabetes so the goal in type 2
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diabetes at least the end goal is to lower blood glucose i would take some issue with that i would say that the goal
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should be to increase insulin sensitivity which will result in a reduction in blood glucose but
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let's put that aside for a moment what you see here is lots of different drugs two of which we're going
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to talk about today we're going to talk about metformin and metformin really acts primarily to reduce
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glucose production it's going to reduce what's called hepatic glucose output maybe it increases glucose
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utilization in the muscles i think that's far less of an effect you know you look at a figure like figure
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two and you might come to the conclusion that those are equal i don't think that's the case
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there's another class of drug we're not going to talk about today but it's a very important class
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of drug and it's a class of drug we have spoken about before we've talked about this on the podcast
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with rich miller and that's the sgl t2 inhibitors specifically we spoke about one called canagaflozin
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so these are drugs that act in the kidneys and they impair glucose reabsorption so you end up
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peeing out more glucose the reason we've spoken about them before is not in the context of that
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but rather in the context of the benefits on longevity as a result of that so metformin we're
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going to talk about today less because of its diabetic effects we're going to talk about it
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through its gyroprotective effects and sgl t2 inhibitors will definitely come back to because
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they're super interesting i think that canagaflozin and its derivatives are very promising drugs
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in the gyroprotective space but just so you can see it this is how they're acting in the diabetes
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space you have sulfonyureas and you have these incretin therapies that we're going to talk about
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today so in a rather large nutshell that's the backdrop to what we're talking about here
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and i think it's important maybe just to kind of remind people that even though that graph we just
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looked at was all about anti-diabetic drugs i'm assuming and i think you'll confirm that a lot of
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people who are reaching out to you to ask questions on these glp1 drugs don't have diabetes correct
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oh yeah it goes without saying that everybody who's reaching out to me on this topic and that's
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ranging from friends to patients to random people i don't know virtually none of these are people with
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type 2 diabetes these are people that are asking the question solely through the lens of weight loss
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and i want to be clear some of these people are in genuine need of weight loss some of these people
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are walking around with 50 of their body weight in body fat or you know 40 of their body weight is fat
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but perhaps more disturbing to me is the people who are reaching out to me who are frankly not
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overweight remotely but are saying like i really want to lose 10 pounds to look good on my vacation
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and i should be taking this right and so you know again those are some of the things that i want to be
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able to address people who have listened to podcasts for a while are familiar with this term but
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it might be good to just give a super quick definition because we've used it twice now when we say
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geoprotective that's just a fancy way of saying do you want to explain to people kind of what you
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mean by that geoprotective is sort of a i mean as its name suggests geero aging protective it's a term
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we use to describe drugs whose exact mechanisms of aging might not be known but they appear to act
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broadly across various different hallmarks of aging so i would argue that lipid lowering drugs
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improve longevity but i don't think i would call them geero protective because they're kind of just
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acting not on a hallmark of aging but rather on one very specific element which is lipoproteins and
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those of course do factor very heavily into ascvd and to a lesser extent dementia but contrast that
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with say rapamycin or sgl t2 inhibitors or potentially metformin where they're probably doing a lot of things
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that overall improve lifespan and health span beyond just whack-a-moaling one disease at a time
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and you mentioned it and i'll just give people a podcast number but richard miller that episode was
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number 148 i think it's such a fascinating episode and for people who kind of want to understand
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the science of these drugs what goes into testing them what to think about can't recommend that enough
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richard miller just amazing insights and that podcast was great so anyone who hasn't listened
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to it 148 definitely go back to it i think the next question that we get a lot is you know when
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the ama29 came out with you and bob i think just semaglutide was on the market and being talked about
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but 2022 you know you mentioned it trizepatide came out and also is showing some really good results and i
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think one of the common questions people have is what's the difference between these two drugs and
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kind of how do they compare to be clear there are other versions of this drug other versions of glp1
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agonists that came earlier not going to talk about them right now so the first time this ever popped up
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onto my radar was like 2013 that was a drug that was used for type 2 diabetes and never gained fda
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approval for obesity at least i don't think it ever did but let's start with semaglutide so semaglutide
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is a pure glp1 agonist to be more clear it has a comparable affinity to pure glp1 so one way that
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we do that there's a chemical way that you can look at the concentration of semaglutide and ask the
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question how much of it do you need to replicate the effect of pure glp1 in the case of semaglutide
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it's on the order of half as potent but nevertheless it's a pure glp1 agonist meaning it's replicating
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as opposed to antagonist you sometimes hear that in pharmacology antagonists block the effect
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of hormone so the branded name for semaglutide in the use for type 2 diabetes is called ozempic
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and it comes in three doses i believe 0.5 one and two milligrams these are auto injector pens
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that need to be refrigerated they're very expensive we're going to talk about that later
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so a patient who's historically been getting this for treatment of their type 2 diabetes
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hopefully they're not paying out of pocket for this they're either giving themselves 0.5 or one
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or two milligrams of this drug and they're doing it weekly which by the way speaks to something i
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should have said earlier remember how earlier i said that semaglutide is not quite as potent as the
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actual glp1 as the native glp1 and you might say well why didn't they make it that way and the
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reason is it was designed that way it was designed to have a much longer half-life if you're thinking
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about drug delivery how long the drug stays in circulation is really important so if you could
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make native glp1 but it only stuck around your system for six hours and you had to inject yourself
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four times a day that's a much worse trade-off than say being able to have it slightly less potent
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and just use a greater dose of it but only inject yourself once a week so anyway a little aside there
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so basically ozempic as semaglutide was approved in late 2017 we'll talk a little bit about the data
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for why that was the case i think a higher dose was actually approved just last year now fast forward
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to i think it was june of 21 the study came out i think in april of 21 that looked at semaglutide it
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was actually using ozempic but the indication was in treating obesity without diabetes we talked about
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that at length in the previous ama and we will touch on it briefly today but nevertheless that led to the
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approval of a new drug called wigovi which is of course the exact same drug so semaglutide is ozempic
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is wigovi the difference is basically branding and dosing wigovi is dosed up to 2.4 milligrams per week
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and that was approved as i said probably in the spring of 21 and it was just recently approved for kids
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age 12 and up at the time of this recording last month i hope that kind of makes sense before i go
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on to terzepatide i think it does and it's kind of good to just hear i think anyone who watches tv will
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have seen commercials and you see wigovi ozempic you see stories about semaglutide so i think it's a good
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overview of just different terms similar things so now we will switch and talk about a newer drug
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called terzepatide terzepatide terzepatide is not the same as semaglutide and it is in fact a drug that
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is known as a co-agonist so it is both gip and glp1 and you'll recall i said that semaglutide is you
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know directionally speaking about half as potent as native glp1 well terzepatide is even less than that
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terzepatide when you use the same sort of chemical assay called a ki or an affinity metric it's a
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quarter as potent as native glp1 however when you compare the gip activity it's virtually identical
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to native gip so you think of semaglutide as a slightly weaker version of glp1 you would think
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of terzepatide is a much weaker version of glp1 but a very potent gip it's basically equivalent
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biologically to gip so this is branded as a drug called manjaro is it worth pointing out
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our text thread on this topic it's really funny you brought that up because one of the things i was
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going to say is rumor is that your alias is johnny manjaro because of your affinity for this drug can
00:21:12.680
you confirm nor deny that i will absolutely deny it i do have an alias and it is not johnny manjaro
00:21:19.100
even though there are people within our organization that are trying to make that happen but no it is
00:21:24.420
not i have a much cooler alias than johnny manjaro although i will admit that's a pretty cool alias
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it's got a good ring to it it kind of rolls off the top it's like a man of mystery johnny manjaro
00:21:33.380
you don't know what he does no no it's insane i mean i hope that somebody listening to this
00:21:37.400
adopts that moniker and is forever more johnny manjaro okay so manjaro which is just a branded
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name for terzepatide comes in same thing it's a pre-loaded pen that you inject so you don't have
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to draw it up or anything like that it comes in increments i believe it's 2.5 5 7.5 10 12.5
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all the way up to 15 milligrams it was approved relatively recently for type 2 diabetes so that
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approval took place like a year ago relatively new drug it has not yet gained fda approval for
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obesity however the new england journal of medicine did publish a study in the fall which is where a lot
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of the hoopla came from that demonstrated that this is even a better drug than semaglutide for
00:22:26.340
weight loss and presumably they're in the process of now gaining approval for obesity use of course
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because a drug is approved by the fda you can basically use it for anything you want it's just
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considered off label and it would never be approved by insurance companies but for people who are willing
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to pay out of pocket there are lots of people who are both being prescribed and using terzepatide or
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monjaro for the purposes of obesity and of course just to be clear whatever approval comes for
00:22:54.900
obesity it's going to have a new name so just as you have wagovi for obesity and ozempic for type 2
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diabetes you have monjaro for type 2 diabetes and you're going to have some equally bizarre name
00:23:05.680
for obesity this may be a naive question just i don't know the science as well will either of these
00:23:12.260
drugs ever be non-injectable like will there ever be a day in which you can take a pill or because of
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what they do in the body do we think they'll always have to be injectable oh not a naive question in
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fact there is an oral semaglutide as well i'm blinking on the brand name it begins with an r it's
00:23:30.740
like ry something it is used somewhat for type 2 diabetes that's its indication and approval
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it's also very expensive and i'm not exactly sure of what the differences are and why one would prefer
00:23:45.180
it over the injectable the only thing i can think of is if a person doesn't want to inject doesn't
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want to use a needle and or refrigeration is a problem because obviously these things need to be
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refrigerated so that might be kind of an issue there that's what i was kind of figuring i assumed
00:24:01.020
someone was trying to figure it out just for those people with a fear of needles is injecting yourself
00:24:06.420
as often as you would have to would be a little tough now that we got the overview the next question
00:24:12.760
we always get is how do those two drugs semaglutide trisepatide compare in their effectiveness so
00:24:20.860
in looking at weight loss hba1c those other things that they're measuring do we see a difference in
00:24:28.080
the results and kind of what do we know about that thank you for listening to today's sneak peek ama
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is formed the use of this information and the materials linked to this podcast is at the user's
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own risk the content on this podcast is not intended to be a substitute for professional medical advice
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diagnosis or treatment users should not disregard or delay in obtaining medical advice from any medical
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condition they have and they should seek the assistance of their health care professionals
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for any such conditions finally i take conflicts of interest very seriously for all of my disclosures
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and the companies i invest in or advise please visit peter atia md.com forward slash about where i keep an