The Peter Attia Drive - #184 - AMA #29： GLP-1 Agonists—The Future of Treating Obesity？

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

00:00:16.500 I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can

00:00:20.460 access the AMA episodes in full, along with a ton of other membership benefits we've created,

00:00:25.440 or you can learn more now by going to peteratiyahmd.com forward slash subscribe.

00:00:31.140 So without further delay, here's today's sneak peek of the ask me anything episode.

00:00:39.160 Welcome to ask me anything episode number 29. I'm joined once again by Bob Kaplan. In today's

00:00:46.280 episode, we discuss all things related to GLP one agonists. And before you say, why the hell would

00:00:53.780 you dedicate an entire episode to an acronym I've never heard of? I would say fair question,

00:00:59.540 but GLP one agonists are the class of drugs that are all the rage right now when it comes to

00:01:07.700 understanding treatments for obesity. So you may not have heard the term GLP one, but there's at

00:01:12.700 least a decent chance you've heard of Ozempic or semaglutide. And even if you haven't heard of those,

00:01:18.800 I suspect you'll find this episode very interesting. Earlier this year, a study was published in the New

00:01:23.400 England Journal of Medicine that looked at the treatment of patients with overweight or obesity

00:01:30.500 who were non-diabetic using a once weekly injection of a drug called semaglutide, also known as Ozempic.

00:01:36.740 And the results were quite frankly, out of this world. So we're going to go through that paper,

00:01:42.160 but of course, to get through that paper, you need to understand the physiology and the history of

00:01:47.040 how these peptides were discovered and what it is they do in their natural state. So this episode's a

00:01:53.080 little bit technical. I'm going to apologize for that in advance. I think as is the case with the

00:01:57.880 majority of our AMAs, this one is going to be easier to follow if you're able to watch it on

00:02:02.500 video because we do share a number of slides and figures, which I think makes it a little easier

00:02:08.360 to understand this subject matter. If you can only listen to it, I think you'll still get the gist of

00:02:12.860 it, but nevertheless, it is a bit technical. And I think that's just the price one has to pay to

00:02:18.760 truly understand why this drug works. And ultimately, if this drug is for you. So if you're

00:02:24.260 not a subscriber, of course, you can catch a sneak peek of this video on YouTube. So without further

00:02:29.440 delay, I hope you enjoy AMA number 29. Hello, Peter. Hey, Baha. How's it going? Good. What do we got

00:02:42.980 going on today? We got a lot of questions around one particular topic, actually one paper. And the

00:02:50.920 title of that paper is Once Weekly Semaglutide in Adults with Overweight or Obesity. And I don't

00:02:57.120 think that a lot of people would be talking about this or asking this if the results of the paper

00:03:01.720 weren't so freaking remarkable as far as the weight reduction with that study. So a lot of questions were

00:03:09.440 around the study. Can you go over the findings of the study? What are the implications? Do we need

00:03:13.620 a drug for obesity? What the heck is semaglutide? How does it compare to other drugs and diets,

00:03:21.020 et cetera, et cetera? I think people want to get more clarity around this study.

00:03:25.200 Yeah. This study, did it come out earlier this year? Was this early 21?

00:03:30.100 Yes.

00:03:30.820 Yeah. Obviously, this is a study that those of us who spend time in this space knew a lot about

00:03:36.160 and we're kind of anticipating the results of this for a while. There are other drugs in this

00:03:41.180 class, liraglutide, that about six years ago showed also very promising results. And basically,

00:03:49.520 once this study came out, I would say many of our patients were asking about it. And we actually did

00:03:58.540 a journal club on this particular paper, the New England Journal of Medicine paper, I think back in

00:04:02.420 the spring. So it's great to see that a lot of people are basically kind of wanting to go deep

00:04:07.520 on this. And I think as we'll get into today, you can't really go deep on this paper without doing

00:04:12.320 a little bit of background on what GLP-1 is, because of course, this drug is effectively just

00:04:18.440 an analog of GLP-1. So yeah, I think we're about to go pretty deep on this topic. So let's start with

00:04:26.620 GLP-1s, huh? Yeah, let's do it. I guess the easiest way to start this discussion is to really 1.00

00:04:33.800 do it through the lens of what is an incretin or what is the incretin effect. I've read that people

00:04:42.320 have been aware of this phenomenon or something like it since the 1800s. I still don't understand

00:04:47.660 how that's the case, because without being able to measure an insulin response, I'm not sure how

00:04:53.760 people would have suspected this, because it's at least to my perhaps naive view, only when you can

00:05:00.840 measure insulin can you understand what the incretin effect is. But it effectively comes down to

00:05:09.720 a bit of a mismatch between how oral and intravenous glucose are processed. But let's take a step back from

00:05:18.340 all of that and just make sure everybody's up to speed on insulin and glucagon, because these are two

00:05:22.980 hormones that you have to really understand to get what incretins are, and then by extension to

00:05:29.160 appreciate what semaglutide is doing. And again, all of this is sort of prologue to make sure that we

00:05:34.500 understand how semaglutide works. So let's start with the basics. Again, I know many of you realize

00:05:39.380 this, but it's always worth reiterating. So insulin is secreted by beta cells in the pancreas. So the

00:05:44.740 pancreas has two broad functions. It has an endocrine function and an exocrine function. 0.60

00:05:51.440 So the exocrine function is kind of the local digestive function. And the endocrine function

00:05:59.200 is the more systemic function. So the release of insulin and glucagon from beta and alpha cells

00:06:06.420 respectively fit into the endocrine portion of this. And I think I could be wrong on this. My

00:06:13.420 recollection is that by mass, only 5% of the pancreas is really endocrine function, is alpha

00:06:22.400 and beta cells, that the majority of the pancreatic mass is for the exocrine, the local digestive

00:06:28.120 function. Anyway, so these beta cells, they secrete insulin. And insulin really has pretty significant

00:06:35.200 effects on obviously muscle cells, fat cells, and liver cells. And it signals all of these tissues to

00:06:42.020 take up glucose. It also tells the liver to stop making glucose. So again, what's the purpose of

00:06:48.780 this? It's insulin is a signal of the fed state. And it's particularly sensitive, of course, to

00:06:54.400 carbohydrates. So it's saying when carbohydrates are abundant, we need to take glucose up into cells,

00:07:00.820 and we need to stop making more glucose. Because remember, the liver has many functions, but one of

00:07:06.000 the most important functions of the liver, in fact, you could argue the function with which we would die

00:07:10.460 the quickest, is its ability to make glucose and put it into circulation. And this is a very important

00:07:16.400 thing that insulin regulates. It also regulates the output of glucagon. So what is glucagon? So glucagon

00:07:23.080 is produced by alpha cells of the pancreas, and it increases blood glucose via hepatic glucose

00:07:29.120 production by stimulating glycogenolysis, so breaking glycogen into glucose and gluconeogenesis. And it also

00:07:35.140 increases lipolysis and ketone production. So you can see how there's a bit of an antagonistic

00:07:42.280 relationship between these hormones, and therefore, when one goes up, it would regulate the other.

00:07:48.180 So how does all this fit into the incretin effect? Well, I think a figure says a thousand words here. So

00:07:55.520 Bob, let's take a look at figure one, and we'll kind of walk people through this, because it is

00:08:00.200 pretty interesting. And I think if you haven't seen this before, it's a bit of a head-scratcher.

00:08:06.100 Absolutely. Okay. I pulled it up. What you're looking at here are three graphs. Let's talk

00:08:12.340 through each of them. So the upper one shows on the x-axis, as they all do, time. So time in minutes.

00:08:19.020 And here on the y-axis, you're seeing plasma glucose. So this is in response to both an oral

00:08:29.260 glucose level and intravenous glucose load. So that means in the solid gray circles is the

00:08:38.840 measured plasma glucose level following a glucose load. So these are done in picomole per liter,

00:08:45.900 but this translates very well to, I think picomole per liter actually is equivalent to milligrams per

00:08:50.640 deciliter. So you're looking at normal glucose, say in the nineties, following the ingestion of oral

00:08:57.660 glucose, you see it goes up, but it peaks at about 60 minutes and then kind of returns such that by

00:09:04.100 three hours, it's effectively back to baseline. And the intravenous glucose dose is delivered in

00:09:12.580 what's called an isoglycemic manner, meaning the IV of glucose is titrated to match the glycemic response.

00:09:21.420 So the first figure, which is the green figure shows what happens to insulin under these two

00:09:29.980 conditions. So now again, we're sampling peripheral insulin. And in the first example, you see insulin

00:09:38.480 goes up and this would be sort of what you would expect from an oral glucose tolerance test. So insulin

00:09:44.960 peaks at about 90 minutes, returns to baseline in about three to four hours. But what's really

00:09:52.540 interesting here is when you look at the insulin response under the intravenous glucose administration,

00:09:58.940 you see it's a fraction of what is delivered or appreciated in the oral glucose administration.

00:10:06.680 In fact, it almost looks like a flat line. So what explains that difference? Well, that difference,

00:10:12.280 which is basically the shaded green area is referred to as the incretin effect, which we'll talk about in

00:10:17.580 a moment. For the sake of completeness, if you look at the red graph at the bottom, you're going to

00:10:22.020 appreciate the same difference with respect to glucagon. So in the case of the oral glucose

00:10:29.240 administration, you're seeing the solid dots. So you're seeing glucagon levels go down, right? Because

00:10:36.660 as glucose becomes more available in the periphery, the pancreas will make less glucagon for the 0.91

00:10:42.100 liver to respond to make less glucose. So looking at the bottom graph now, you see the same effect,

00:10:48.660 but for glucagon. So remember, glucagon is secreted by the pancreas as well, and it acts primarily on

00:10:55.260 the liver to regulate glucose output, glycogen breakdown, and glucose production. And you can see

00:11:01.700 with the oral glucose administration, the attenuation of glucagon is less than with the intravenous

00:11:09.920 administration. So again, that delta is referred to here as the incretin effect. So why does this

00:11:17.480 happen? I guess is the question, Bob.

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The Peter Attia Drive - November 15, 2021

#184 - AMA #29： GLP-1 Agonists—The Future of Treating Obesity？

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