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

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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 episode number 29. I'm joined once again by Bob Kaplan. In today's episode we discuss all things related to GLP1 agonists. And before you say why the hell would you dedicate an entire episode to an acronym I've never heard of, I would say fair question. But GLP1 agonists are the class of drugs that are all the rage right now when it comes to understanding treatments for obesity. So you may not have heard the term GLP1, but there's at least a decent chance you've heard of Ozempic or Semaglutide. Even if you haven't heard of those, I suspect you'll find this episode very interesting. Earlier this year a study was published in the New England Journal of Medicine that looked at the treatment of patients with overweight or obesity who were non diabetic using a once weekly injection of a drug called Semaglutide, also known as Ozempic, and the results were, quite frankly, out of this world. We're going to go through that paper, but of course to get through that paper you need to understand the physiology and the history of how these peptides were discovered and what it is they do in their natural state. So this episode's a little bit technical. I'm going to apologize for that in advance. I think as is the case with the majority of our AMAs, this one is going to be easier to follow if you're able to watch it on video because we do share a number of slides and figures which I think makes it a little easier to understand this subject matter. If you can only listen to it. I think you'll still get the gist of it, but nevertheless it is a bit technical and I think that's just the price one has to pay to truly understand why this drug works and ultimately if this drug is for you. So if you're not a subscriber, of course you can catch a sneak peek of this video on YouTube. So without further delay, I hope you enjoy AMA number 29.

Hello Peter. Hey Mahab how's it going?

Good. What do we got going on today?

We got a lot of questions around one particular topic, actually one paper, and the title of that paper is Once Weekly Semaglutide in Adults with Overweight or Obesity. And I don't think that a lot of people would be talking about this or asking this if the results of the paper weren't so freaking remarkable as far as the weight reduction with that study. So a lot of questions were around this study. Can you go over the findings in the study? What are the implications? Do we need a drug for obesity? What the heck is semaglutide? How does it compare to other drugs and diets, et cetera, et cetera? I think people want to get more clarity around this study.

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

Yes.

Yeah. Obviously, this is a study that those of us who spend time in this space knew a lot about and were kind of anticipating the results of this for a while. There are other drugs in this class, liraglutide, that about six years ago showed also very promising results. And basically, once this study came out, I would say many of our patients were asking about it. And we actually did a journal club on this for particular paper, the New England Journal of Medicine paper, I think, back in the spring. So it's great to see that a lot of people are basically kind of wanting to go deep on this. And I think as we'll get into today, you can't really go deep on this paper without doing a little bit of background on what GLP1 is, because, of course, this drug is effectively just an analog of GLP1. So, yeah, I think we're about to go pretty deep on this topic. So let's start with GLP1s, huh?

Yeah, let's do it.

I guess the easiest way to start this discussion is to really do it through the lens of what is an incretin or what is the incretin effect? I've read that people have been aware of this phenomenon or something like it, since the 1800s. I still don't understand how that's the case, because without being able to measure an insulin response, I'm not sure how people would have suspected this, because it's at least to my perhaps naive view, only when you can measure insulin can you understand what the incretin effect is. But it effectively comes down to a bit of a mismatch between how oral and intravenous glucose are processed. But let's take a step back from all that and just make sure everybody's up to speed on insulin and glucagon, because these are two hormones that you have to really understand to get what incretins are and then by extension, to appreciate what semaglutide is doing. And again, all of this is sort of prologue to make sure that we understand how semaglutide works. So let's start with the basics. Again, I know many of you realize this, but it's always worth reiterating. So insulin is secreted by beta cells in the pancreas. So the pancreas has two broad functions. It has an endocrine function and an exocrine function function. So the exocrine function is kind of the local digestive function, and the endocrine function is the more systemic function. So the release of insulin and glucagon from beta and alpha cells, respectively, fit into the endocrine portion of this. And I think I could be wrong on this. My recollection is that by mass, only 5% of the pancreas is really endocrine function is alpha and beta cells. That the majority of the pancreatic mass is for the exocrine, the local digestive function anyway. So these beta cells, they secrete insulin. And insulin really has pretty significant effects on, obviously, muscle cells, fat cells, and liver cells. And it signals all of these tissues to take up glucose.

Take up.

It also tells the liver to stop making glucose. So, again, what's the purpose of this? Insulin is a signal of the fed state, and it's particularly sensitive, of course, to carbohydrates. So it's saying when carbohydrates are abundant, we need to take glucose up into cells and we need to stop making more glucose. Because, remember, the liver has many functions, but one of the most important functions of the liver, in fact, you could argue the function with which we would die the quickest is its ability to make glucose and put it into circulation. And this is a very important thing that insulin regulates. It also regulates the output of glucagon. So what is glucagon? So, glucagon is produced by alpha cells of the pancreas, and it increases blood glucose via hepatic glucose production by stimulating glycogenolysis, so breaking glycogen into glucose and gluconeogenesis. And it also increases lipolysis and ketone production. So you can see how there's a bit of an antagonistic relationship between these hormones, and therefore, when one goes up, it would regulate the other. So how does all this fit into the incretin effect. Well, I think a figure says a thousand words here. So, Bob, let's take a look at figure one, and we'll kind of walk people through this because it is pretty interesting. And I think if you haven't seen this before, it's a bit of a head scratcher.

Absolutely. Okay, I pulled it up.

What you're looking at here are three graphs, and let's talk through each of them. So the upper one shows on the x axis as they all do time, so time in minutes. And here on the Y axis, you're seeing plasma glucose. So this is in response to both an oral and intravenous glucose glucose load. So that means in the solid gray circles is the measured plasma glucose level following a glucose load. So these are done in picomol per liter, but this translates very well to, I think picomol per liter actually is equivalent to milligrams per deciliter. So you're looking at normal glucose, say in the 90s, following the ingestion of oral glucose. You see, it goes up, it peaks at about 60 minutes and then kind of returns such that by three hours, it's effectively back to baseline. And the intravenous glucose dose is delivered in what's called an isoglycemic manner, meaning the IV of glucose is titrated to match the glycemic response. So the first figure, which is the green figure, shows what happens to insulin under these two conditions. So now again, we're sampling peripheral insulin. And in the first example, you see insulin goes up. And this would be sort of what you would expect from an oral glucose tolerance test. So insulin peaks at about 90 minutes, returns to baseline in about three to four hours. But what's really interesting here is when you look at the insulin response under the intravenous glucose administration, you see it's a fraction of what is delivered or appreciated in the oral glucose administration. In fact, it almost looks like a flat line. So what explains that difference? Well, that difference, which is basically the shaded green area, is referred to as the incretin effect, which we'll talk about in a moment for the sake of completeness. If you look at the red graph at the bottom, you're going to appreciate the same difference with respect to glucagon. So in the case of the oral glucose administration, you're seeing the solid dots. So you're seeing glucagon levels go down. Right, because as glucose becomes more available in the periphery, the pancreas will make less glucagon for the liver to respond to make less glucose. So looking at the bottom graph now you see the same effect but for glucagon. So remember, glucagon is secreted by the pancreas as well, and it acts primarily on the liver to regulate glucose output, glycogen breakdown and glucose production. And you can see with the oral glucose administration, the attenuation of glucagon is less than with the intravenous administration. So again, that delta is referred to here as the incretin effect. So why does this happen, I guess is the question.

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