#184 - AMA #29： GLP-1 Agonists—The Future of Treating Obesity？
Episode Stats
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Summary
In this episode, Dr. Bob Kaplan and I discuss all things related to GLP-1 agonists and their use in obesity treatment. We cover the history of how these peptides were discovered, the mechanism of action, and the benefits and drawbacks of GLP 1 agonists.
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 Atiyah. At the end of this short episode, I'll explain how you can
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access 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 peteratiyahmd.com forward slash subscribe.
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So without further delay, here's today's sneak peek of the ask me anything episode.
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Welcome to ask me anything episode number 29. I'm joined once again by Bob Kaplan. In today's
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episode, we discuss all things related to GLP one agonists. And before you say, why the hell would
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you dedicate an entire episode to an acronym I've never heard of? I would say fair question,
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but GLP one agonists are the class of drugs that are all the rage right now when it comes to
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understanding treatments for obesity. So you may not have heard the term GLP one, but there's at
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least a decent chance you've heard of Ozempic or semaglutide. And even if you haven't heard of those,
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I suspect you'll find this episode very interesting. Earlier this year, a study was published in the New
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England Journal of Medicine that looked at the treatment of patients with overweight or obesity
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who were non-diabetic using a once weekly injection of a drug called semaglutide, also known as Ozempic.
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And the results were quite frankly, out of this world. So we're going to go through that paper,
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but of course, to get through that paper, you need to understand the physiology and the history of
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how these peptides were discovered and what it is they do in their natural state. So this episode's a
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little bit technical. I'm going to apologize for that in advance. I think as is the case with the
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majority of our AMAs, this one is going to be easier to follow if you're able to watch it on
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video because we do share a number of slides and figures, which I think makes it a little easier
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to understand this subject matter. If you can only listen to it, I think you'll still get the gist of
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it, but nevertheless, it is a bit technical. And I think that's just the price one has to pay to
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truly understand why this drug works. And ultimately, if this drug is for you. So if you're
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not a subscriber, of course, you can catch a sneak peek of this video on YouTube. So without further
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delay, I hope you enjoy AMA number 29. Hello, Peter. Hey, Baha. How's it going? Good. What do we got
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going on today? We got a lot of questions around one particular topic, actually one paper. And the
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title of that paper is Once Weekly Semaglutide in Adults with Overweight or Obesity. And I don't
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think that a lot of people would be talking about this or asking this if the results of the paper
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weren't so freaking remarkable as far as the weight reduction with that study. So a lot of questions were
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around the study. Can you go over the findings of the study? What are the implications? Do we need
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a drug for obesity? What the heck is semaglutide? How does it compare to other drugs and diets,
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et cetera, et cetera? I think people want to get more clarity around this study.
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Yeah. This study, did it come out earlier this year? Was this early 21?
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Yeah. Obviously, this is a study that those of us who spend time in this space knew a lot about
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and we're kind of anticipating the results of this for a while. There are other drugs in this
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class, liraglutide, that about six years ago showed also very promising results. And basically,
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once this study came out, I would say many of our patients were asking about it. And we actually did
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a journal club on this particular paper, the New England Journal of Medicine paper, I think back in
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the spring. So it's great to see that a lot of people are basically kind of wanting to go deep
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on this. And I think as we'll get into today, you can't really go deep on this paper without doing
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a little bit of background on what GLP-1 is, because of course, this drug is effectively just
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an analog of GLP-1. So yeah, I think we're about to go pretty deep on this topic. So let's start with
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GLP-1s, huh? Yeah, let's do it. I guess the easiest way to start this discussion is to really
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do it through the lens of what is an incretin or what is the incretin effect. I've read that people
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have been aware of this phenomenon or something like it since the 1800s. I still don't understand
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how that's the case, because without being able to measure an insulin response, I'm not sure how
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people would have suspected this, because it's at least to my perhaps naive view, only when you can
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measure insulin can you understand what the incretin effect is. But it effectively comes down to
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a bit of a mismatch between how oral and intravenous glucose are processed. But let's take a step back from
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all of that and just make sure everybody's up to speed on insulin and glucagon, because these are two
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hormones that you have to really understand to get what incretins are, and then by extension to
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appreciate what semaglutide is doing. And again, all of this is sort of prologue to make sure that we
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understand how semaglutide works. So let's start with the basics. Again, I know many of you realize
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this, but it's always worth reiterating. So insulin is secreted by beta cells in the pancreas. So the
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pancreas has two broad functions. It has an endocrine function and an exocrine function.
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So the exocrine function is kind of the local digestive function. And the endocrine function
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is the more systemic function. So the release of insulin and glucagon from beta and alpha cells
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respectively fit into the endocrine portion of this. And I think I could be wrong on this. My
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recollection is that by mass, only 5% of the pancreas is really endocrine function, is alpha
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and beta cells, that the majority of the pancreatic mass is for the exocrine, the local digestive
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function. Anyway, so these beta cells, they secrete insulin. And insulin really has pretty significant
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effects on obviously muscle cells, fat cells, and liver cells. And it signals all of these tissues to
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take up glucose. It also tells the liver to stop making glucose. So again, what's the purpose of
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this? It's insulin is a signal of the fed state. And it's particularly sensitive, of course, to
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carbohydrates. So it's saying when carbohydrates are abundant, we need to take glucose up into cells,
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and we need to stop making more glucose. Because remember, the liver has many functions, but one of
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the most important functions of the liver, in fact, you could argue the function with which we would die
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the quickest, is its ability to make glucose and put it into circulation. And this is a very important
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thing that insulin regulates. It also regulates the output of glucagon. So what is glucagon? So glucagon
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is produced by alpha cells of the pancreas, and it increases blood glucose via hepatic glucose
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production by stimulating glycogenolysis, so breaking glycogen into glucose and gluconeogenesis. And it also
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increases lipolysis and ketone production. So you can see how there's a bit of an antagonistic
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relationship between these hormones, and therefore, when one goes up, it would regulate the other.
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So how does all this fit into the incretin effect? Well, I think a figure says a thousand words here. So
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Bob, let's take a look at figure one, and we'll kind of walk people through this, because it is
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pretty interesting. And I think if you haven't seen this before, it's a bit of a head-scratcher.
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Absolutely. Okay. I pulled it up. What you're looking at here are three graphs. Let's talk
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through each of them. So the upper one shows on the x-axis, as they all do, time. So time in minutes.
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And here on the y-axis, you're seeing plasma glucose. So this is in response to both an oral
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glucose level and intravenous glucose load. So that means in the solid gray circles is the
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measured plasma glucose level following a glucose load. So these are done in picomole per liter,
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but this translates very well to, I think picomole per liter actually is equivalent to milligrams per
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deciliter. So you're looking at normal glucose, say in the nineties, following the ingestion of oral
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glucose, you see it goes up, but it peaks at about 60 minutes and then kind of returns such that by
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three hours, it's effectively back to baseline. And the intravenous glucose dose is delivered in
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what's called an isoglycemic manner, meaning the IV of glucose is titrated to match the glycemic response.
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So the first figure, which is the green figure shows what happens to insulin under these two
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conditions. So now again, we're sampling peripheral insulin. And in the first example, you see insulin
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goes up and this would be sort of what you would expect from an oral glucose tolerance test. So insulin
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peaks at about 90 minutes, returns to baseline in about three to four hours. But what's really
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interesting here is when you look at the insulin response under the intravenous glucose administration,
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you see it's a fraction of what is delivered or appreciated in the oral glucose administration.
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In fact, it almost looks like a flat line. So what explains that difference? Well, that difference,
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which is basically the shaded green area is referred to as the incretin effect, which we'll talk about in
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a moment. For the sake of completeness, if you look at the red graph at the bottom, you're going to
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appreciate the same difference with respect to glucagon. So in the case of the oral glucose
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administration, you're seeing the solid dots. So you're seeing glucagon levels go down, right? Because
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as glucose becomes more available in the periphery, the pancreas will make less glucagon for the
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liver to respond to make less glucose. So looking at the bottom graph now, you see the same effect,
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but for glucagon. So remember, glucagon is secreted by the pancreas as well, and it acts primarily on
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the liver to regulate glucose output, glycogen breakdown, and glucose production. And you can see
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with the oral glucose administration, the attenuation of glucagon is less than with the intravenous
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administration. So again, that delta is referred to here as the incretin effect. So why does this
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