[0:00] Welcome, my name is Dr. Warrick Bishop. I'm a cardiologist, an author and a keynote speaker. I'm CEO of the Healthy Heart Network. I'm all about trying to help people [0:12] Live as well as possible, for as long as possible. [0:15] heart disease is huge in Australia. [0:18] Every 20 minutes someone suffers a heart attack. Most of these could probably have been avoided if only we knew what to do. This podcast is all about helping you understand blood pressure, weight, cholesterol and weight. [0:32] for better health. [0:33] If you enjoy this podcast, I would be honored for a five-star review. [0:37] you can share it with your family and friends. It may well save [0:41] someone you love. [0:42] Hi, it's Dr. Warrick here and thank you so much for joining me on my podcast and videocast station. As always, I really appreciate if you've chosen to spend your valuable time listening to some of the resources I've created. Today, I've actually got a special guest. For those who have listened with any regularity, you'll realize I had my first podcast. [1:05] father and son interview uh literally a couple of weeks ago with the chiropractors cream from hobart uh steven and sam and that was an absolute pleasure but today is a different father and son routine i have my son max bishop joining me hi max hey [1:26] I don't. [1:27] And you might be wondering why Max is joining me. He's not a doctor. He's certainly interested in science. He has nearly completed... [1:37] a biomedical science degree at Melbourne Uni and we [1:45] when we recently spent some time together, got to talk about some aspects of medicine, which Max knows a fair bit about, and that's the GLP-1 agonists. And those GLP-1 agonists are... [2:02] the drugs that have really exploded into our modern world the uh zampic and mojano type agents which are helping with weight loss treatment of diabetes management of heart related conditions and a whole range of things but what I wanted to do is really get some of the science behind these agents and [2:26] Well, as I spoke with Max, I could think of no one better place to share. So, Max, thanks so much for joining us. I'm really looking forward to having a chat with you about these agents. [2:35] Thanks for having me. [2:37] Look, um... [2:39] Many of the people listening to this will have heard of... [2:43] Wagovi, Zampik, maybe Tezapatide, Bojano, these agents that are being used now for weight loss, and they've really exploded, as you're probably aware. But where did these drugs originate from? Where did we first... [3:01] Well, when did science first discover them? [3:05] Um, [3:06] The drugs came a little bit later after the discovery of the endogenous signaling system, the system that exists within us already called the incretins, which were they started. [3:25] The term was coined in the 30s, in the 1930s, and then in the 70s and 80s, they were named after being isolated. The two incretions are GIP and GLP-1, which is probably what we're going to talk most about because most of these drugs have been developed based on GLP-1, which is a human... [3:48] hormone. It's a peptide hormone. [3:53] And the name incretin comes from [3:55] intestine and to excrete. So they're hormones that are made in the small intestine predominantly by [4:01] these things called L cells. [4:05] So just for those listening and for me as well, if... [4:10] I'd never heard of the term in Cretan before. [4:15] What would you say an incretin does? Is it something that increases... [4:21] the function of a particular organ system or cells? How does an incretin work? And although I say I haven't heard of an incretin before, I'm pretty sure I've heard of incretins in the same sentence or same paragraph as ghrelins. Can you relate those two for me and just... [4:42] Tell me, what are they actually doing physiologically for us? [4:47] Form the foundation of where GLP-1As fit in, I guess. Yeah, of course. We can start with ghrelin. That's reasonably simple. Ghrelin is probably... [4:56] or arguably one of the most important [4:59] um hunger signaling um hormones that we have it's produced predominantly in our stomachs as a response to them being empty and it makes us feel hungry um [5:12] The incretins endogenously, in our bodies, under natural physiology, they have the opposite effect. [5:20] They have a role in insulin regulation. So they increase the sensitivity of the pancreas, those beta cells, to blood glucose and release insulin in response to that. They don't directly make the beta cells release insulin. They just make them more sensitive to blood glucose changes as they normally do. Yeah. [5:41] Um... [5:43] But they have a host of other actions, the things that have... [5:47] but the action they have that's made them sort of [5:51] spring into this internet sensation and this thing that everyone's talking about when it comes to glp ones and the zempic etc is um they cross the blood-brain barrier into the arcuate nucleus of the hypothalamus which is the sort of center for control of of hunger and satiety in the brain and they they really suppress the feeling of hunger and promote satiety and we get on to side effects later but they they also [6:16] are responsible in part. Um, they play a really key role in that feeling of fullness, even over fullness and nausea that can come with that. That feeling like you've eaten too much is, um, is quite, quite, um, uh, [6:33] quite directly a result of the release of Incretans, especially GLP-1. [6:39] Well, we certainly see when we commence people on these agents, one of the most significant side effects is nausea. [6:47] Yeah. And, um, [6:49] So my practice, and this for anyone who's listening who may have started on these agents or is even thinking about starting on these agents, my own practice these days is to start people at a half of a beginning dose for a week or two and make sure they tolerate it. [7:04] So, [7:05] So these agents obviously alter the way the metabolism works, alter insulin sensitivity, but probably most powerfully reduce appetite. [7:16] and that would be the main way that they would affect weight in an individual. [7:21] Yeah, absolutely. Although, interestingly, that wasn't [7:25] why they were first created or what they were first approved for by, by FDA and other therapeutic, um, administrations around the world. Um, they were first targeted for type two diabetes because of that insulin regulation, um, that increasing insulin sensitivity in the pancreas. [7:43] Now, I'm [7:45] We don't, these drugs aren't GLP one. They're not that human compound because it's not stable enough. [7:53] to be useful therapeutically. It has a half-life of about two minutes. [7:58] which is vanishingly short in the plasma. [8:03] you could get hold of these drugs of this of this hormone sorry uh and and and put it into your body um and it would do what it's supposed to do but it would only stick around for for a few minutes so you're saying that the actual [8:17] peptide or the actual hormone it produces, has a very short half-life. So these agents that we are used to and we've heard about being injected and which we... [8:28] We now take once a week. These are obviously manufactured or a synthetic type of peptide. [8:35] Yeah. That lasts longer, yeah? [8:38] Yeah, so that GLP one, I think it's a 31 or 32 amino acid long [8:42] peptide, signaling peptide, and there's an enzyme that cleaves it. [8:47] with with great um speed and that's why it gets broken down so quickly um but there was research being done into you know how we could modify it or find a way to make it hang around longer because we sort of knew what the effects of it were um and the the first answer to that actually came um from something called a healer monster which is a venomous lizard reasonably large one i think they're sort of on the scale of a couple of feet long i think they're native to america [9:17] And they don't eat very often. [9:19] as many reptiles do. And the heeled monster actually, I believe, completely sheds its digestive tract and relines it between meals. And it could be on the scale of months. So not only do they need satiety control, control of their hunger over a much greater time span, they also need control over that insulin over a much greater time span. [9:39] um and healer monsters have an analog to glp1 a very similar compound that's similar in its function and role and structure but slightly different and those small molecular differences um i mean it has a far greater half-life um you know on the scale of days in the human body um it's called extended four and that was the [10:02] yeah, the first sort of breakthrough, I suppose, into getting these drugs developed for type 2 diabetes, which happened sort of, [10:11] in the 90s. [10:14] with [10:16] Yeah, the development of liraglutide, liraglutide. [10:20] So these agents are actually derived from... [10:24] from a biological source, a natural source, which was in fact a big lizard from Central America, North America, somewhere. Yeah, it's amazing. A venomous one too, which is cool because there's not many venomous lizards in the world actually. [10:42] might be one of the very few actually. But that, [10:46] The discovery of this and the realization that I had a longer half-life was what allowed... [10:52] lab scientists that I think was an over Nordisk first to create a synthetic compound. [11:00] more similar to that than the human GLP one. [11:04] And... [11:05] was able to get something that could be injected. I think originally it was twice daily, then there was a once daily and then there was a once weekly as they sort of made small adjustments to those amino acids to prevent breakdown without sacrificing their activity at receptors. [11:23] Well, they've certainly changed the landscape of what we've done when it comes to... [11:29] weight control. It's fascinating to think that we're actually using [11:35] a signaling system or a peptide that already exists in our own bodies and we've actually [11:42] stolen that signaling system from a lizard [11:46] to improve our own signalling system or take advantage of exactly the same markers. [11:55] The really interesting thing for me, which I'd be interested in your comments, is as I've seen [12:02] patients on these medications, there's no question that the [12:07] There's significant suppression of appetite and obviously improved insulin sensitivity. [12:13] But the reduction in the quantity of food that [12:17] individuals eat in relation to the amount of weight they lose [12:22] Seems that they almost lose more weight than you'd expect for the reduction in weight. [12:28] Am I misreading that, or is there a mechanism that would tie in with that? [12:36] Thank you. [12:37] Oh. [12:38] There is a mechanism that would explain that observation. I think that... [12:43] that observation [12:45] I think that the mechanism, the physiological mechanism of that, which is that normally when you go into caloric deficit, your body shuts down your metabolic rate a fair bit and sort of does everything it can to conserve energy. But these are compounds or signaling molecules that are released when you have been well-fed. [13:02] So when you take them, your body doesn't try and store energy. It's, it's trying to utilize it. It promotes it. It's, it's, [13:10] telling these molecules are telling your body you've just had a big meal [13:15] let's use that energy and not feel the need to take in more [13:19] I think that's trivial in terms of it. [13:21] My gut feeling is that the effect of that's probably not that big. The bigger thing is probably that most people, when they diet, they end up eating... [13:32] snacks or high calorie [13:35] binges perhaps uh it might be a bit of an extreme term but that consistency is really hard to get when it comes to dieting without the assistance of drugs especially like this um you might see your patients reporting that they've started a diet without the assistance of this sort of drugs saying i'm only eating this much every day i'm only eating broccoli and one pear and a tin of sardines in spring water um [14:00] But there's... [14:02] There's always other things. People end up eating more calories because they get hungry when they diet most of the time unless they're taking these drugs. [14:09] I think that's probably the bigger effect size in that that you're observing. But it is a significant thing to know that the metabolic depression, if you will, the slowing down of the metabolic rate that comes with being a caloric deficit is somewhat softened by these drugs because their very nature is to... [14:29] Push the body to expend and utilize energy. [14:33] So there is a physiological basis for that. I don't think it's really of a huge effect size, but it's probably not completely negligible either. [14:42] I, um, as you were... [14:44] sharing there, I was thinking that I've also observed that there appears to be some modification or dampening down of addictive behavior. So behaviors like, well, alcohol, for example, or even carbohydrates. And I wonder if that would also feed in, which people would have a lot of difficulty [15:05] offering as clear history because their habits that are already ingrained in their day to day. But I almost get the sense there's a significant impact on... [15:18] Yeah, addictive behavior. Would that tie in with the appetite suppression? [15:23] As far as you know. [15:25] So we eat for two reasons, right? We eat for pleasure and we eat because we're hungry. [15:31] And... [15:32] to become significantly overweight or obese, you... [15:36] A the nade [15:38] and it's rare, a significant sort of genetic predisposition or alteration in your normal brain function to never feel full and to become obese because you're hungry. Our bodies are, they're really designed that we should only be hungry when we need calories. [15:59] The really significant reason that people become overweight and obese is because of the pleasure factor, because our food is so palatable, because we have, you know, mixtures of carbohydrate and fat that in nature are almost impossible to find other than in breast milk. And then you add to that. [16:15] The ability to season it with everything, the ease at which you get it, you know, everything behavior wise as a biological drive is a trade off between how much you have to work to get it and the reward. And those things get mismatched in our society because food's plentiful for most of us for those privileged enough to live where we live. And it tastes great. [16:34] insanely good relative to to what [16:38] the human organisms that sort of evolved these systems were exposed to. [16:44] So that dampening of addiction... [16:48] is very key actually to GLP-1's success. [16:54] They make, like, there's a lot of [16:57] There's a lot of merit to them making you feel fuller, actually, because they make you feel, as we discussed before, potentially quite uncomfortably full, even when eating small quantities. So there's a sort of a negative modulation of behavior there. But there's also... [17:13] Yeah, an easing of... [17:16] the [17:17] the pleasure or the drive to eat sweet things because that is – [17:20] addiction. That's a dopamine-mediated process actually and there is [17:28] There's GLP-1 receptors all across the brain linked into dopamine signals across a whole host of... [17:35] behaviors. [17:38] It's very interesting. [17:43] discussion really that because [17:46] they seem to maybe even have sort of [17:50] potential benefits for things like you said, like alcohol and I believe even drugs and substances of addiction, like, you know, cocaine and other recreational drugs like that. [18:02] Amen. [18:05] Certainly there appears to be an effect [18:09] Far beyond just the gut. [18:12] Far beyond just a bit of sugar control and appetite and other interactions in the brain seem absolutely... [18:18] Um... [18:20] Well, they seem really important components of this nuanced response that these drugs are able to deliver. Just in the interest of time, Max, we might wrap it up there. [18:30] Um... [18:31] and maybe line up for a second podcast where we can talk about who should be on these agents. [18:39] And what do they need to know? What are some of the problems or side effects from them? But in summary, how would you summarise? [18:47] what we've covered to date. [18:50] Um, [18:52] GOP-1 antagonists are... [18:56] the most effective, we haven't really talked about that, but we should probably mention very quickly that they are by far the most effective weight loss drugs that we've ever seen come to market. They were originally developed as type 2 diabetes drugs for their role in insulin secretion and blood glucose control. They seem to have [19:13] far more broad-reaching effects than probably could have been envisioned ever. And they've made it really... [19:20] big difference to people actually that are really struggling to lose weight. And that is through sort of those two key mechanisms of making you feel fuller and diminishing that sort of addictive side of overeating. [19:32] I think it's very cool to recognise that they're an extension of our own bodies' signalling and that they're grounded in understanding a physiological response that we have ourselves, but also healer monsters in a more exaggerated way. So absolutely fascinating background to these agents, which are now massive. I'm going to thank you so much for joining me. [20:02] You've been working all day today. [20:05] You rushed around to get all tidied up and ready for this. So I really appreciate you making the time for now. I'm going to wrap up, but make sure you subscribe and come and listen to part two, where we're talking about who should be on them and what should they know. Max, thanks again for joining me and those listeners and viewers. [20:27] For those listening, I hope you learned something. If you've got any queries or questions, drop us a note. If you've got any ideas for future podcasts, let us know. Otherwise, I'll see you next time. [20:36] I do hope you live as well as possible for as long as possible. Take care. [20:39] And bye for now. [20:41] Did you know that coronary artery disease kills one in four people? So most of us are likely to carry some risk or know someone who does. If you're interested in finding out more about how to evaluate that risk, [20:57] Check out [20:58] www.virtualheartcheck.com.au. It'll give you information about risk, [21:05] And what else can be done to be even more precise?