[0:00] Welcome, my name is Dr. Maureen Bishop, I'm a cardiologist, an author and a keynote speaker. [0:06] I'm CEO of the Healthy Heart Network. I'm all about trying to help people [0:12] Live as well as possible. [0:13] 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. [0:26] This podcast is all about helping you understand blood pressure, weight, cholesterol and [0:32] for better health. [0:33] If you enjoy this podcast, I would be honoured 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. Thank you so much for joining me on my podcast and videocast station. This is a part two podcast and it's on GLP.com. [0:54] one, [0:56] agonists, which are these amazing drugs which we're using for weight loss broadly around the world. My son, Max, joined me for part one, and Max is going to join me again for part two. Hi, Max. How are you going? Hey, all good. [1:11] For those who missed part one, go back and have a listen. We talk about where these agents come from, what they actually do physiologically. They're a peptide in our own bodies, but there was research that showed us that there were certain animals, and in particular a lizard called the gila gila. [1:32] or healer monster that had long-acting GLP-1, and we... [1:38] used some of the [1:41] science of that to develop the agents we've currently got. So go and check out... [1:47] podcast one of these... [1:49] to get some of that background, some of that size, and... [1:54] Then stay tuned for the rest of this, which is going to be who should be on these agents and what do people need to know about them? So, Max... [2:03] I know you don't prescribe these agents, but I know you've been reading around them. [2:09] Who would you be thinking would be ideal candidates for the GLP-1 agonists? [2:17] Well, [2:18] Historically, these drugs were all approved first and developed for... [2:22] people with type 2 diabetes to improve insulin regulation and and improve [2:28] blood glucose levels and they worked really well for that and they still do work really well for that um and people realize that these people also lost a heap of weight [2:37] which has a host of benefits but also improves type 2 diabetes outcomes. [2:42] So that's still an excellent treatment for people that have type 2 diabetes, and that's still sort of top of the list. [2:50] Um, but the thing that's got people talking is, is weight loss. Um, and, [2:57] These drugs are incredibly effective, like... [3:00] twice as good as anything we've seen before that you can take to help you lose weight. And, um, [3:08] That's made them really powerful and sort of created some waves, really. [3:14] So just for those who may have missed... [3:18] the first podcast out of these two, or anyone who's forgotten... [3:23] What's the main mode of action that these drugs use to help people with their weight loss journey? [3:30] There's two primary roles. [3:34] These drugs, they cross the blood-brain barrier into the hypothalamus, which is part of the brain really responsible for those feelings of hunger and the feelings of being full. And they really down-regulate those feelings of hunger and at the same time promote that feeling of fullness, maybe even to the level of over-fullness, feeling like you couldn't possibly eat more, maybe even feeling sick at how much you've eaten. [3:57] And that's very powerful at getting people to eat less and then they consume fewer calories and lose weight. They also have some really interesting roles in relation to sort of dopaminergic or addictive sort of diet. [4:09] circuitry in the brain. [4:11] especially relating to food. So they can sort of decrease the... [4:15] The pleasure-seeking behaviors people might have towards food, that tendency to overeat things, not because they're so hungry that they need to eat more, but because it tastes so good that they keep eating. So it's a sort of dual mechanism there, really, for weight loss. But the overall effect is they make you feel full and make it easier for you to say no to eating more. [4:36] And that helps people lose weight very effectively. [4:40] So one of the things from a cardiovascular perspective, and I'm actually going to a meeting tonight that's been organized locally. [4:50] And that meeting is going to be talking about the concept of cardiometabolic health and this... [4:57] sort of [4:59] collection of different problems that are all stemming from a combination of obesity, raised sugar, raised blood pressure, renal impairment, risk of dementia. And this is becoming a really significant component of what we're trying to target within cardiovascular medicine. [5:21] One of the things with the GLP-1A is there's actually been a study called the SELECT trial. Now, I don't know if you know much... [5:31] in terms of the details surrounding the Select trial, but my understanding was that... [5:38] These agents... [5:40] In individuals, randomized to therapy, demonstrated reduction in cardiovascular event, which was separate. [5:48] when corrected for weight loss. So this is over and above just the weight loss effect. And it really sort of talks to, I don't know, more global impact on the body or metabolic impact on the body that I think we're still trying to get our heads around. Do you want to speak, or are you able to speak about the SELECT trial at all, Max? [6:08] Yeah, I can a little bit. [6:10] Select was done as a trial on semaglutide. [6:14] It was done with people who had BMIs over 27. These were overweight individuals. They weren't necessarily... [6:22] uh, obese individuals. It wasn't done as a weight loss. It was done to assess, um, [6:27] Yeah, a potential reduction in adverse cardiac events in a population of people that had had a cardiac event. [6:36] already. [6:39] Thank you. [6:39] It was 2.4 milligrams a week and it showed a 20% overall reduction, I believe, in heart attack, stroke and cardiac related death. [6:52] which was... [6:54] I would have to check if that was corrected. [6:57] against the weight loss. Yeah, I can tell you it was because I've been lucky enough to have that data presented to me on a number of occasions and the really striking thing about it is over and above the wonderful benefit that you would get from a metabolic perspective, these agents appeared to have... [7:17] Thank you. [7:17] a significant effect when corrected for weight. So yeah, no, it's a really interesting space. And I know when we've spoken about these agents before, you were talking about mechanisms where the GLP-1 agonist may actually have a role in cardiovascular system. Would you like to share that? [7:39] Yeah, of course. [7:41] It's a pretty new area, so I think this research is going to keep rolling out, and we're going to develop a better understanding of it. But the picture that's currently standing is – [7:49] It's quite multifaceted, almost very surprisingly. It doesn't come across as very intuitive that these sort of signaling pathways would involve cardiac stuff. [7:59] But there's a few things... [8:02] that are known to [8:06] impact on that system when it comes to these drugs. They directly lower blood pressure. [8:13] These receptors are actually expressed in endothelial cells, smooth muscle cells of blood vessels, and trigger this ENOS pathway thing. They make them dilate. They make them relax. So you have an instant reduction in blood pressure. [8:28] I'll jump in there, Max, because you shared that to a bunch of scientists, [8:36] these peptides have receptors in blood vessels and through those receptors create a thing called nitric oxide which you may have heard of and nitric oxide has this amazing ability to dilate [8:51] the arteries and keep them healthy. And you're right. How counterintuitive is that? Who would have thought? So, uh... There's more, actually. Keep going. I also downregulate... [9:05] A couple of pro-inflammatory cytokines, particularly interleukin-6 and TNF-alpha. [9:12] Details are not so important, but these have a role in macrophage activation, some peripheral nerve cells, not nerve cells, sorry, peripheral immune cells. [9:25] And that actually changes plaque progression. [9:28] down-regulating the activity of these macrophages can sort of slow down the progression of atherosclerotic plaques. You're probably far better versed to talk about this than me, but these cells are expressing these receptors and it's having an anti-inflammatory role on them, which then has this knock-on effect in the cardio space. [9:50] So this really is a very important area where we talk about coronary artery disease having a component of inflammation, generally seen in the plaque that's most lipid-laden or cholesterol-laden, often oxidized LDL cholesterol. The IL-6 is interleukin-6 and TNF-alpha tumor necrosis factor. These are... [10:18] molecules that really do incite the inflammatory processes and are involved, as far as we can tell, in... [10:27] plaque rupture. So the plaque... [10:30] Within the arteries there's more likely to rupture is the one that's inflamed, not the one that's... [10:35] Let's inflame. So... [10:37] A couple of mechanisms there... [10:40] vasodilatation, keeping those arteries healthier, maybe dropping blood pressure a little bit, and reducing inflammation could be the end results of GLP-1A use in [10:51] in reducing event rates in the SELECT trial and in the populations that it's used in too. [10:57] There's a couple of other potential factors that might have been partially responsible for those findings in the SELECT trial. There's also some evidence that there's antithrombotic effects of GLP-1 agonists, so reducing platelet aggregation and potentially downregulating some of the tissue factors that start that clotting process, which is obviously going to make it more difficult to have a cardiovascular event if your blood's less likely to clot. [11:27] Um, and there's also some evidence that shows there's a general improvement in myocardial function in the, in the cells of the heart, um, um, [11:35] through a process of decreasing oxygen stress and death of these cells and also just increasing their ability to uptake glucose and that sort of metabolism probably through those sort of insulin pathways that we spoke about a lot um in the first um podcast so sort of [11:53] helping your heart cells to be more resilient almost by improving that sort of metabolic pathways. So perhaps if you had an event or were at risk of an event, maybe making your heart a bit more resilient to those. So that's, I have to say, Max, that's news for me. Do you know how they assess that? Because that's a really interesting space. [12:14] Are you aware or have you just read that? I don't have to come back to that. [12:18] Okay. Yeah. [12:19] We might discuss that one offline because that's a really interesting space and one [12:25] If there is an improvement in... [12:29] myocardial cell function through using these agents. That's a very important piece of information that can help people, particularly as they age and particularly as their heart gets a little bit stiffer. So let's have a chat about that later because I'd love to follow up on that. And for those listening, I'll probably touch on it in another podcast. That gives you a great reason. [12:50] to subscribe, like, and share. In terms of where these GLP1As really make a difference, if we were thinking about the average cardiovascular patient, [13:02] Obviously there's [13:04] weight loss, but we've said that they probably help beyond weight loss. But if we just simply talk about weight loss, [13:11] Do you know some of the knock-on effects from reducing weight that we'd see in an individual person? [13:16] You'd probably expect some reduction in blood pressure too. The changes in lipid profile are really big. GLP ones have sort of quite significant impacts on an individual's lipid profile really quickly and blood glucose control. [13:32] It's sort of, [13:34] A lot of these things that we've spoken about already, you spoke about at the start of this podcast, sort of fall out of that umbrella of metabolic syndrome, that sort of interconnected web of people that have... [13:48] Yeah, groupings of closely related groups. [13:51] disease that are linked through metabolic processes, through being overweight, through perhaps reduced insulin sensitivity, that sort of thing. [14:01] And, of course, these GLP-1s, it's the knock-on from weight loss, but it's also the knock-on from improved glucose control and improved utilization of glucose by cells. [14:12] Yeah, there's knock-on effects to lipid profile, and you're probably better placed to talk about. [14:18] those effects then onto the cardiovascular system. But there's a lot of those indirect effects too that are really significant for people. [14:32] all the organs, all the major organs in the body being impacted by [14:36] obesity, hypertension, such that... [14:40] Reduction in weight, reduction in blood pressure, reduction in inflammation, not only is good for the heart, good for the liver, good for the kidneys, but also ends up being good for the brain and reducing risk of progression to dementia. [14:58] These agents make a lot of sense. [15:01] particularly for those individuals who [15:03] who are obese, who do need to get their weight down and do need to reduce those risks, multi-system, multi-organ type problems. But look, it can't all be beer and Skittles. [15:19] These agents sound fantastic, but... [15:24] What's the concern with them? What sort of issues would people be needing to look out for if they were on them long term? [15:34] Um, [15:36] Not necessarily just long-term issues. [15:38] Would you like to speak just about long term issues or...? [15:42] However you'd like to. [15:44] The biggest side effect that's... [15:46] sort of always has to be dealt with and managed is nausea. [15:50] And potentially amasis, potentially vomiting as well, if that's really severe. And that is really stemming from the mechanism of action of these drugs. They make you feel really full. So when you eat, that's added to. [16:03] It's the feeling that most of us are probably familiar with, which is that of having eaten too much. It's an uncomfortable feeling. It can make you feel nauseous. It may even make you throw up. And these drugs are really turning that dial up in the hypothalamus in the brain. [16:20] And there's receptors for them all through those areas of the brain that are responsible for promoting that feeling of nausea. [16:29] That's reasonably easy to manage. That's a dose-dependent side effect, and it's also something that's [16:37] exacerbated by eating large meals while on these drugs. So, you know, [16:43] Starting patients on these drugs at low doses, as you sort of talked about in the first podcast, and checking in with them about the dosing, how they're feeling, as well as making sure their meals aren't huge or overly fatty or anything else that might contribute to those feelings would often make it quite healthy. [17:01] not a single [17:03] Thank you. [17:05] Um... [17:07] and [17:08] Changes in stool behavior also can be quite common. These drugs really slow the emptying of the stomach. We didn't talk a huge amount about that, but... [17:18] not only do they signal to your brain that you're really full, they physically keep you fuller for longer actually because they signal there's nutrients in the small intestine. We don't need to move food out of the stomach. [17:29] So food starts moving slowly up the top end in the stomach. And when your stomach's really full, things at the back end speed up actually to make space for it naturally. So when you've got food held up in your stomach, you can have... [17:45] Um... [17:47] changes to your stool frequency and takes shot. It can go both ways for people. It often resolves as your body sort of gets used to a different rhythm through the intestinal system. [17:59] Yeah. [18:00] So... [18:02] Yes. [18:03] doesn't normally... [18:05] the path through [18:07] These symptoms is just a bit of time, making sure that people are eating some fibre and drinking enough water. [18:12] they have changes by themselves on your stool behavior. And if you feel full all the time, it can be difficult to consume enough water and fiber. [18:22] Um... [18:23] So... [18:24] So one of the things that... [18:26] People may have heard on the news or... [18:30] read in social media or just in the media or in conversation is that not all [18:36] white lost is fair. [18:40] Some of that white lost might be... [18:43] muscle and changing body composition for that reason. So not just [18:48] Fat loss, but muscle loss. That... [18:53] Have you got any insights into that and what people could do to avoid that? [18:58] Thank you. [18:59] Yeah, of course. [19:01] that. [19:03] weight loss, [19:04] of any sort is going to lead to some muscle loss. That's... [19:09] No. [19:11] Something that's unique to these drugs when you enter a caloric deficit your body starts burning reserves for fuel now normally That's preferentially fat [19:21] but biological systems don't work in sort of perfect binaries, if you will. Muscle tissue get degraded to amino acids for energy. [19:34] And sort of adding to that is the majority of anabolic processes, the hormone signaling systems in our body that, [19:43] allow us to build or maintain muscle. [19:46] They are directly influenced by what we're eating and how much food we have available. Because if food is really scarce, it's no good to keep putting on muscle. You just end up burning more calories and you starve quicker. So it's a really difficult thing to avoid with any form of weight loss. [20:04] I don't think there's much evidence that suggests GLP-1s are worse. In fact, in some ways, as we discussed in the first podcast, I think... [20:11] some of those metabolic effects and signaling effects, um, [20:15] compared to just [20:17] dieting without them are actually reduced a little bit because these drugs are signaling to your body that you're full. You have an abundance of food. So some of that might actually be mitigated a little bit. The thing that makes it [20:29] I suppose, quite talked about and a significant concern is the weight loss is really... [20:35] big. It's a huge change and it's often very rapid. And that can... [20:40] exacerbate. Um... [20:42] loss of skeletal muscle, or make worse sarcopenia for patients sort of over 65 years of age and are already losing muscle. [20:53] Um... [20:55] But there were MRI studies done that showed... [20:59] muscle loss with GLPs is comparable to the same amount of muscle lost. Okay. To just reduce your calories by an equivalent amount without the drug. Okay. That doesn't mean it's not a significant concern or something that should be thought about. Muscle loss is something that needs to be addressed through a combination of things. [21:19] Um, protein intakes very important and resistance training is also really important. Um, um, [21:26] Those are sort of the two key tenets of maintaining or building skeletal muscle mass. They hold true in this case. [21:34] But they hold true for everyone sort of all the time anyway. This is going to increase the risk of someone losing muscle mass, so perhaps some more focus and attention can be brought to those things. [21:45] I think it's probably important for those listening who may be on these drugs or considering them to know that that concern around muscle loss is not necessarily unique to these agents. It's part of a process for anyone who's in calorie deficit. So I guess that's important rather than making these drugs a scapegoat. [22:15] place. [22:18] Some of these things get bandied about. Have you heard or any comments on any of those? [22:25] Yeah, um... [22:27] There's two types of exemplary gear. One of them is a bit of a medical problem. The rest of it is cosmetic stuff. You've got fat around your station tubes. [22:36] And if you lose it really rapidly, it can cause you to use station chips, not close properly, and can give people some sort of... [22:45] auditory sensations that shouldn't normally be there. They normally resolve by having people gain a little bit of weight back. And in some cases, they need a bit of intervention. It's not a very big deal. It's not very common. Most of what you're talking about, though, is... [22:59] is loose skin after people quickly lose that. If you've lost weight of any form, regardless of who you are, if you lose that quickly, especially if you're older and your skin's not as elastic, you will end up with loose skin. [23:14] It doesn't... [23:15] It doesn't really have anything particularly to do with these drugs. [23:21] Um... [23:22] mechanism of action. [23:24] other than the fact that they make you lose weight really quickly. If you were to lose that amount of weight without these drugs, people would suffer the same, well, not necessarily suffer, people would experience the same. [23:35] changes in their body. There was something there. [23:39] that was stretching our skin out, the skin had to grow. [23:43] to accommodate that and very rapidly it's, it's shrunken. It's, um, and that, um, [23:51] It will change how people's skin set on their body, but that's to be expected. [23:56] It's a very normal thing. [23:59] Is there anyone who shouldn't use GLP-1s? [24:03] GOP-1-I-E. [24:04] agents at all [24:06] Yes. [24:07] There's a few contraindications. [24:10] Um... [24:11] People that have had a personal or close family member who have had issues with thyroid cancer. [24:18] Amen. [24:19] It's... [24:20] I'm not sure it's a complete contraindication, but it's not necessarily someone that you'd be jumping to start on them. People that are pregnant or breastfeeding... [24:30] Thank you. [24:32] Thank you. [24:33] there's a host of reasons why you don't want to introduce drugs like this to, to an infant. Um, not only because they haven't been fully researched, but, [24:43] you know, developing brains, all sorts of reasons. [24:46] Obviously anyone has a sensitivity or an allergy to... [24:50] these compounds or similar compounds should be very careful. [24:55] Um, [24:55] peptides are something that an immune response can be mounted to. [24:59] Um... [25:00] and [25:01] And injectable peptides can be an issue for people because they can be perceived by your immune system as foreign. And you can have really quite significant reactions, not necessarily instant. It might take time for your body to develop sort of memory and mount full-scale attacks. [25:21] People with intestinal problems like irritable bowel disease or gastroparesis, people that already have issues with sort of the transit of stools or inflammation in their guts. [25:31] Again, this isn't an absolute contraindication. [25:35] these drugs could potentially make... [25:38] those things worse by changing sort of the motility of the gut in a way that might adversely impact on them. [25:45] Um... [25:47] Also people with a history of pancreatitis. [25:50] Yeah. [25:51] It's a side effect of these drugs. It's very, very uncommon. I think it's... [25:56] quoted as less than 0.1% of patients experience pancreatitis, but if you've had a past history with them, a physician... [26:04] probably wants to monitor you a bit more closely and might try alternatives first. It's not an absolute contraindication. The risk of pancreatitis is very small. [26:13] Um, but it is, um, [26:17] That's something to consider. Also, people with diabetic retinopathy. [26:22] A very rapid, drastic change to blood glucose levels can have really adverse effects on that. People with liver and kidney disease, I think a lot of this is just a clearance issue, a sort of drug metabolism problem. You've got to be careful with individuals that have these disease when you're sort of thinking about any kind of drug regime. [26:47] And the last thing, it's not really a group of people, but it's something to watch out for is... [26:52] Surgery and anesthesia. The delayed gastric emptying means that food stays in the stomach a lot longer. People have to fast before surgery, so they don't... [27:03] asphyxiate. [27:05] after they've been put under and... [27:08] Taking these drugs makes your stomach empty a lot slower. [27:11] Yeah. [27:12] It's just something to look out for. [27:15] And just from a practical perspective, if you're already on insulin or another diabetic... [27:22] agent, and these get added in there. They're additive to your sugar lowering [27:30] regime. So... [27:31] risk of hypoglycemia. So really important to have... [27:36] Dose adjustment. [27:37] Look, I'm going to wrap it up just in the interest of time, Max. These are an amazing group of drugs and I'm going to leave with a sort of where you see these agents maybe in the next five or ten years. Do you think we'll be waiting for people to actually have gained weight to be implementing these sort of agents or do you think we might see strategies where... [28:02] at, um, [28:04] at [28:05] very small increments above ideal weight, people have access to these agents to help them maintain safety [28:12] Um... [28:14] within a particular range. [28:16] Any thoughts around that or... [28:19] That's an interesting question. [28:23] Most of the time, that's what we're trying to avoid. [28:25] Giving people drugs when they don't. [28:28] necessarily need them. I think if there was a really good evidence base that suggested [28:32] We knew this group of people... [28:34] would have a really high likelihood of gaining more weight to the point that it was going to be problematic. [28:39] Something like that could be considered. These drugs, they have some side effects. They cost money. [28:46] They're not just to be given to everyone willy-nilly to sort of replace... [28:51] healthy eating habits and exercise. I don't think that's going to be the [28:56] the first change or the biggest change that we'll see in the near future. [29:01] These drugs, I think, are getting more powerful. There's currently a drug in, I think, Phase 3 clinical trials that is a GLP-1 agonist, but it's also a GIP, which is the other incretin that we talked about in the first podcast. And it also has activity on ghrelin receptors. [29:21] So it's targeting three different hormones in that satiety signaling thing with a goal at minimizing the side effects because it can be sort of lower amounts of modulation of each of those systems that are all coming together to increase the effect. I think that... [29:42] that's going to be the natural progression. These drugs will get better as we, as we keep developing them. There's also been some very interesting studies in obese monkeys done, [29:54] to... [29:57] counteract some of those things we talked about, about muscle loss and psychophenia. Looking at some other biological compounds, my statin and activant A antagonists, which are... These are... [30:09] They're signaling pathways responsible for making sure you don't build too much muscle. But blocking them makes people, or monkeys in this case, difficult. [30:20] Builds muscle. [30:22] Wow. These are very, very powerful anabolic compounds. And I don't have the numbers off the top of my head, but these monkeys that were overweight – [30:32] when they were given these two compounds and... [30:35] I think it was semiglutide as well. They lost a huge amount of weight. [30:40] as one would when they put on some glutide. But at the same time, they built muscle. Wow. And it's trivial now, like a huge amount of muscle with no training and very little change to diet. Wow. [30:55] I think... [30:57] that sort of space is going to [31:01] had very interesting effects on... [31:07] how we go about preserving lean muscle mass for everyone. [31:10] And... [31:14] And for those that are losing weight, that sort of combination therapy is going to be really interesting. [31:22] Um... [31:22] I think that's going to happen soon. I think that's going to be a bigger difference. That's going to be one of the biggest sort of changes, I guess, that we see in this space is those sort of things starting to become [31:33] starting to move into art and human trials. Yeah. No, it's, there is so much happening at the moment. Look, I, [31:42] Again, in the interest of time, I'll wrap it up there. It's been fantastic talking, talking about who should be on these agents and what they need to know. Thanks so much for sharing, Max. So thank you for joining us. For those listening, really appreciate you hanging in and tuning in. I know your time is valuable, so thank you for giving it to this podcast or videocast. Thank you. [32:10] Drop us a note if you've got any queries or questions. [32:13] Otherwise, until next time, I really do hope you live as well as possible. [32:18] for as long as possible. Take care and bye for now. Hi, ever wondered what your risk of heart attack is? You should. It's the single biggest killer in the Western world. We're talking one death. [32:31] less than every 30 minutes in Australia, one death, [32:35] Less than every 60 seconds in the United States, nine seconds. [32:40] million deaths globally. [32:42] per annum. Well how do you check your risk? Well you can go to [32:47] www.virtualheartcheck.com.au. You'll find out about your risk and what can be done beyond that to be even more precise.