Welcome to Dr. Warrick's podcast channel. Warrick is a practicing cardiologist and author with a passion for improving care by helping patients understand their heart health through education. Warrick believes educated patients get the best health care. Discover and understand the latest approaches and technology in heart care and how this might apply to you or someone you love. Thank you for joining me today on my podcast and videocast station and I'm delighted to say I've got with me Dr. Karim Kostner, a lipid expert not only recognised Australia-wide but internationally for his expertise in lipid management and his research. We're going to be talking today about ezetimibe, also known as ezetrol, and I'd like to welcome Dr. Kostner. a good friend and colleague. Hello, Karim. Thank you for joining me. Hello, Warrick. It's an absolute pleasure to be with you and thank you for inviting me. So I'm quite excited to talk about Ezetamide or Ezetrol, which is the trade name. It's been a little bit more in open view in the last couple of years. It's a drug that used to sit on the shelves a fair bit. one that wasn't written very often, but we've started to use it a little bit more. Well, before we get into why that's the case, Karim, what actually is ezetimibe? Ezetimibe is an interesting story. It's a cholesterol absorption inhibitor, and it's the only drug in its class. But the interesting thing worried about ezetimibe is that the mechanism was actually discovered after the drug was discovered, and that's rarely the case. So what azetamide does, it blocks a receptor in our intestine that's responsible for cholesterol uptake and reabsorption. And by doing that, it leads to a reduction in cholesterol levels by up to 20-25% in some individuals. So the receptors of blocks are clearly receptors that are associated within the gut or within the liver, Cara? They are mainly in the intestine. They're not in the liver. So it's the Neiman-PKC1-like protein 1 receptor. And it is a receptor that is responsible for reabsorbing cholesterol that is excreted into the bile and pieces. So the body tries to reabsorb that cholesterol to use it and also, unfortunately, to transport it back to arteries. And blocking that receptor prevents that process. And by doing that, plasma cholesterol levels are reduced. Okay, so I'm not going to even try and remember the name of that receptor, and I'm sure most of the listeners won't be remembering the name of that receptor, but does that mean that ezetimibe stays in the gut or is it absorbed into the body? Do we get blood levels, Conor? That's a good question, Boris. Most of it stays in the gut. A very small amount ends up in the blood, but the reason it is tolerated very well... is that the main concentration remains in our intestine and doesn't get absorbed into the bloodstream and doesn't get into our muscles and other organs at any sort of significant degree. So when you're talking about side effects, it really shouldn't give muscle side effects, for example. That would be surprising because there's no transport of that medication through the bloodstream to get to the muscles. Is that correct? That is absolutely correct. I mean, the only side effects that we see with azotrol and any other medical therapy that's available as a tablet is some mild gastrointestinal discomfort, reflux in some cases, but it does not cause more muscle side effects than a placebo or sugar pill, for example, and it certainly doesn't cause any other significant interactions or adverse events, in my experience. Because it's mainly staying in the gut, is there a particular time of the day that you should take it or are there particular foods you should or shouldn't take it with? Yeah, it's a good question too, Warrick. You can take it any time of the day. I mean, it works for 24 hours. It is only available in one concentration, which is 10 milligrams. And it is often given at night because cholesterol production is slightly more when we're asleep, similar to what we say about statins. But it doesn't really matter if people prefer to take it in the morning, they can take it in the morning. And as I said, it works for 25 hours. And I may be misled in this space, but I thought that there could be quite a variance in response to this medication between individuals. Is that the case? You're absolutely correct. And that has genetic backgrounds. So people who are very good absorbers of dietary cholesterol, which is about 20% of the population, will respond with a bigger lowering of LDL cholesterol and total cholesterol with ezotrol than people who are very good producers of cholesterol, synthesizers of cholesterol. But that also explains why the combination of ezotrol with estatin is so effective, because it basically deals with both important cholesterol pathways in the body, absorption, and production. So if you're on a statin and endotrol, you get a very, very good response with regards to cholesterol lowering because both of these pathways are dealt with, if that makes sense. It's really literally pushing and pulling at the same time to improve the effectiveness. My understanding as well, and I'd be grateful for your comment on this, is if we get people on a statin, which is a... most common agent we use for lowering cholesterol, say at an intermediate dose, say, let's say 20 milligrams of Lipitor is a very average sort of dose. My understanding is that if we add azetamide in at 10 milligrams, we get a much better lipid lowering or cholesterol lowering, particularly of that bad LDL cholesterol, than if we were to double. the atorvastatin from 20 to 40. Is that correct, Carmen? What sort of figures would we expect in those spaces? Yeah, that's absolutely correct. So doubling the statin dose will usually lead to a 6% additional LDL or total cholesterol lowering. But adding etatrol to even the lowest dose of the statin, 10 milligrams of atorvastatin, gives you the same effect as you would get from the highest dose of atorvastatin in the same way for subastatin. simvastatin, fluvastatin, and pradastatin, and pitivastatin. So by adding etatrol 10 milligrams to virtually any low statin dose, you get the same effect as with the highest statin dose. And especially for patients who do not tolerate statins at higher doses due to muscle-related side effects, that is an important thing. So that's great news, really, I guess, because my own experience is I do find people who have some issues with statins. We can find a dose that they tolerate and they can live with that. And then what you're saying is that even better than doubling the satin they're on to get their cholesterol down, the addition of this azetamide may give us nearly a 20%... absolute reduction in their cholesterol levels, which is just fantastic, I guess. And from what you say, it's very well tolerated as well. It's very well tolerated, and it's available as a fixed-dose combination with a tolostatin and zivostatin, and it's available as a co-pack with rosulostatin. And the good news is patients only pay one script fee, so it's virtually the same price as just taking a statin in itself. And even if you prescribe ezotrol on a private script, it's about $13 to $14 a month, and people spend more on vitamins sometimes. So, you know, it's an affordable therapy. Well, that's good to know, isn't it? So it's affordable, it's accessible. You touched on these statin-azetamide combos, for want of a better term, because of the efficacy they bring. I guess if you gave someone a high-dose statin plus azetamide, what sort of percentage reduction of their... Non-treatment cholesterol, might you expect, Karen? Yeah, you can get up to 70% LDL reduction. You know, if you add azitrol to 40 milligrams of superstatin or 80 milligrams of atolastatin, we have seen up to 60-70% LDL reduction, and that's something that 5-10 years ago was unheard of. So it's really a very effective therapy. So I'm going to... really trying to underline an important point here and that is why do we bother with all this getting the cholesterol down and why are we measuring levels and all that sort of stuff and one of the aspects that I think has changed this was one of the trials where azetamide really came to light and I can't remember exactly the name of that trial you might be able to help me but talk us through why we're getting those cholesterol levels down. what the evidence is and what we're really trying to achieve. Yeah. The trial that you're referring to is the Improvic trial. And the Improvic trial shows that if you add acetrol to cymbostatin and compare it to thousands of patients who are just taking cymbostatin, you get less atherosclerotic events. You get less repeat heart attacks, less unstable angina, less reverse scolarizations. But you're absolutely correct. There's many other trials now that have shown that getting to very low cholesterol levels with statins, with statins and ezotrol, with PCSK9 inhibitors, with aparesis, really reduces cardiovascular events, reduces heart attacks, reduces strokes, reduces stenting and bypass surgery. And that is a very important message that you are trying to get across there. And we have the means now, we have the therapies to achieve this. One of the explanations I give to my own patients, and you can correct me if I'm misled on this, but I was under the impression that the IMPROVER trial or subsequent trials demonstrated that if we got cholesterol levels under about 1.8 to 1.7 millimoles per litre, we can actually get... reduction or regression of plaque. This means that as people continue to take their medication, the buildup of their cholesterol in their arteries can become less and less, which I believe is an exceptional aspirational goal. Do I understand that correctly or is there more detail around that I should know? Absolutely. And in fact, the imaging modalities that you use and that you're very experienced in have clearly shown that, you know, and your own work has supported that, that if you get to these very low LDL cholesterol levels, you can not only reduce plaque in coronary arteries, but you can also stabilize plaque and that causes, again, less heart attacks than stroke. So very important point you're making there. Azetamib seems like a fantastic agent. Obviously gets about a 20% reduction in cholesterol. It seems to be well tolerated. It stays in the guts, in the stomach and the digestive tract, so it doesn't cause too many problems. Would patients be able to take this as the first-line therapy instead of even trying a statin? What's the take on that, Karim? Look, statins are more effective because they lead to cholesterol reductions about 50-60%, and they have even more evidence behind them than ezotrol. So statins have shown in many, many trials to reduce cardiovascular events and morbidity, and there have been many more trials with statins than with ezotrol because they have been available much longer. So it's not a substitution for statins unless people do not tolerate statins. So if you really develop severe muscle pain on statins... and that's not many patients that you and I see, then obviously you can use Estrol alone. But as you mentioned, it only leads to an LDL reduction on average between 15% and 25%, even though there are some better responders, and it is not sufficient if you tolerate a statin. Combining it is certainly a better approach. Certainly, I know from my own clinical practice, I have a number of patients, and it's... a vast minority so only very few who have a lot of trouble taking their statins but we're able to find a dosing regime of one or two tablets per week or three tablets per week at a low dose and with those patients i've had no troubles adding in azetamide over the top and actually getting surprisingly satisfying cholesterol lowering, remembering that we're aiming for this aspirational goal of stabilizing plaque or even regressing it. So it seems to be, I imagine you use a similar technique. Exactly what you do, you know. I think you can do exactly that in people who have trouble tolerating dose, high doses of statins or statins. I do exactly the same. Well, look, we've covered a heap of stuff about azetamide. It's been... An absolute pleasure speaking with you again. I really enjoy it and I get something out of it every time. For those who are listening, thank you so much for joining. I'm going to thank Dr. Costner for joining me. So say goodbye. Absolute pleasure. Thank you, Eric, for having me. I enjoyed it myself. I look forward to a chance to share about some other. aspects about particularly lipid care because that's your area of expertise. For those who are listening, if you've got any queries or questions, drop us a note at members of Dr Warrick Bishop. I hope you found today as informative as I did. Look after yourselves. Till next time, please don't die from a heart attack and goodbye. You have been listening to another podcast from Dr. Warrick. Visit his website at drWarrickbishop.com for the latest news on heart disease. If you love this podcast, feel free to leave us a review.
