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. Hi, my name is Dr. Warrick Bishop and welcome to my podcast and videocast station. Today I'd like to give you an update on cholesterol therapy in 2022. Look, it would be fair to say that there is mixed messages out in the community about where cholesterol sits. Is it good or bad? And recently I was even part of a debate on the very topic. I was on the side suggesting that cholesterol is important, and believe it or not, our side lost really reflecting sentiment to a large degree of the audience who participated in that event. Look, the data is robust, it is clear, and it tells us that if you've got high-risk plaque, that is if you've had a stroke or a heart attack, problems with build up of cholesterol in your arteries then lowering cholesterol reduces future risk. There's no question about that. The questions come when quite reasonably people say should we be lowering cholesterol in otherwise healthy individuals on spec without any idea of their propensity to put plaque in their arteries. And in that space I think that's a reasonable question. But when it comes to identifying high-risk individuals with high cholesterol, or even intermediate or low cholesterol, we know if you have a propensity to put plaque in your arteries that's high risk, then lowering your cholesterol will help you. And we even know if we get that cholesterol low enough, we can give rise to plaque regression, meaning that the arteries actually get healthier. with time well our most recent studies in first world countries would suggest that even though we have in place targets for cholesterol lowering in these high-risk individuals that these targets are poorly met broadly large percentages of people are just not getting to where they should be to obtain the protection they should be one of the reasons for that is in regard to the medication and it would be fair to say that statin side effects particularly muscle aches and pains probably are reported but in between five to fifteen percent of patients and this tends to be dose related so the higher risk the individual the higher the doctor will want to push the lipid lowering therapy to drive that cholesterol down then the greater the risk of some side effect, because side effect is a dose-related response. So, we do know that for high-risk individuals, cholesterol, the lower, the better. And there doesn't appear to be a clear indicator of a point where you can go too low, in spite of a lot of the chatter that we see and hear on social media. There are other drugs available. And in Australia, ezetimibe, which is an agent that binds cholesterol in the abdomen, in the guts, and alters absorption, is available. It is generic, and it's pretty cheap and effective. It's generally very well tolerated and works extremely well with the statins. So a lowish dose of statin with ezetimibe will provide a better cholesterol lowering than a lowish dose of statin. being doubled. A really nice way to try and get better efficacy in those high-risk individuals. So ezetimibe, underutilized in Australia, generic, cheap as chips, we really need to be aware of it. PCSK9 is one of the proteins that sits next to the LDL receptor and it's been targeted for therapy because if you block that protein you improve the circulation and the re-expression of the ldr receptor well what does all that mean it means that the liver receptor for cholesterol or the cholesterol particle is circulated more effectively and therefore lowers cholesterol very very effectively through a different mechanism to the statins, and a different mechanism to ezetimibe. Well, PCSK9 can be inhibited by proteins, antibodies, designed to sit on that PCSK9 protein and block it. A little bit like an antibody would react to an infection that you had. But we're able to use a monoclonal antibody, which is an antibody directed to PCSK9, And we can inject that into individuals to get their cholesterol down. That injection is once a fortnight or once a month. And it's an incredibly powerful way to get cholesterol down, offering up to a 60% reduction in LDL levels. That protein, PCSK9, is also a target for mRNA intervention. medications which are close to clinical utilization, which can stop or interfere with the production of PCSK9 within the liver cell, the hepatocyte. This mRNA interference is not too dissimilar to the sort of technology that we're aware of with the Pfizer and Moderna vaccines, where a piece of DNA type material, RNA type material, goes into the cell and literally causes a change in what that cell produces from a protein perspective. When it comes to PCSK9 messenger RNA interference, then the agent is a compound called inclicerene. And that, at the moment, is very close to... completing clinical outcome trials it turns out injection of this mRNA interference molecule will give almost six months of reduced LDL cholesterol levels which is astounding think of it a little bit like going along to the chemist with your script rolling up your arm getting your injection there and there and you're vaccinated against coronary disease for the next six months. There's some other agents that are on the horizon. We haven't seen them clinically yet. There's an agent called bempedoic acid, which works through the ATP citrate liase pathway, which is just upstream of where statins work. But interestingly, bempedoic acid has an enzyme action that is unique to the liver only and doesn't cross over with muscles. So we think that there's a very good chance it will be potentially able to be utilised in patients who have a statin intolerance or muscle aches and pains in response to statin therapy. There's a group of drugs called CTEP inhibitors, cholesterol ester transport proteins, and these agents work to lower LDL cholesterol. and raise HDL cholesterol. They've been looked at in the past, but not successfully up to date. But there is a new agent called Obisetrapid, which seems to hold promise. Watch this space. There's also angiapointin-like-3 inhibition, and this is a central enzyme to the process of LDL formation, not requiring LDL receptors. and therefore able to be used in people who have poorly functioning LDL receptors on the liver. This is an agent called Evanacumab. You don't need to remember that. And it's only going to be used in very specialized settings. But it's fascinating to know what's out there and what's on the horizons. And most excitingly, there is even the talk of RNA modulation. or gene editing which could last a lifetime already primate early primate data has shown that if you like an inoculation of these gene editing rna proteins can deliver over 200 days of cholesterol lowering this truly is an exciting future so Whatever happens, if you're high risk through cholesterol building up in your arteries, there are plenty of options available now. But very excitingly, there's a lot coming up ahead in the future. I hope you found that interesting. If you've got any queries or questions, drop me a note. If you've got any ideas for any future podcasts, well, drop us a note at info at drorickbishop.online. And look. Please feel free to share this podcast if you've enjoyed it. I'm going to wish you the very best, hoping you live as well as possible for as long as possible. Take care and bye for now. 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.
