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's Dr Warrick Bishop and welcome to my videocast and podcast channel. Today I'd like to speak with you about a new class of drug which is used to lower cholesterol. It's quite possible I've mentioned this before on some of my podcasts, but I'd like to bring it up again as in the last couple of weeks I've been having... the conversation about these medications with a number of patients. The availability of these agents has also become more accessible in recent time. We all know about the statins. These work through an enzyme system in the liver called the HMG-CoA reductase enzyme system. And statins are HMG-CoA reductase blockers, so they stop. progressive cholesterol formation in that pathway. The statins have been very available, very affordable, very effective and in general terms very well tolerated so they really form the foundation of what we use. They are also the agents that over the last two decades have represented the agents that we've studied the most and understand really work in terms of cholesterol lowering. There's an agent called azetamide, which is often now combined with statins. And there was a trial a couple of years ago that showed that using azetamide at 10 milligrams in combination with statins can improve outcomes over and above the statin alone, showing really that lowering cholesterol of its own was beneficial, whether it was with a statin or not. With that as a background, there is a new class of drug on the market. They are called PCSK9 inhibitors. You don't need to remember that. PCSK9 stands for something like pro-protein convertase substancin K subtype 9. And what that gobbledygook means is that it's the protein or a protein structure that's associated with the LDL receptor. The LDL receptor is the receptor that grabs the so-called bad cholesterol out of the bloodstream and pulls it into the liver. If you can imagine a liver cell with an LDL receptor on it, then right next door is PCSK9, this special protein. If the protein is next to the LDL receptor, when the receptor binds with cholesterol, LDL cholesterol, then the receptor as it is drawn into the liver for metabolism also draws in the PCSK9 protein. If it does that, then the PCSK9 protein seems to have an effect of leading to degradation or breakdown of the LDL receptor. So the receptor goes from the cell surface with the PCSK9 and is degraded or broken down in the cell. End of story. If the LDL receptor is taken into the cell without PCSK9, without that protein in association, then the LDL receptor with LDL cholesterol is taken into the lysosome, into the metabolic pathway of the liver cell. The LDL is extracted from the receptor and the receptor is recycled back to the surface of the liver cell so it can do its job again. This increase in efficiency of the LDL receptor by it not being broken down and able to be reused means that the LDL receptor is then able to pull more LDL cholesterol, the so-called bad cholesterol, out of the bloodstream and therefore lead to lowering. of cholesterol. This was found out or stumbled upon or recognised probably 15 odd years ago when through genetic observation of individuals who had either overactive PCSK9, they observed an increase in cardiovascular mortality over their lifespan versus individuals or family groups. with low PCSK9 levels, who had longevity that was not impacted by cardiovascular events, and this simple split of people with one type of genetic predisposition versus another type of genetic predisposition, i.e. overactive or underactive PCSK9, this is called genetic or Mendelian randomisation, so that you can look at the outcome of a particular protein. or structure within two populations and see if that makes a difference to outcome. It was through this sort of work that PCSK9 was recognised and in the decade and a half that's followed, a very rapid investigation, evaluation, clinical trials set and then progress to market has occurred, which is quite extraordinary if we look at the history of drugs coming to market. The PCSK9 inhibitors are an amazing group of drugs which are very, very precise. They are called monoclonal antibodies or we call them biologicals. They target just that protein, literally. The monoclonal antibody is like if you had a cold and your body produces an antibody directed specifically to that particular cold or flu virus. So the monoclonal antibody against PCSK9 is directed to that very specific protein signal. So this is an incredibly targeted and specific way of neutralising this protein by an antibody landing on it and literally covering it up and stopping it working. These agents have shown a remarkable ability to lower LDL cholesterol, and in clinical trials, lowering LDL cholesterol 50% or 60% over and above what we're able to achieve with normal statins plus azetamide in high-risk patients. Really quite astounding. Not only have they shown that reduction in measured LDL cholesterol, but in two trials, the Fourier trial, There was a suggestion that if that trial had run longer, there would have been a clear benefit from the reduction obtained from the PCSK9 inhibitor. And more recently, in the trial called the Odyssey trial, there was a mortality benefit in the high-risk group of patients given these particular sort of agents. So a really interesting space, a very exciting opportunity. and one that I'm going to cover more and more as we progress. Right now, right here in Australia, these agents are available for people with very high-risk features. That's people who have a condition called familial hypercholesterolemia. Within the family, familial hyper, meaning increased cholesterol, the fat that we're talking about, and emia. meaning in the blood. So familial hypercholesterolemia, families with high cholesterol in the blood, these families have very high risk of coronary disease and there are certain criteria where the Australian government will now fund people with this condition to access PCSK9 inhibitors. Beyond that, In the last couple of weeks, I've had a number of patients who don't quite fulfill the PBS criteria for support for these agents, which are relatively expensive. These patients don't have familial hypercholesterolemia, but do have high-risk coronary artery features. The conversation I've had with these people, and these people in particular, have been well-funded. is that they may wish to subsidise their own purchase of a PCSK9 inhibitor. I'll talk you through that very briefly. One year's supply of a PCSK9 inhibitor for someone with their cholesterol very, very high is in the order of $5,000 to $10,000. Let's say $6,000 or $7,000 for a year's therapy. group of people I'm talking to who have lower cholesterol levels we might be able to use a half dose and still achieve very adequate LDL lowering. We'd only know by trying but it is certainly worth thinking about. If we were to use a half a dose then $6,000 becomes $3,000. These individuals are also within a private health fund. And so if the health fund contributes, for example, $1,000, say $1,500, to that individual's therapy for the ear, then that leaves approximately $1,500 for that individual to pay in themselves to invest in a lipid-lowering regime that suits them the best possible way. These are individuals who may have been having troubles with taking statins, and we've tried over and over, but we just can't get there, are having troubles with ezetimibe, don't tolerate nicotinic acid, have trouble with cholestyramine. At $1,500 odd dollars per year, we're only talking about $100 per month for a state-of-the-art Very, very well tolerated, highly effective agent that really does lower LDL cholesterol. And a little bit more than that, and we can cover this in another talk, it also lowers these new agents, the PCSK9 inhibitors, also lower lipoprotein, small a levels. So certainly if those levels were elevated, then this conversation becomes even more relevant. So there's an introduction to PCSK9 inhibitors. They will turn up more and more. They are available with subsidy in Australia for individuals in particular circumstances, but they are also now freely available on an open script for anyone who's prepared to fund themselves if that's what they need to find their very best solution for their cardiovascular risk management strategy. Well, I hope that's made a bit of sense. If you have any queries or questions, please drop us a note because I'd love to hear from you. And if you do have any topics you'd like me to cover, please also let me know. As always, I wish you the very best till next time. And thank you for joining me on my podcast and videocast channel as part of the Healthy Heart Network. 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.