**Episode Title: "Day 12: Medications Beyond Statins"** **Speaker 1:** Well, here we are at day 12, only a couple of days to go. But let's talk about what medications we can use other than statins to get that cholesterol down. One that's been around for a while is called ezetimibe, and this is a really handy agent. Ezetimibe stays in the gut; it blocks a receptor that absorbs cholesterol into the body, and it can give us an extra 20-odd percent cholesterol lowering for a given dose of statin. That's really important to know because if we take a given dose of statin and we double it, we only get about a five, six, or seven percent further reduction in cholesterol. So why would we take a mid-range statin for someone who needs to get their cholesterol down further? Why would we double that for only a small percentage improvement when we could add in ezetimibe without increasing the risk of side effects for either agent? Because they're at a low dose, we can get a 20-odd percent improvement in cholesterol lowering outcome. It makes perfect sense. I use ezetimibe a lot. There's an agent called bempedoic acid, which is on the very near horizon as I'm recording this. That agent works just like the statins, but only in the liver. It's delivered as a prodrug, and that prodrug is only activated within liver cells, meaning that it can't end up in the muscles. For that reason, there's evidence that would suggest it doesn't cause some of the muscle aches and pains that people report from the statins. It's not quite as powerful as the statins, and I think what we'll see is people taking a small dose of statin, a small dose of bempedoic acid, plus ezetimibe to pull their cholesterol down. Probably one of the most exciting cholesterol-lowering agents or classes of drugs that we've had in recent years has been the PCSK9 inhibitors. I won't even try and tell you what that stands for, but PCSK9 is a protein that sits on the surface of the liver cell. Now, it sits right beside the LDL receptor. If that PCSK9 protein is taken into the cell with the LDL receptor, then the LDL receptor gets destroyed. But if that protein gets blocked or taken away, then the LDL receptor is taken into the liver cell, it gives up its cholesterol, and then gets recycled back into the bloodstream. In that particular process, it is very powerful at helping keep cholesterol levels down because that LDL receptor pulls more of that LDL cholesterol out of the bloodstream. There are two ways that the PCSK9 inhibitors can be blocked. One is direct antibodies against those receptors, but the other incredibly clever way that's been used in the last couple of years is using mRNA technology to block it from being built in the liver in the first place. Absolutely fascinating. We also have other agents on the horizon, and incredibly, in the future, we may well see genetic therapy that leads to a single treatment blocking something like the PCSK9 protein in an individual's body for life. It's a very exciting world. I'm going to talk about some women-related cardiovascular issues in our second to last day. So stay tuned, and I look forward to seeing you tomorrow. I hope you live as well as possible for as long as possible. Take care and bye for now.