Changing paradigms in LDL-c reduction

Hello, my name is Kausik Ray, I'm Professor of Public Health at Imperial College in London, United Kingdom. I'm here to talk to you about changing paradigms in LDL reduction. These are a list of my disclosures.

We often think about data in multiple forms. Some of that may be for regulatory approvals, and some of those get incorporated into clinical guidelines because they are randomized controlled trials, a highest level of evidence. Then we actually try and put all of this together, in terms of implementation, putting into everyday clinical practice. Evidence comes in multiple different forms. Evidence may come from observational data, where there may be some residual confounding, but we have nature's randomized trials, genetics, Mendelian randomization. Of course, ultimately, the randomized controlled trials themselves that tell us whether or not doing something, make something else better or worse and is safe. Largely for regulatory approvals, randomized controlled trials are done. We basically look at the population that was studied, and we try and incorporate that into our clinical practice, but the regulatory approval is exactly for that patient population. We've sometimes had to think outside the box. The guidelines tell us what we should be doing with these data in whom we should be doing that. Then we've got to remember that ultimately, it's people like you and I that put this into clinical practice, it's us, and it's real life. We have to look at all of these together.

Put very simply, what we're interested in is to reduce circulating levels of ApoB-containing lipoproteins, which are mostly in the form of LDL, and their cholesterol cargo, LDL-C, LDL-cholesterol, And it's very simple. The nature has given us a really efficient way of doing this, the LDL receptor. If we make more LDL receptors, for example, with the use of statins, and even ezetimibe which reduces cholesterol delivery to the liver, actually up-regulates the LDL receptor, we basically can reduce circulating levels of LDL-cholesterol. Nature has given us another protein, which is up-regulated whenever we diet, whenever we give people statins, whenever we give people ezetimibe, for example, and this protein is called PCSK9. Even though we actually make more LDL receptors, some of these are being destroyed, they're not recycled back to the cell surface. Monotherapy, on its own, is unlikely to be able to achieve 70%, 80%, 90% reduction in LDL. Really, we should be thinking about combination therapies. To do that, we can think about targeting PCSK9, for example. The way we've traditionally done that is with monoclonal antibodies injected every two weeks, and this is a bit like a bucket catching everything in blood. The source of that what is leaking PCSK9 is the liver, 80% of what's in blood comes from the liver. If we switch off the leaking tap, with so-called gene silencing approaches targeting the message, stopping it being translated into protein, we can basically do exactly the same thing.

There are other therapies that have emerged that also work through the LDL receptor pathway, notably bempedoic acid approved over the last few years. What this does is it works in the same pathway statins, but two steps up. The profile is slightly different. It's a pro-drug. As a pro-drug that needs to be activated into the active metabolite in the liver. The enzyme that does this is not present elsewhere, for example, in skeletal muscle, so you don't get the muscle-related side effects that potentially limit the use of statins. Ultimately, this is very similar to statins in terms of the pathway through which it's working.

Why do we do all of this? Well, people think it's to treat hypercholesterolemia, it isn't. It’s to treat risk, is to reduce the long-term risk of cardiovascular disease. Unless you think about global risk, you will never be able to really truly appreciate the benefit from any LDL lowering therapy. In these plots that I'm really very fond of, which on the vertical axis looks at the number of events prevented, number of events prevented depends on two things, how much you lower LDL-cholesterol in clinical trials, and the baseline risk. The higher the baseline risk, the greater the benefit from any level of LDL lowering. The people that benefit most are those at highest risk and in whom we achieve the greatest reduction in LDL.

Guidelines adopt an approach where you don't want to over-treat low risk, but you also don't want to under-treat high risk. We have risk-based goals that try to match levels of cholesterol LDL to the level of risk. For very high-risk patients we should be aiming for LDL below 55 milligrams per deciliter or 1.4 millimoles, irrespective of whether you've got established cardiovascular disease or you're a very high-risk primary prevention patient, however that is defined.

As a result of this approach, we need to start with statins, but statins have a limit. If you start with anybody with an LDL level above 2.8, for example, it's unlikely that even with the most potent statins at the highest doses, you'll achieve more than a 50% reduction in LDL and therefore, anything north of 2.8, you've got to start thinking about combination therapies to get to goal. That's an important message.

Now nature has already given us some answers. Nature has told us that if I basically mimic the drug targets, nature's randomized trials, and I standardize LDL differences over a lifetime do I achieve more or less with one or other approach? The answer is nature doesn't care. You achieve exactly the same benefit in terms of cardiovascular events if you basically look at the same period of follow-up, and the same amount of reduction in LDL.

What's so disappointing is despite all of this data when we look at implementation, this is data from SWEDEHEART, what you can see is we start patients on cholesterol-lowering therapy in the hospital, but if we look at what happens to them before they come in, 75% of patients come in roughly are statin naive. This means the day before, the month before, the year before nobody thought they were at risk of a heart attack so cholesterol-lowering treatment wasn't initiated. 50% of these patients have an LDL between 2.3 and 3.8. That's not hypercholesterolemia. Many doctors may actually not treat those people yet I've just shown you they've had a heart attack. 75% of these patients, they get cholesterol-lowering therapy for the first time, largely statin-based monotherapy, achieve an LDL between 1.8 and 1.9. About a quarter of patients that come into hospital are already on a statin and they are as you'd expect prior cardiovascular disease, high-risk conditions, but we don't change anything. If you don't change the LDL, what will happen to the outcomes? I can show you on the left-hand side that you have the highest risk of death, major cardiovascular events and myocardial infarction, so we've really got to move away to combination therapy.

Uptitrating statins as shown in the simulation study is not going to be enough. You only get another 6% lowering. It's really that use of combination therapy, early use of ezetimibe, and then PCSK9 lowering therapies that's going to change the population distribution, and get the whole of our population to goal.

Now to basically avoid this delay and clinical inertias, we came up with a strategy which was early use of combination therapies. Basically, once you've assessed risk and your patient is either a very high-risk patient or extremely high-risk patient, everybody should be on a statin and ezetimibe. Now in the very high-risk patient with two drug oral combination therapy, if you achieve a 50% reduction in LDL and an LDL below 1.4, you don't need to do anything else. For those that remain above 1.4, you can add in a PCSK9-directed therapy or an agent like bempedoic acid, but if you're an extreme risk patient, recent ACS, polyvascular disease, you probably should be thinking about early triple combination therapy with statins, ezetimibe and a PCSK9 directed therapy.

In conclusion, LDL lowering needs to become like blood pressure lowering. Think about early use of combination therapy, and that's really what's going to help us get to goal earlier. The aim is to increase the number of LDL receptors and keep them alive longer. Multiple therapies are now available with synergy that can help us achieve these goals. Now, all we have to do is put it into clinical practice. Thank you for listening.