Hello. My name is Kausik Ray. I'm Professor of Public Health at Imperial College London and current President of the European Atherosclerosis Society. I want to talk to you today about the evolving need and challenges to reach LDL cholesterol targets, particularly in very high-risk patients. These are a list of my disclosures.

We often talk about how cardiovascular disease is the number one killer in the world. 80 million deaths from cardiovascular disease, most of which will be from atherosclerosis. Now, what we forget is that whole process of atherosclerosis starts in the first decade of life and progresses over time. It's really quite important to remember that this process is silent for the vast majority of people until you present with an acute event, for many, sadly. We need to consider this concept of time, because what this means is our approach to treating or thinking about risk in a 30-year-old is going to be very different than a 60-year-old. If you start to intervene in a 60-year-old, there's going to be much more atheroma that's present in the vessel wall, there are many missed years of opportunity compared to, let's say, starting earlier. When we think about how the cholesterol gets into the vessel wall, it gets there through three major lipoproteins. The commonest or the most likely source, the culprit, if you will, is the low-density lipoprotein particle, which carries most of the cholesterol cargo in the so-called ApoB-containing lipoproteins. There are people with obesity and diabetes who are insulin resistant, they overproduce triglycerides, principally carried in VLDL, very low-density lipoprotein, and they have high triglycerides. If you divide by 5 or 2.2 millimoles per liter, you could calculate the amount of cholesterol. Some people will have a contribution from that. Then there's a third particle, lipoprotein (a), which is an LDL-like particle with an extra part, that also carries cholesterol, which can get into the vessel wall.

If we think about starting early versus starting late and lifetime risk. This is what Brian Ference, a colleague of mine produced for the World Heart Federation Cholesterol Roadmap. What we can see on the left-hand side, for example, are two individuals, otherwise identical, separated at birth, if you will, by an LDL difference of 50%. Now, the person with the higher LDL cholesterol has a much higher lifetime risk compared to the dotted line. If that individual with the higher cholesterol interacts with healthcare at different stages of their life, we can actually get considerable gains. How much we get depends upon when we interact with them or when they approach us and we make a change. If we basically encounter that individual at age 60, then lowering their LDL by 50% will reduce, if you like, for the remainder of their life, their risk of cardiovascular disease by 27%. If we do that same intervention but now at age 50, that reduction is more like 37%. If we do that even earlier in the 30s or 40s, that gain is closer to 50%. Starting early gives you, if you like, a lower forward trajectory of risk. The earlier you start, the more the benefit from any intervention. On the right-hand side, we answer the question about, "Does it matter if I start at a different age? Do I need to achieve the same amount of LDL reduction?" The answer is no, because if you basically started at age 40 and lowered LDL by 33%, you'd actually reduce risk much, much more for the remainder of their life than starting later, age 55 and lowering LDL by 50%, so time clearly matters.

This means we have to have a conceptual framework shift. Start thinking about risk very early, think about lifetime risk because this really determines how aggressively you're going to want to treat. Second thing is risk is not dichotomous; high, low, but it's a continuum. We need to go past just looking at this particular time point, an individual time point, when we see a patient, and ask ourselves, "In a room of 100 men or women, for that same age, do they have more atheroma or less atheroma?" Because that's giving us the interplay between inherited genetic vulnerability to the world around us and how they've lived to date. The presence or absence of additional risk factors at that point gives us a trajectory into the future about future risk of cardiovascular disease also, which might guide how intensively you treat.

As our guidelines have moved towards lower cholesterol targets for those at highest risk, what we've forgotten to tell the world is those lower targets can only really be achieved with the use of combination therapy, that's how they came into effect. It was on a background of statins, add-on therapy was being added, whether that be ezetimibe or a PCSK9-directed therapy.

Do we have evidence that we need to change our approach? Yes, we do. We have two registries. One conducted between the 2016 and 2019 guidelines in Europe called DA VINCI, It answered the question about what was our approach to practicing lipid-lowering therapy. The answer is unlike hypertension, we use monotherapy, 84% statin-based monotherapy, combination therapy only in 10%. That basically meant that with the easier-to-achieve 2016 guidelines, one in two would get to goal, but as soon as you change the goalpost, only one in three gets to goal with that same approach. You can keep using the same approach and you're going to get the same result. When we look at the post-2019 guidelines and the first registry done, SANTORINI, larger than DA VINCI focusing on high and very high-risk patients, we see a small improvement in the use of combination therapy, but that's not enough because still only 20% of our patients are getting to goal. There are huge differences geographically, my own country uses very little in the way of combination therapy. UK, Ireland, Finland, 70% or more use monotherapy, but there are countries that are showing us the way Portugal, Spain, Italy, where use of combination therapy is much, much greater. If you look at this slide and you look at LDL cholesterol levels at the bottom and in orange the proportionate goal, what you can see is that with the use of combination therapy on the far right, this is when the greatest proportion of patients now achieve goal. We need to use appropriate dose of statins, but beyond that, for those lower goals, we need a second or a third agent.

When we look at SANTORINI, we concede that yes, its use of combination ezetimibe has gone up from 9% to 16%, mAb use as an add-on to statins or ezetimibe has gone up from 1% to 4.5%, but it's still really poor overall, 24% use of combination therapy. There are signs of hope. In the follow-up study of SANTORINI, where we looked at one-year follow-up to see if lipid lowering was improved, the answer is it does get better, but it's still not enough. We improved overall LDL goal attainment from 21% to 31% associated obviously with a lowering of LDL. We see a similar pattern whether you're in high or very high-risk groups because the additional optimization of statins and maybe a little bit use of combination therapy brings LDL down by about 0.4 millimoles per liter. It means that 0.4 millimole per lowering LDL at a population level gives us an extra 10% at goal, but that is still not going to be enough.

What we really have to do is ask ourselves the question, if we want to prevent atherosclerotic cardiovascular disease, the event, we've got to alter the trajectory and the problems in the vessel wall. Then that's very simple. It's cholesterol years. It's a number of years. If you start late, you need a bigger reduction. You start early, you need a smaller reduction. We've got to bring our healthcare systems and our patients and our physicians together because we've got to implement all of these things in a very simple way that is acceptable and that is affordable. The biggest challenge that we have and highlighted in the cholesterol roadmap is in addition to improving awareness, rolling out population-based approaches, reinforcing the need for assessment, and looking at quality measure outcomes, the biggest, the elephant in the room is implementation. We are very bad at implementing the basic things that we have available around the world. Really in summary, if you don't estimate risk properly, you're going to undertreat. We've seen that, for example, in SANTORINI. It's great to optimize the dose of statins, but when you double that dose of a statin, you're getting about another 6% further lowering. Actually, instead of when you're a long way away from goal just trying trial and error to double the dose of statins, why not think about optimizing with combination therapy? Because that second treatment is going to give you 25%, 30%, 40% additional lowering of LDL over and above what's achievable with statins. That really is where we need to move to for those at highest risk if we're going to improve population-level control. With that, I want to thank you for listening.

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