The topic of my talk is exploring the role of icosapent ethyl in current clinical evidence. I will focus on the REDUCE-IT trial. This is my disclosure slide.

Well, we have a number of lipid-target therapies as you all know, and what should be added to statins in patients with very-high or high vascular risk. Well, of course we have the statin therapy. It's the base. We all know that if you can tolerate it, please take it if you are at high cardiovascular risk. On the other hand, of course we can even further reduce your LDL-cholesterol. The LDL-cholesterol can be lowered by, for instance, ezetimibe or PCSK9 inhibition. We could look at combined LDL-cholesterol HDL-cholesterol. We could try to elevate your HDL-cholesterol. None of them have been really successful, but we could also look, on the very right side at icosapent ethyl. This is a quite novel item.

It comes from the triglyceride discussion. Are triglycerides a real causal factor? And this is the balance between what is good for you? What are risk factors? And what are innocent bystanders? We always thought that HDL was the good guy and if it was too low it was the guilty guy and the triglycerides were the innocent bystanders but nowadays we think otherwise. The focus is back again at triglycerides.

And actually, this is corroborated by genetic evidence. This is triglyceride lowering lipoprotein lipase variants and LDL-cholesterol-lowering LDL-receptor variants, and they are all associated with similar lower risk of CHD per unit difference in ApoB. So, genetically, the lower your triglycerides are, the better your prognosis. This is very interesting because here, the influence of the environment is gone, this is only genes, so what you've got from birth on.

So we try to attack this, we try to do it with fibrates, was not a big success. We tried niacin not a big success, and then we went on to kind of fish all like things the EPA and DHA mixtures and they were tested in big trials like Origin and Omega and Ascend and Strength and none of them really hit the target. They were not bad, but they were not a good as we hoped they would be.

And then we had a novel kid on the block from the IPE the icosapent ethyl, and it had a beautiful cardiovascular outcome trial. Before we go to that we have the first evidence for IPE, that is JELIS trial and then we go to the REDUCE-IT and REDUCE-IT safety and tolerability.

This is the JELIS trial, which is a Japanese trial with IPE in Japanese hypercholesterolemic patients. As you can clearly see, over time the event curves are clearly in favor of the IPE. This is the whole study with the P-value of 0,001. In primary prevention cohort, the effect was less robust but in the secondary prevention, it was again significant, as you can see.

And then, of course the next step is a huge cardiovascular outcome trial. And this was presented and published in the New England Journal of Medicine as you can see here, by Deepak Bhatt.

And this is the REDUCE-IT study. It evaluated statin-treated patients so it's a background of statins with well-controlled LDL-cholesterol levels. And multiple cardiovascular risk factors. Over 8,000 patients were included. They were all at high risk for cardiovascular events, due to mild or moderate, triglyceride elevation. Plus, they had to have an established coronary vascular disease problem or diabetes and being over 50 years. They were subsequently randomised to or stable statin therapy plus IPE 4 grams a day or stable statin therapy with placebo.

Primary and key secondary endpoints you can see here. The primary endpoint was beautifully made, CV death, MI, stroke coronary revasc and unstable angina were clearly reduced by 25%. Absolute risk reduction of almost 5% and somewhat more stringent endpoint only CVD, MI and stroke was also reduced by 25-26%. So this is very clear support for the icosapent ethyl treatment group.

Then of course we looked at pre-specified hierarchical testing. Then you go from the top to the bottom. The primary composite, I just showed you, the key secondary output as I just showed you and then you go to the bottom and you see all these endpoints are clearly to the left of the line of unity. And even death from any cause was almost significant which I think is a major achievement. The rates of all endpoints up to death from any cause were significantly lower in the icosapent ethyl group than in the placebo group.

Well, do we have remaining questions then? What is the right patient? Who, when, why, what should we do?

And then of course you start by looking at subgroups. These are many subgroups. The lettering is quite small, but the idea is always the same. If you're old or young or man or female, it doesn't matter. In principle, all the point estimates are to the left side of the bar of unity.

Let's look at some specific groups then. This is, for instance, the patients with diabetes. It was one of the inclusion criteria, One of the enrichment criteria. So it's almost 5,000 patients. And as you can clearly see here that icosapent ethyl reduced the first as well as the total primary and secondary endpoints with 23 to almost 30%. So this is clearly an impressive result from this I think, quite unique trial with icosapent ethyl.

So, some other highlights, REDUCE-IT prior peripheral artery disease. It was just presented on the last AHA. Of course it was a virtual congress, presented by dr. Bhatt again. Here you see the patients without PAD and patients with PAD and you can,

of course, clearly see what you would expect. That the patients with PAD have a higher event rate. And then you look at the patients with PAD again and then you see that it's all, that the event rate is much higher and it's much more in favor of the active group. So here you can see what this compound actually does.

Are all questions then answered? Well, I think some interesting questions remain yet to be answered. First of all, we were, of course, looking to the triglyceride levels, the baseline. So you should have by definition, entry criterium, a somewhat higher baseline or somewhat more elevated baseline triglyceride but if we then looked if there was a difference in outcome for these patients it was independent of your baseline triglyceride. So if you had higher or lower triglycerides the relative risk reduction was always the same which is a very interesting observation. Only, if you look at the combination of a higher triglyceride combined with a somewhat lower HDL, then you can see that there was a significant term of interaction that the patients with elevated triglycerides and a low HDL were doing the best.

You could also see and look at what is then the baseline LDL-cholesterol level? Does it matter? Does it only help in patients with elevated LDL-cholesterol or only with severe low cholesterol levels? But as you can clearly see over here, to see benefit for the icosapent ethyl reported was the same independent of your baseline LDL quartile. Indicating that CV benefit associated with EPA was independent of the LDL-cholesterol levels.

Then the final word of course, always an important word safety and tolerability. The most frequently reported adverse reactions with the icosapent ethyl were bleeding 11.8%, peripheral edema, afib, constipation and musculoskeletal pain. Mostly were not different from placebo, but the bleeding actually was and we saw a slight, slightly more atrial fibrillation, atrial flutter. Nobody has an idea what caused this and it is perhaps also associate with the bleeding. If you were looking at this type of patient, of course, they have more anticoagulants, you see the results over here. I think the debate here is to be said. This is not a serious side effect, but it is noteworthy.

In conclusions, ladies and gentlemen, IPE actually interferes, it's just a general thought, with the cardiovascular disease continuum at multiple points to reduce the event. I think that is the baseline take-home message I would like to give you. So it's interfering with risk factors. It probably gives you a better endothelial function there's evidence for that. The amount of cholesterol crystals is influenced, there is less inflammation probably and there's also very beautiful evidence for that the membrane stability is improved.

Finally, you will then end up with less plaque instability and less ischemic events and less cardiovascular deaths by IPE. And this is also now reflected in the guidelines. This is the recommendation for the use of icosapent ethyl and it's clear that that's now on top on top of statins and on top of ezetimibe that it can be considered for your high risk patient. As you can see here, class two recommendations. Thank you very much for your attention and greetings from the Netherlands.

Do you prescribe icosapent ethyl to patients with residual CV risk based on the findings from REDUCE-IT?

• Yes
• No

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