Hello, my name is Maciej Banach. I'm a professor of preventive cardiology and lipidology from the Medical University of Lodz and the president of the International Lipid Expert Panel. I have a great pleasure to say a few words about the new ILEP guidance on the bempedoic acid management in lipid disorders and cardiovascular risk. The paper we published two days after the release of the CLEAR Outcome study, which was presented for the first time and published at the same time in New England Journal of Medicine on the 4th of March during the Congress of the American College of Cardiology. This is my conflict of interest.

You know it very well that we have been waiting for the results of the CLEAR Outcomes study and you know the mechanism of action of bempedoic acid. The bempedoic acid works in the same pathway of cholesterol metabolism. We might have assumed from the very beginning that there will be a synergistic effect with statins. We know it very well that the bempedoic acid targets ATP citrate lyase, the enzyme upstream of HMG-CoA. What is more, we know it very well that is a prodrug in muscles. From the very beginning, we knew that it is a very safe drug in relation to statin-associated muscle symptoms simply. It is going to be active only in hepatocytes.

What we knew from the phase III trials, we knew that it is a very effective drug in the reduction of the LDL cholesterol because the reduction was between 17% to 25.7%. We also noticed something which was very important for us because it is something that it might be considered as a similar to statin pleiotropic effect because we've noticed that bempedoic acid has a potential also, especially in those patients with baseline level of hsCRP over 2 to reduce this inflammation biomarker. We know that it might help us to be on the target and to reduce the risk of inflammation related residual cardiovascular risk. We have had also data that suggested that this reduction potential of LDL cholesterol might be even further and larger, taking into account that, within the fixed-dose combination of bempedoic acid and ezetimibe, it might reduce LDL cholesterol by 40%.

In our meta-analysis published based on phase III data, we also notice that it's a well-tolerated drug because obviously there was some discontinuation. There was a slight increase of serum uric acid, so we knew that we need to monitor those patients, especially with chronic kidney disease. We also noticed that it might be protective against new onset diabetes, something we sometimes observe in patients on especially high intensity statin therapy.

What we've noticed based on the CLEAR Outcomes, which was also part of our ILEP recommendations. If we look at the baseline characteristics, please notice that in fact they were very elderly patients. The mean age is 65. They were also patients with a high baseline level of LDL cholesterol, 139. Many of those patients were with overweight and obese. Many of those patients were at hsCRP category over 2 milligram per liter. What is more, we have a lot of patients with chronic kidney disease below 60 of the GFR. What is critically important, they were also patients for the first time in primary prevention. There were a lot of patients with no diabetes, normal glycemia and prediabetes. In those patients, we could have observed whether this protective effect of bempedoic acid is real and it really works. If we look at those patients and the therapies, it is also so important because almost 23% of those patients were on the lowest doses of statin. In fact, the dose was below the doses we usually have. For example, lower than 5 milligram of rosuvastatin per day.

What we've noticed, we've noticed maintained significant reduction of the LDL cholesterol by 21.1%. It was about 30 milligrams per deciliter of absolute reduction, significant 22% reduction of hsCRP. This reduction of LDL cholesterol was associated with this significant 13% reduction of primary endpoint of four-component MACE, which was associated also with a significant fatal and non-fatal MI by 23%, and coronary revascularization of 19%.

The results were really encouraging and that is why, in the group of experts, as I mentioned at the very beginning, we decided that it is critical for the practitioners, critical for the physicians to have very clear information what patients might benefit the most and how to use bempedoic acid in lipid-lowering management. That is why we presented, first of all, what kind of reduction of the LDL cholesterol, what level of reduction of LDL cholesterol we might expect having bempedoic acid in monotherapy as it was in the CLEAR Outcomes study in patients in statin-naïve as well as on top of statins. The same for fixed dose combination of ezetimibe and bempedoic acid with even over 30% reduction, as well as with different combination based on the data we have had, as you can see, including also four drug lipid-lowering combination therapy with expected level of reduction of LDL cholesterol over 85%. What is more, we also presented something which is critical important. If you have your patients with a typical, with a suggested or indicated here level of LDL cholesterol and you know what is the expected reduction level in order to be on the target for very high risk patients, please notice that, in fact, you can use this table in order to know what kind of combination including bempedoic acid you should use in order to be on the target.

Okay, let's focus on the recommendation. In the phase III trials, as well as in the CLEAR Outcomes, which was the first study in patients, randomized controlled trial intervention, randomized controlled trials in statin-intolerant patients when high and very high risk patients were included, including also those with atherosclerotic cardiovascular disease, we know it very well that these patients will benefit the most from bempedoic acid.

Please have a look at some general recommendations we put in our paper. When initiating, bempedoic acid should be used as a part of the treatment strategy design considering the patient's base LDL cholesterol level. Something I have just showed you in both tables. Bempedoic acid should be preferable used as a fixed dose combination with ezetimibe. It is very important because we know the approach the lower the better, the earlier the better, the longer the better. Having the drug, fixed-dose combination with the potential reduction of LDL cholesterol, even over 40% it is so important to use this option for our patients. Finally, beyond statin therapy and ezetimibe, bempedoic acid should be used in combination with PCSK9-targeted therapy approach where it is necessary to achieve very large reduction. I also has just showed you, however, due to the fact that we do not have such data, the level of recommendation is IIa-C so it is rather expert-based recommendation.

Okay, so let's move it further. What about the patients that might benefit the most? We knew, based on the CLEAR Outcomes and phase III trials, that we have no doubt that patients with atherosclerotic cardiovascular disease, patients with FH as well as patients who were statin intolerant should be recommended to use bempedoic acid. That is why-- Please notice that, for those groups of patients, we have A, I level of recommendation. What is more, we discussed it very extensively, but also the CLEAR Outcomes as well as phase III trials, give us the information about partial statin intolerance because you remember that in phase III trials, we had also patients at low doses of statins and it was here the same. Fortunately we had also patients with a very low, lower than usually applied doses of statins that were used for those patients. That is why we do not have any doubt that also in partial statin intolerance, combination therapy withbempedoic acid is recommended in combination with maximal tolerated statin and other non-statin agents to enable patients to reach therapeutic goals.

How to proceed with the statin intolerant patients? Here we adapted the recommendation we published previously as a ILEP recommendation in those patients with statin intolerance and nocebo, placebo effects, so you can follow them step by step in order to achieve the LDL target in this very challenging group of patients. What is in summary? If we have atherosclerotic cardiovascular disease patients and heterozygous FH patients with the baseline level of LDL cholesterol between 110 and 160, it should always start with the upfront combination therapy of statin-ezetimibe. Then, if you are still over the target, you should add bempedoic acid and then you should add PCSK9 targeted therapy in this order because then we have a finally possibility to be on the target without very effective, very innovative, but still very expensive and limited due to the reimbursement criteria, PCSK9 targeted therapy. In those patients, especially with heterozygous FH and level of LDL cholesterol over 160, we should start with the triple upfront combination therapy. With high intensity statin therapy and fixed dose combination of bempedoic acid and ezetimibe. Only then if we are still over the target with the expected level of reduction of the LDL cholesterol, 75%, we should add the PCSK9 inhibitors. Finally, in those patients with statin intolerance with the partial as well as complete statin intolerance, we should always start with upfront combination therapy of bempedoic acid and ezetimibe, and if we are still over the target to use PCSK9 targeted approach.

What is more, based on the data from the phase III trials, we knew that in patients with diabetes, with prediabetes, especially in those, the bempedoic acid might be very effective, not only to reduce LDL cholesterol, but also to help to optimize the treatment of diabetes because it might reduce hemoglobin A1C, especially in those patients with diabetes and prediabetes. Based on our paper published in Diabetes Obesity Metabolism, based on the pooled data from phase III trials, we know it very well that it helps to have significantly more patients on the hemoglobin A1C below 6.5%.

In fact, that is why by the end of 2022, we also published the recommendation that in those patients with metabolic disturbances, we should always try to consider bempedoic acid because it is very effective, not only to reduce LDL cholesterol but also to help those patients with metabolic disturbances, including prediabetes and diabetes, to be also on the target taking into account the glucose level as well as the hemoglobin A1C.

In fact, if we look at the results of the CLEAR Outcomes, and we were a little bit surprised because from one hand there was a numerical 5% reduction of the risk of new onset diabetes and about up to 1% absolute reduction of the risk, especially in those, in comparison to that they were a normal glycemic and with prediabetes at baseline, but the results were not as significant as they were in the phase III trials. That is why this issue still needs to be confirmed and investigated. One message is critically important, bempedoic acid does not increase the risk of new onset diabetes, and still, I strongly believe might be very helpful in order to optimize the treatment of diabetes. That is why we said in the recommendation to IIb, B level, that bempedoic acid may be considered in patients at the high and very high cardiovascular risk with prediabetes and diabetes to reduce the risk of new onset diabetes and improve glycemia. It is the same with obviously hsCRP because, in phase III trials, we noticed even over 40% reduction. In CLEAR Outcomes, it was over 20%, but it's still significant. That is why we also suggested that bempedoic acid may be considered in patients at high and very high cardiovascular risk with elevated levels of hsCRP. Finally, it is so important to remember and to emphasize that due to the fact that we have 30% of primary prevention patients, in which we also observe significant effect of bempedoic acid to reduce cardiovascular outcomes. Obviously, taking into account the data, taking into account the numbers, and it was not powered enough to be conclusive. That why we still need more data. It is completely enough to say that, in primary prevention patients at high and very high cardiovascular risk, despite optimal maximal tolerated doses of statins and ezetimibe are not on the LDL cholesterol target, bempedoic acid might be considered with IIb, B level of recommendation.

Finally, the safety. I don't want to focus on it much because in fact the results of the CLEAR Outcomes only confirmed the data from the phase III trials. We obviously should be a little bit careful in those patients with the history of gout. We should monitor those patients with chronic kidney disease. In fact, if we look at those data, bempedoic acid is really well-tolerated and very safe drug. That is why I strongly believe it will be a very important part of the lipid-lowering management. Thank you very much.

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