The LDL challenge in high cardiovascular risk will be the implementation of already very good available medical therapies to lower LDL. We know that regardless of how it's achieved, the longer the lower LDL, the better it is. Furthermore, we have to expand possible benefits across the spectrum of cardiovascular disease.
These are my disclosures. Please, pay attention that I'm a member of the steering committee of the Dutch Guideline of Cardiovascular Risk Management. Available LDL lowering drugs, really potent, are the PCSK9 inhibitors. We have the PCSK9 inhibitors antibodies like evolocumab and alirocumab, but we also have the small interference RNA, inclisiran. Actually, PCSK9 regulates LDL receptor recycling, while PCSK9 inhibition upregulates the LDL receptors. The mechanism of loss of function of PCSK9 was the mechanism what actually causes a lot of benefits because of more LDL receptors. However, because of the size of the molecules, they're only available as injectables so far.
Like I said, we have three different PCSK9 inhibitors available, two antibodies, evolocumab and alirocumab, and one small interference RNA, inclisiran. The antibodies already showed significant cardiovascular risk reduction.
Here in the FOURIER trial, evolocumab studied in stable coronary artery disease, and alirocumab in the ODYSSEY OUTCOMES trial studied in patients after acute coronary syndrome. However, treating with expensive injectables leading to a pretty low absolute risk reduction and a pretty high number needed to treat can raise some questions. However, I want to emphasize that these studies are done in a patient population which already was treated with maximum tolerated high-intensity statin therapy. Furthermore, you have to take into account that the lower LDL for longer, so the earlier you start, the better it is.
All cardiovascular risk reduction graphs show a divergence in progress of treatment time, regardless of the therapy. Elegantly shown here in this graph in the FOURIER trial, where you see that the relative risk reduction increases over treatment time. Secondly, in the FOURIER open-label extension trial, where we followed patients another five years up to seven years, and the placebo group of the FOURIER study got evolocumab in comparison with already treated patients with evolocumab, you see that the loss of treatment of these two years never has been catched up.
Also, atheroma volume regression was already shown in the GLAGOV study after 76 weeks of treatment with evolocumab monthly. In the HUYGENS with evolocumab and PACMAN study with alirocumab, we saw already atheroma volume regression when started in less than 24 hours after PCI for acute coronary syndrome, showing, again, the proof of principle that the earlier you start to lower LDL aggressively, the better it is. In addition, I want to emphasize that the higher the cardiovascular risk, the more benefit and the less number needed to treat you need.
Like shown here, for example, with residual multivessel cardiovascular disease or number of prior myocardial infarctions, you see that the number needed to treat is lower when the cardiovascular risk is higher. Like Bonaca already showed in this FOURIER analysis with patients with peripheral artery disease. You see that patients with cardiovascular coronary artery disease and peripheral artery disease, the higher the risk, the more benefit of LDL lowering.
Despite the success of PCSK9 inhibition, they stay really expensive in comparison with other LDL-lowering therapies like ezetimibe, statins, but also the new bempedoic acid. However, the more use of PCSK9 inhibition, the less expensive they will become.
The advice is to start the fast first-time right with optimal guideline-directed medical therapy. For high-risk cardiovascular patients, start with at least a high-intensity statin, maybe already combined with ezetimibe and/or PCSK9 inhibition when the expected LDL lowering may be calculated with calculators like, for example, the lipid tools, shown LDL lowering will not be sufficient with only a high-intensity statin therapy.
In the Netherlands, we have already, I think, almost as first in the world in 2016 reimbursement for PCSK9 inhibition for patients if an LDL is not lower than 1.8 millimole per liters despite optimal oral LDL lowering with ezetimibe as obligation and familial hypercholesterolemia, a recardiovascular event, diabetes and a cardiovascular event or a cardiovascular event and statin intolerance. In the Netherlands, we noticed in the PENELOPE study in 23 hospitals that really strictly guideline-directed medical therapy made that with a high-intensity statin and ezetimibe, 89% of the patients after acute coronary syndrome reaches their goal of an LDL less than 1.8 millimoles per liter. The expensive PCSK9 inhibitors were only necessary in around 11% to get everybody below the LDL of 1.8 millimoles per liter. However, stopping this strictly guideline-directed medical therapy showed directly a decrease of LDL lowering. We need really a good guideline-directed medical therapy, but also continuously.
I want to conclude that we have to start with a good cardiovascular risk stratification for example, a U-Prevent calculator based on cardiovascular risk, treatment benefits, and patient's preferences and estimate LDL levels by certain LDL-lowering therapy with, for example, the calculator lipid tools. Secondly, I want to emphasize that we have to start optimal LDL lowering therapy immediately after a cardiovascular event, keeping in mind that the lower LDL for longer, so the earlier you start, the better it is, and that the higher the cardiovascular risk, the more benefit. In the Netherlands, we want to start a protocol like this, a study like this, the golden trial, where after acute coronary syndrome or revascularization, we really start optimal guideline-directed medical therapy at once, and start with diminishing the number of medication later on, instead of the way we are now doing, maybe not starting the right medication at once, but then up-titration period later on. Last, I want to conclude that we have to expand the benefits across the spectrum of cardiovascular disease, also for the use of PCSK9 inhibition if necessary. Not only for patients with coronary artery disease, but also for patients after a stroke or with peripheral artery disease. In the Netherlands, we were able, after a discussion of two years, to expand the reimbursement criteria from a really strict definition to a more broader way that PCSK9, at least antibodies, are reimbursed in the Netherlands if the LDL is still above 1.8 millimoles per liter despite optimal oral LDL lowering, without ezetimibe as obligation, and when there is still a very high cardiovascular risk according to the guideline. Of course, it's also available for FH patients.
A glimpse into the future, do not forget the possible PCSK9 inhibitor, like a small interference RNA inclisiran, where you can give once in the six months PCSK9 inhibition as a vaccination for population health, or that maybe we will get oral PCSK9 inhibition in the future.
Thank you.
This lecture by Fabrice Martens, MD, PhD was part of the EBAC-accredited symposium "The LDL-c challenge in high cardiovascular risk: Integrating innovative therapies in clinical management" held during the ESC congress 2023.
Prof. Fabrice Martens, MD, PhD is a cardiologist and full professor Preventive Cardiology at the Amsterdam UMC in The Netherlands.
This recording was independently developed under auspices of PACE-cme. The views expressed in this recording are those of the individual presenter and do not necessarily reflect the views of PACE-cme.
Funding for this educational program was provided by an unrestricted educational grant from Amgen, NewAmsterdam Pharma, Sanofi and Viatris.
The information and data provided in this program were updated and correct at the time of the program development, but may be subject to change.
CV-risk reduction with PCSK9i 01:43
The higher the CV risk, the more benefit 04:21
Conclusions and take home messages 08:02
Share this page with your colleagues and friends: