Welcome to this lecture on the continuum of the multifactorial benefits of icosapent ethyl. I'm Magnus Bäck. I'm Professor of Cardiology at the Karolinska Institute and University Hospital in Stockholm, Sweden. These are my disclosures of which I'm editor in chief of the European Heart Journal Open from which I will present some results today.
I will start with a little bit of a historical introduction. This is more than 60 years ago that the benefits of the marine dietary intake was discovered and has been kept all along, and even is part of the prevention guidelines that are the current guidelines of eating fish.
We also know that the beneficial effects are related to the content of fatty acids. Also here, I show very old findings just explaining why we call them omega-3. If you count the number of atoms until the first double bond, it will be omega-1, 2, and 3, and that's the omega-3 fatty acids.
Now, it's not only in fish that we can find omega-3, but also in some vegetable sources. What is important is that all this lipid metabolism is also regulated on a genetic level. Here we find some of the genetic variations have been discovered as risk variants for cardiovascular disease. For example, variations in the fatty acid desaturates, FADS 1. Looking on the benefits of omega-3 intake in relation to the genotype, we have shown that the beneficial genotype has less effect than the non-beneficial genotype in which the vascular stiffness can be reduced by a high omega-3 intake.
Then going from diet to omega-3 supplementation, as you know, there have been many studies looking on cardiovascular effects of omega-3 supplementation and the results are highly variable. The results I show here are the last meta-analysis that was done by us including the latest trials. The general conclusion is that there is an overall beneficial effect, but what is driving this beneficial effect are mainly two studies. I'll point out here the JELIS trial from 2007 and the more recent REDUCE-IT trial.
They have one thing in common and it's the choice of omega-3 supplementation being EPA and at a dose, which I will come back to. The results of the JELIS trial and then also the results of the REDUCE-IT trial using EPA in the formulation of icosapent ethyl, which by removal of an ethyl group becomes the omega-3 fatty acid EPA. The findings, also reduction of 25% in the cardiovascular outcome by EPA treatment.
Going further looking at the dose, we did a meta-regression and comparing the two different omega-3 fatty acids, EPA and DHA. As you can see here, the dosing is very important, so the higher the dose, the more beneficial effect, and that this also is a difference between EPA and DHA.
When it comes to these continuum multifactorial effects, I want to point out three main pathways. Effects on lipids but also on thrombosis and inflammation, which may be important for their effects.
Starting at lipid effects. This shows the principle of lowering triglycerides mainly through effects on hepatic secretion of triglyceride-rich lipoproteins.
Indeed, EPA in early trials showed to reduce the triglyceride levels, and that this is also dose-dependent, that a higher dose has a more pronounced effect.
There are also important differences between the different omega-3 fatty acids, where EPA has more beneficial effects on other lipoproteins, for example, not affecting LDL levels.
When it comes to the observed beneficial effects in the REDUCE-IT trial, there is indeed a reduction in the triglyceride levels, but that the reduction is less than the net effect on cardiovascular events. This implicates that there are also other mechanisms involved going beyond the triglyceride lowering.
Let's go back to this scheme and look at the different pathways that are possible. We spoke about the triglyceride lowering, but I want to remind you also of effects on the thrombotic pathways. This is due to substrate competition for forming the prothrombotic thromboxane. Arachidonic acid through the cyclooxygenase pathway will generate prothrombotic thromboxane, and this is a target for the aspirin treatment. When EPA is there, there is also here a competition so that the thromboxane which is generated is just a move of a double bond, which makes it biologically inactive. In contrast, the anti aggregatory prostacyclin is completely active, independent, if it comes from arachidonic acid or EPA, meaning that the balance will go in the beneficial way, tipping towards anti aggregation.
When it comes to being a substrate for forming lipid mediators, the omega-3 fatty acids can also play a role in lipid mediators of inflammation and forming lipid mediators of a resolution of inflammation. In the last part, I just want to remind you that indeed, atherosclerosis is a highly lipid-driven disease, but we also have inflammation and inflammation is a very important component in the progress of the atherosclerotic process.
The principle of its resolution is that an adequate immune response is induced, and that this will give the green light to the inflammation. When the immune response is no longer needed, there are stop signals turning this into a red light for the inflammatory response and healing and return to a normal state. The key here is the balance between the pro-inflammatory and pro-resolving mediators.
In, for example, the coronary arteries, there is a decisive step in terms of if it's net inflammation or net resolution. This evokes the resolution pharmacology, which can represent an alternative to anti-inflammation to put a stop to the cardiovascular inflammation and the atherosclerotic process.
Indeed, looking on biomarkers, it can be shown that in terms of the fatty acid metabolites, if we look on the balance between them and see which part is prevailing. If there is a prevailing pro-inflammation and a green light, there is a higher sign of subclinical disease, but if there is a prevailing pro resolvin response with the resolvins, which are products from omega-3 fatty acids, this is associated with less subclinical disease.
To summarize this, I would like to remind you of the three parts of the continuum of the multifactorial benefits of icosapent ethyl. This is triglyceride lowering, which is part of the beneficial effect, which most probably goes beyond this into being also antithrombotic by intervening in the thromboxane biosynthesis and the omega-3 fatty acids, including EPA, serves as precursors, as substrate for forming lipid mediators mediating a resolution of inflammation, being stop signals for the atherosclerotic inflammation. This evokes also the role of a resolution pharmacology to stop the atherosclerosis process. Finally, I also showed you results on genetic variations which may intervene in the metabolism of omega-3 fatty acids, which may lead to the perspective of future more personalized approaches for this treatment. With this, I would like to thank you very much for watching this presentation.
This lecture by Prof. Bäck was part of the EBAC-accredited symposium "New frontiers in ASCVD risk reduction: integrating icosapent ethyl in clinical practice" held during the ESC congress 2022.
Magnus Bäck is Professor of Cardiology in Stockholm, Sweden. He is the Director of Cardiovascular Research and Education at the Karolinska University Hospital and Head of Translational Cardiology at Karolinska Institutet.
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 Amarin.
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.
Omega-3 FA intake and supplementation 1:20
EPA clinical trials 2:54
3 pathways 4:55
Lipid effects 4:13
Anti-thrombotic effects 5:27
Resolution of inflammation 6:32
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