Potential mechanisms of benefit of icosapent ethyl

My thanks to the organizers for this opportunity, to share some thoughts on the potential mechanisms of benefit of icosapent ethyl as seen in the REDUCE-IT trial.

These are my disclosures.

Let's take some insight from REDUCE-IT and STRENGTH trials to gain some possible mechanistic pathways. The first thing to note in this subgroup analysis from REDUCE-IT is that the relative risk reduction was not linked to the baseline triglyceride level or to the change in triglyceride level on the active drug EPA. The investigators were able to show that the relative risk reduction was increased according to the achieved EPA level within the trial. However, when investigators from STRENGTH undertook the same analysis, looking at individuals with a high achieved EPA level that in the REDUCE-IT trial give rise to a substantial risk reduction. They found no benefit at all and it's possible that DHA co-administration offset the EPA benefit within the STRENGTH trial.

It's been known for a number of years that oily fish intake is associated with the lower cardiovascular risk, that the active ingredients are the omega-3 fatty acids, and they have multiple effects on pure metabolism and the atherogenic process. The key features I would like to focus on in the next few slides are the action on lipoprotein assembly and secretion in the liver and intestine, alterations in the plasma lipid profile in remnant lipoproteins LDL and HDL, potential anti-inflammatory effects of EPA and antithrombotic effects in the artery wall, then perturbations in cell membrane cholesterol metabolism.

So, let's take those in turn.

It's been known for many years through metabolic investigations, that high doses of EPA and DHA decrease the production of large triglyceride-rich VLDL from the liver and chylomicrons from the intestine following a fat meal. The net effect is the reduction in postprandial alimentary lipemia and a reduction in the level of apoB containing VLDL particles and their remnants in the circulation and apoB-48 containing chylomicrons and their remnants in the circulation. However, we should remember that REDUCE-IT and STRENGTH both recruited hypertriglyceridemia individuals with approximately the same baseline triglyceride level and the change in triglyceride driven by this change in synthesis was pretty much the same in both trials. So, this can't explain the differential benefit that was seen.

If you look now at the plasma lipoproteins. we can see the major changes were seen in chylomicron VLDL remnants with smaller changes in LDL and HDL.

Looking at the MARINE and ANCHOR studies done with IPE, we can see a reduction in the largest VLDL particles of about 42% and remnant RLP Cholesterol fell by 25-30%. Omega-3 fatty acids give rise to small changes in LDL and HDL or a small increase is possible, and in our studies DHA seems to do that more than EPA in terms of an increase in LDL cholesterol. However, looking at the trials again in REDUCE-IT and STRENGTH the major lipid indicators non HDL cholesterol, LDL and HDL were changed by small amounts within the active group treatment groups, and there was no difference between the two trials. One possibility is that EPA versus DHA has a differential effect on the quality of the remnants rather than their quantity. And these remnants are highly atherogenic with a high cholesterol to apo-B ratio, decrease particle fluidity, and partial lipolysis products from the lipolytic reaction and possibly these were different in the two treatment regimens.

Looking now at the potential for chronic inflammation to be important. We see that EPA and DHA have both pro and anti-inflammatory actions. An increase in the EPA to arachidonic acid ratio generates anti-inflammatory mediators such as resolvins and they may have beneficial effects on endothelial dysfunction, and inflammation seen in the artery wall. And experiments have shown that particle oxidation of remnants, or LDL particles can be interrupted by EPA to a great extent with DHA, and therefore there is an oxidation benefit in terms of EPA ingestion. So, what's happening in the artery wall? It might be that EPA as opposed to DHA is giving rise to benefit through multiple mechanisms, reduced endothelial dysfunction, reduced oxidation potential of lipoproteins and therefore reduced macrophage cholesterol accumulation. But in REDUCE-IT, while there was a drop in CRP on the active treatment there was no interaction between Baseline CRP and relative risk reduction, which would be expected if it had been a strong anti-inflammatory action that drove the benefit and in STRENGH, there was no change in CRP.

Looking at thrombotic mechanisms, we know that high intakes of omega-3 fatty acids are associated with increased bleeding times and reduced thrombogenic potential. So when a plaque ruptures then the formation of the clot is important in occluding the artery, and then maybe a less potential for that occur with high EPA consumption as shown here.

However, REDUCE-IT showed no difference in bleeding adverse events in the two treatment groups and STRENGH was the same. There was no difference in hemorhagic stroke and no difference in stent thrombosis. So, no strong indicators that thrombosis or reduction in thrombosis played a strong impact on risk reduction in these trials.

One potential mechanism that's come to light recently through the work of Mason et al. is in model systems it's been shown that EPA stabilizes cholesterol within cell membranes, in a way that DHA does not because of their different physical structures. EPA seems to be able to stop cholesterol domains micro domains forming cholesterol rafts don't form and these are the starting points for cholesterol crystallization within cells that can be damaging and toxic.

So if we look at the atherogenic sequence that leads from macrophages to foam cell formation with a high cholesterol ester content in droplets and a high free cholesterol content, the next step in atherogenesis, which is critical, is the formation of necrotic cells and a necrotic core in the plaque and it's been shown that if there's an inability to accommodate excess free cholesterol then necrosis will ensue, will be released of free cholesterol the formation of cholesterol crystals and an increase in low attenuation plaque.

On the other hand possibly using EPA, if there is stabilization of the cholesterol within the membranes that improved macrophage survival might lead to regression and decrease low attenuation plaque as was seen in the evaporate trial with IPE.

So, we have a number of potential mechanisms, whereby IPE can change the course of atherogenesis whether it's through the quality and quantity of remnant lipoproteins, lipid oxidation inflammatory function, endothelial dysfunction or changes in cell cholesterol metabolism macrophage viability, or thrombosis. They could all lead to a less or greater extend to the risk reduction that was seen within the REDUCE-IT trial.

Thank you for your attention.