The inescapable scientific (maybe not legal) conclusion after reviewing Mori data is that it taught NOTHING vis-a-vis EPA and LDL. There was some change (who knows which way--suggested slightly up by absolute number but could have been down, due to overlapping confidence intervals, an n=19 test set and inadequate statistical power). I have reviewed this with a prominent EPANOVA STRENGTH investigator and he feels the same in retrospect at the time of publication. The apoB effects of EPA are compelling to me (Kurabayashi misinterpratation notwithstanding) Irrespective of what you think of Mori, here are thoughts on EPA DHA and lipid effects worth reading:
There were a number of differences between STRENGTH and REDUCE-IT.... Putting...these differences aside, a couple of things are of interest. In REDUCE-IT, the beneficial effect of icosapent ethyl was statistically greater in the subgroup with low HDL (≤35 mg/dL) and higher triglycerides (≥ 200 mg/dL), but the baseline HDL level was not part of the inclusion criteria, as it was in STRENGTH. One might have predicted a greater chance for beneficial effects in STRENGTH, as the investigators selectively employed a low HDL/high triglyceride population.
However, there are differences in DHA vs. EPA. Both lower triglycerides and non-HDL, but DHA plus EPA raises LDL levels, especially in those with very high triglycerides and low HDL, whereas EPA doesn’t raise and may lower LDL. In fact, in patients with triglycerides 200 mg/dL to 500 mg/dL treated with statins, EPA lowers LDL by about 6%, which is similar to doubling the dose of a statin. Also, DHA plus EPA has varying effects on apolipoprotein B levels, but EPA has been shown to lower ApoB. And REDUCE-IT showed EPA lowered the inflammatory marker high-sensitivity C-reactive protein, whereas DHA plus EPA does not consistently affect CRP levels. There have also been mechanistic studies suggesting EPA may have membrane-stabilizing effects, whereas that may not be the case with compounds containing DHA plus EPA.
What we know is that EPA, when given in the form of icosapent ethyl to patients with diabetes older than 50 years with additional risk factors or to patients with established atherosclerotic CVD 45 years or older, reduces risk in patients with triglycerides 150 mg/dL (perhaps 135 mg/dL) to 499 mg/dL. In addition, the JELIS study from Japan used a different form of EPA (Epadel, Mochida) and showed benefit in patients who were not significantly triglyceridemic and had relatively high cholesterol.
It seems that EPA might be where the action is in terms of benefit. We all look forward to future studies that will explore the mechanisms for these differences.
How much of this is an anti-inflammatory effect? How much of this is a lipid-related effect? Are there other mechanisms at play? Does icosapent ethyl work in other populations?
A big question is, if you have a patient on maximally tolerated statins plus ezetimibe with mildly elevated triglyceride levels and an LDL level that is persistently mildly elevated, do you go to a PCSK9 inhibitor or EPA first? Both drugs are associated with favorable ASCVD outcomes, but comparative efficacy studies have not been performed.
At this time, we need to be cautious about using DHA-containing compounds and we should be moving toward using EPA in certain hypertriglyceridemic patients who are maximally treated with statins but still maintain high risk...."
Carl E. Orringer, MD, FNLA Associate Professor of Clinical Medicine University of Miami Miller School of Medicine Past President, National Lipid Association
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