There were a number of differences between STRENGTH and REDUCE-IT. STRENGTH had HDL enrollment criteria and REDUCE-IT did not. There were slightly different inclusion criteria for triglycerides: In REDUCE-IT, it was 150 mg/dL to 499 mg/dL, in STRENGTH it was 180 mg/dL to 499 mg/dL. REDUCE-IT had a mineral oil placebo, STRENGTH had a corn oil placebo.
Both studies had patients on what appeared to be good statin regimens. In REDUCE-IT, baseline LDL was 40 mg/dL to 100 mg/dL. In STRENGTH, baseline LDL was less than 100 mg/dL but could be greater than or equal to 100 mg/dL on maximally tolerated statin therapy.
Putting those 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.
The bottom line is that we did not know whether therapy with DHA plus EPA would provide similar, greater or lesser benefit on CV outcomes compared with those demonstrated with icosapent ethyl, a highly purified EPA product. The premature termination of STRENGTH for futility tells us that this formulation of marine omega-3 fatty acids was not effective in preventing these events. We do not know whether any of the above differences in the patient characteristics, study design or the biological characteristics of the two marine omega-3 fatty acid preparations explain the divergent outcomes.
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.
The role of diet and exercise in this context should also be explored further. There was no intense dietary intervention in REDUCE-IT. Perhaps if more careful attention is given to counseling on heart-healthy dietary and exercise habits, fewer patients might need icosapent ethyl.
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.
This was a very interesting and somewhat surprising result. This is why we do the studies.
Carl E. Orringer, MD, FNLA
Associate Professor of Clinical Medicine
University of Miami Miller School of Medicine
Past President, National Lipid Association
Disclosures: Orringer reports no relevant financial disclosures.