REDUCE-IT, 20192
- Who
- Adults on statins with heart disease, or diabetes plus risk factors, and raised triglycerides
- Dose
- 4 g/day icosapent ethyl (EPA ethyl ester)
- Follow-up
- 4.9 years (median)
25%lower risk of major cardiovascular events
PURO Ikosa-EPA Science Hub
What the science says about purified EPA
Large heart studies tested purified EPA and mixed EPA+DHA in people already taking statins. The results were not the same. Here is what the research found and how EPA works.
Why scientists studied EPA: the risk statins leave behind
Statins lower LDL cholesterol and prevent many heart attacks and strokes. Even so, people on statins can still have a heart attack or stroke. About 1 in 4 people with heart or artery disease have high triglycerides even when their LDL cholesterol is under control.1 Researchers wanted to know whether an omega-3 could lower this remaining risk.
The evidence
Purified EPA vs mixed EPA+DHA
Four large trials gave omega-3s to people already on statins and counted heart attacks, strokes and other major cardiovascular events. The two trials of purified EPA lowered risk. The two trials of mixed EPA+DHA did not.
Risk of major cardiovascular events
Omega-3 compared with placebo, in people on statins. Hazard ratio with 95% confidence interval.
How to read the chart
Square = the resultThe further left of the dashed line, the bigger the drop in risk.
Whole line on the left = real benefitFewer people had major cardiovascular events. This is purified EPA.
Line crosses the dashed line = no proven differenceThe trial could not show it worked better than placebo. This is mixed EPA+DHA.
Step 1 of 6
Two kinds of omega-3 were tested
Purified EPA
EPA ethyl ester on its own
Mixed EPA+DHA
Two omega-3s combined
EPA
DHA
Illustration only
Keep scrolling to see each trial appear on the chart.
Step 2 of 6
Purified EPA
Step 3 of 6
Purified EPA
JELIS, 20073
- Who
- Japanese adults with high cholesterol, on statins
- Dose
- 1.8 g/day EPA ethyl ester
- Follow-up
- 4.6 years (mean)
19%lower risk of heart attacks and related heart problems
Step 4 of 6
Mixed EPA+DHA
STRENGTH, 20204
- Who
- High-risk adults on statins with raised triglycerides and low HDL
- Dose
- 4 g/day omega-3 carboxylic acids (EPA+DHA)
- Follow-up
- 42 months (median), stopped early as no benefit was likely
No difference in major cardiovascular events
Step 5 of 6
Mixed EPA+DHA
OMEMI, 20215
- Who
- Adults aged 70–82 after a recent heart attack, 95% on statins
- Dose
- 1.8 g/day (930 mg EPA + 660 mg DHA)
- Follow-up
- 2 years
No difference in major cardiovascular events
Step 6 of 6
The pattern
Both purified EPA trials sit entirely inside the gold zone: lower risk of major cardiovascular events.
Both mixed EPA+DHA trials cross the "no difference" line: no proven benefit.
The results
What "25% lower risk" means
- 8,179adults
- 4.9 yrsmedian follow-up
- 100%on statins2
Placebo + statin
22 in 100 had a major cardiovascular event
Purified EPA + statin
17 in 100 had a major cardiovascular event
25%
Relative risk reduction
Compared with placebo, the risk of a major cardiovascular event was 25% lower (hazard ratio 0.75).
Lower risk was seen across individual outcomes in REDUCE-IT2
- 20%Cardiovascular death
- 31%Heart attack
- 28%Stroke
- 35%Urgent procedures to reopen arteries
- 32%Hospital stay for unstable angina
Relative reductions vs placebo. "Major cardiovascular events" here means: death from heart disease, heart attack, stroke, procedures to reopen arteries, or a hospital stay for unstable angina (worsening chest pain).
JELIS: the earlier result from Japan, at a lower dose
18,645 Japanese adults on statins took 1.8 g of purified EPA a day or no EPA. After 4.6 years, heart attacks and related heart problems occurred in 2.8% with EPA and 3.5% without, a 19% relative reduction.3
Why they differ
Why didn't mixed omega-3 work the same way?
Scientists are still studying this. These are the leading explanations in the published research, not settled facts.
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EPA and DHA are different molecules
They have different shapes and effects. In a head-to-head study, DHA raised LDL cholesterol by about 8%, while purified EPA did not raise it.6
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They behave differently in cell membranes
EPA sits straight and stable in the membrane and helps protect it from oxidation. DHA makes membranes more fluid and has less of this protective effect.6
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How much EPA reaches the blood
In REDUCE-IT, the EPA level reached in the blood appeared to matter for benefit. Mixed products deliver less EPA per gram, so blood levels may stay lower.6
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EPA helps switch off inflammation
The body turns EPA into compounds that help inflammation settle down once it has done its job. Mixed products supply less EPA for this pathway.6
How EPA works
Five ways EPA acts on your arteries
EPA does more than lower triglycerides. Research points to a network of effects inside the artery wall and the blood.9
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Lowers harmful blood fats
EPA reduces the triglyceride-rich particles that carry cholesterol into artery walls.
Triglycerides−21.5%VLDL cholesterol−24.4%Non-HDL cholesterol−13.6%Apolipoprotein B−9.3%ANCHOR, 4 g/day vs placebo, 12 weeks7
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Calms inflammation
Inflammation in the artery wall drives plaque growth. EPA lowered two inflammation markers.
hsCRP−22.0%Lp-PLA2−19.0%ANCHOR, 4 g/day vs placebo, 12 weeks7
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Steadies plaque and membranes
EPA settles into cell membranes and helps block oxidation of cholesterol particles. In a heart-scan study, plaque grew more slowly with EPA.
Total plaque growth, EPA15%Total plaque growth, placebo26% -
Supports the artery lining
EPA helps the inner lining make nitric oxide, which lets blood vessels relax and widen normally.
Laboratory and clinical studies9
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Makes platelets less sticky
EPA reduces platelet clumping and the clot-promoting signal thromboxane A2.
Laboratory and clinical studies9
Key takeawayLowering triglycerides alone does not fully explain the benefit seen in REDUCE-IT. Researchers think these effects work together, which may be why purified EPA lowered heart problems beyond what its triglyceride effect would predict.9
Safety
Safety and precautions
Purified EPA was generally well tolerated in the studies. These are the points to know before you start.
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Irregular heartbeat
In REDUCE-IT, slightly more people taking EPA were hospitalised for an irregular heartbeat (atrial fibrillation or flutter): 3.1% vs 2.1% on placebo.2 Tell your doctor or pharmacist if you have had an irregular heartbeat.
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Bleeding
Serious bleeding occurred in 2.7% with EPA vs 2.1% with placebo, a difference that was not statistically significant.2 If you take blood thinners or antiplatelet medicines such as aspirin or clopidogrel, check with your doctor or pharmacist first.
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Fish or shellfish allergy
EPA comes from fish oil. Use caution and speak to a pharmacist if you have a known fish or shellfish allergy.
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Keep taking your prescribed medicines
In the studies, EPA was taken together with statins, not instead of them. Do not stop or change any medicine without talking to your doctor.
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Ask before you start
Speak with your doctor or pharmacist before starting any supplement, especially if you have a heart condition or take other medicines.