Omega-3 and Triglycerides: What the Trials Show

What each trial gave

REDUCE-IT randomized 8,179 adults who were on a statin, had fasting triglycerides between 135 and 499 mg/dL, and had established cardiovascular disease or diabetes plus one more risk factor. Half received 2 g of icosapent ethyl twice daily with food, which is 4 g per day of a purified EPA ethyl ester with no DHA in it. Half received placebo. Median follow-up ran 4.9 years, and the trial was funded by Amarin Pharma, the company that sells the product.

STRENGTH randomized 13,078 patients at high cardiovascular risk on statins with atherogenic dyslipidemia. Half got 4 g per day of an omega-3 carboxylic acid formulation supplying roughly 2.2 g of EPA and 0.8 g of DHA. Half got corn oil. Median follow-up ran 42 months, and the data monitoring committee recommended stopping on 8 January 2020 after 1,384 primary endpoints.

Same dose class, same background therapy, same kind of patient. One molecule apart.

How far triglycerides fell

In REDUCE-IT triglycerides fell 18.3% at one year, a median drop of 39.0 mg/dL, while the placebo group rose 2.2%. In STRENGTH they fell 19% against 0.9% on corn oil.

Those numbers sit almost on top of each other, which is the interesting part. Two formulations moved the same biomarker by the same magnitude, then went in opposite directions on events. REDUCE-IT's primary composite occurred in 17.2% of treated patients against 22.0% on placebo, hazard ratio 0.75 with a 95% confidence interval of 0.68 to 0.83. STRENGTH came in at 12.0% against 12.2%, hazard ratio 0.99 with an interval of 0.90 to 1.09.

Nobody has a settled explanation. The three candidates in circulation are the DHA content, the higher on-treatment EPA level reached in REDUCE-IT, and the placebo. Plasma EPA rose about 269% in STRENGTH against roughly 394% in REDUCE-IT. REDUCE-IT used mineral oil as placebo, and the placebo arm's LDL cholesterol climbed about 10% over the first year. Health Canada's review estimated mineral oil could account for up to roughly 10% of the observed relative risk reduction; the FDA's exploratory analysis put the ceiling near 3%. Both figures are published, and they don't agree.

The prescription dose and the capsule dose

4 g is 4,000 mg. The standard fish oil softgel sold over the counter lists 1,000 mg of fish oil on the front and about 300 mg of combined EPA and DHA on the Supplement Facts panel, most often as 180 mg of EPA plus 120 mg of DHA. Reaching 4,000 mg of EPA from that softgel means something in the order of 13 capsules a day, with DHA in every one.

Concentrated products carry more per capsule, and some list 300 mg of EPA plus 200 mg of DHA inside a 1,000 mg softgel. Labels vary that much, so read the panel.

There's a ceiling here too. The FDA has concluded that supplements providing no more than 5 g per day of combined EPA and DHA are safe when used as directed, and doses of 2 to 15 g per day of EPA or DHA may lengthen bleeding time. A 4 g prescription course runs under clinical supervision, which isn't the same as assembling 4 g out of retail bottles.

Neither trial tested an over-the-counter supplement. Both tested prescription formulations at prescription doses, in patients selected for high cardiovascular risk.

Where LDL cholesterol comes in

High dose omega-3 often nudges LDL cholesterol upward, and the direction depends on which fatty acid is in the capsule.

A review by Jacobson and colleagues pooled 22 randomized trials lasting at least four weeks. In the six comparing EPA with DHA head to head, DHA raised LDL cholesterol by 2.6% against control fat while EPA came in at minus 0.7%, a net gap of 3.3%. LDL cholesterol rose in 71% of the DHA-only groups and in none of the EPA-only groups.

In STRENGTH, LDL cholesterol finished about 1.2% above the corn oil group. In REDUCE-IT it finished about 6.6% below placebo, which is the mineral oil problem read from the other end.

A small rise in LDL cholesterol next to a large fall in triglycerides leaves a risk picture that neither number describes alone, and reading the two together is clinical work.

The safety signals at 4 g

Both trials found more atrial fibrillation. REDUCE-IT hospitalized 3.1% of treated patients for atrial fibrillation or flutter against 2.1% on placebo. STRENGTH reported a hazard ratio of 1.69 with a 95% interval of 1.29 to 2.21.

Serious bleeding occurred in 2.7% of the icosapent ethyl group against 2.1% on placebo in REDUCE-IT, a gap that didn't reach significance. STRENGTH recorded gastrointestinal adverse events in 24.7% of treated patients against 14.7% on corn oil.

Two large trials now point the same direction on atrial fibrillation at this dose, and that holds whether or not the cardiovascular benefit turns out to be real.

Frequently asked questions

Does fish oil lower triglycerides?

Yes, and the trials agree on that part. The disagreement starts after the numbers come down. Prescription doses brought triglycerides down roughly 18 to 19%, and the two formulations still produced very different results on cardiovascular events.

Can I reach the trial dose with supplements?

A 4 g dose works out to about 13 standard 1,000 mg softgels a day when each supplies 300 mg of combined EPA and DHA, and the mixture carries DHA. The FDA's guidance is not to exceed 5 g per day from supplements. Nobody has tested whether matching a prescription regimen with retail capsules does anything.

Why did one trial succeed and the other fail?

Three explanations have published support: the DHA content, the higher blood EPA level reached with 4 g of purified EPA, and the mineral oil placebo. No trial has been designed to separate them.

Does omega-3 raise LDL cholesterol?

DHA does, by a small margin, roughly 2 to 3% in pooled trial data. Purified EPA hasn't shown that in the same analyses.

What should I do about a high triglyceride number?

That's a conversation with whoever manages your lipid therapy, and it starts with the full panel rather than one line on it.

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This article is for general information only and does not constitute medical advice. Statements about dietary supplements have not been evaluated by the Food and Drug Administration and are not intended to diagnose, treat, cure, or prevent any disease. Talk with your health care provider before using omega-3 supplements, especially if you take prescription medication.

Sources

• Bhatt DL et al., Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia, NEJM 2019
• Nicholls SJ et al., Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil (STRENGTH), JAMA 2020
• Jacobson TA et al., Effects of EPA and DHA on LDL cholesterol and other lipids: a review, J Clin Lipidol 2012
• NIH Office of Dietary Supplements, Omega-3 Fatty Acids Fact Sheet for Health Professionals
• Health Canada, Regulatory Decision Summary for icosapent ethyl, 2019
• NIH Dietary Supplement Label Database, fish oil softgel label, 180 mg EPA plus 120 mg DHA