Recent evidence reviews have questioned the value of omega-3s to heart patients.

But in a major reversal, the results of a large, lengthy clinical trial vindicate their value for cardiovascular patients and folks with major risk factors — even those who take statin drugs.

The newly published five-year trial involved more than 8,000 people diagnosed with cardiovascular disease or who were at high risk for it.

And the trial's results vindicate the value of omega-3s, in resounding fashion:

  • 25% fewer cardiovascular deaths, heart attacks, and strokes.
  • Major reductions in stubbornly high blood triglyceride levels.

Before we examine the trial in more detail — see "Landmark clinical trial", below — let's quickly review the history of research into omega-3s and heart disease.

Background to the encouraging new findings
The benefits of omega-3s for heart patients receive their first robust support from two large clinical studies: the JELIS trial from Japan and the GISSI trial from Italy.

The findings from those trials and others prompted the American Heart Association to make these recommendations:

  • People without coronary heart disease: Enjoy two servings of fish per week.
  • Heart patients who need to lower their blood triglycerides: Take 2 to 4 gm of omega-3s daily.
  • Coronary heart disease patients: Consume 1,000 mg (1 gm) of omega-3s daily, preferably from fatty fish or fish oil supplements.
  • Heart patients taking more than 3 grams of omega-3s daily should do so under a physician's guidance.

As we said, the clinical evidence published since the JELIS and GISSI trials has been more mixed —probably due in some cases to lack of the funds needed to mount sufficiently large, lengthy trials.

Most recently, an evidence review conducted under the guidelines of the respected Cochrane Collaboration triggered negative headlines (Hooper L et al. 2018).

However, most reporters who covered the story probably weren’t equipped to judge the evidence review’s design or conclusions — we consulted a biochemist expert in omega-3 fatty acids and their use for heart disease.

Less forgivably, two of the three scientists whom the Cochrane group invited to comment couldn’t have read the review closely, because they failed to note the flaws of many of the included studies.

We published our own examination of the Cochrane review in Study Doubts Omega-3s’ Heart Health Benefits, which provides links to our analyses of prior, similarly flawed evidence reviews and media reports.

And, as we reported last year, two relatively recent evidence reviews came to positive conclusions: see Take Heart! Value of Omega-3s Vindicated, Again.

Sadly, those positive evidence reviews weren’t widely reported in the media — probably because good news doesn’t attract as many readers or revenue-generating clicks.

Landmark clinical trial vindicates the value of omega-3s for heart patients
The new trial was funded by Amarin Pharma Inc. and employed their proprietary omega-3 prescription “drug”, called Vascepa.

Vascepa is unusual in that it contains only EPA, which, along with DHA, is one of the two major omega-3s in fish oil.

DHA and EPA are both clearly beneficial for cardiovascular health, with DHA offering some benefits not produced by EPA, and vice versa.

Amarin’s rationale for using only EPA in Vascepa seems rather weak and may have as much or more to do with marketing as medical science — see “Why is Vascepa EPA-only?”, below.

Nonetheless, the outcomes of the trial provide welcome vindication of the cardiovascular-health value of seafood-source omega-3s.

In two earlier, much smaller clinical trials — called MARINE and ANCHOR — high doses (4 grams per day) of Vascepa-brand omega-3 EPA lowered triglyceride levels substantially in men and women with very high levels.

Those reductions in triglyceride levels simultaneous reduced the number of low-and high-density LDL-cholesterol particles, which is a known side-benefit of reducing blood triglyceride levels.

Vascepa-brand EPA also reduced markers of artery-damaging inflammation, which is a known benefit of both omega-3s: EPA and DHA.

The big news is that Amarin Pharma just announced the results of a much larger, longer randomized, double‐blind, placebo‐controlled study called REDUCE-IT, which stands for Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial.

Icosapent Ethyl is simply Amarin Pharma’s invented name for EPA in the ethyl ester form, which is the form used in many, though not all, supplemental fish oils.

The REDUCE-IT trial began in 2011 and involved 8,179 men and women who’d been diagnosed with cardiovascular disease or type-II (adult onset) diabetes, who were followed for an average of nearly five years.

Prospective participants with diabetes had to have at least one additional cardiovascular risk factor to be included in the trial.

And prospective participants also had to meet these criteria to be included in the trial:

  • Be taking a statin drug* daily.
  • LDL cholesterol levels between 41 and 100 mg/dL.
  • Display cardiovascular risk factors, including persistently high triglyceride levels (150-499 mg/dL)

*Anyone who wasn’t already taking statin drugs — which lower cholesterol levels and exert anti-inflammatory effects — began taking a daily statin drug.

The REDUCE-IT study had two major goals, achievement of which would determine the extent of the trial's success or failure:

  • Significantly lower participants’ blood triglyceride levels
  • Significantly reduce rates of death and adverse cardiovascular events (e.g., heart attacks).

After seven years, the trial achieved both goals by producing these striking benefits:

  • Major reductions in high blood triglyceride levels.
  • A 25% drop in cardiovascular deaths and adverse cardiovascular events, including non-fatal heart attack or stroke, coronary artery bypass surgery, and unstable angina requiring hospitalization.

These very positive outcomes show that an omega-3 trial that’s large and long enough — and provides sufficiently high doses — can produce very big benefits, even among people who are also taking a statin drug.

Unsurprisingly but importantly, equally small proportions of patients in the omega-3 and placebo groups experienced adverse side effects.

Why is Vascepa EPA-only?
The answer to this question may have more to do with marketing spin than medical science.

Amarin Pharma has said that it chose to produce an EPA-only omega-3 product because omega-3 DHA raises LDL cholesterol levels slightly — by about 3% on average.

However, that’s a small increase, and — importantly — the kind of LDL-cholesterol that DHA tends to raise slightly is the large, fluffy, significantly safer form.

The real risk of LDL-cholesterol comes from high levels of small, dense forms of LDL, which DHA helps lower.

In fact, omega-3 DHA provides distinct cardiovascular benefits* that EPA either hasn’t displayed or hasn’t displayed to the same extent:

  • Lowers dense, risky LDL cholesterol.
  • Higher, healthier levels of HDL cholesterol
  • Higher, healthier ratio of HDL to non-HDL cholesterol
  • Lowers blood triglycerides more than EPA (13.3% versus 11.9% in one trial)
  • Raises blood levels of “good” HDL cholesterol, versus a slight decrease from EPA-only treatment.
  • Increases the omega-3 index — a blood marker strongly linked to reduced risk of sudden heart-related death — more than EPA does. (An omega-3 index of 8% or more is highly protective; index levels below 4% are considered risky.)

*As shown in several clinical studies: von Schacky C 2014; Allaire J et al. 2016, 2017, 2018; and Sekikawa A et al. 2018.

Many observers suspect that Amarin Pharma chose to produce an EPA-only product in part to differentiate Vascepa from the only other prescription omega-3 product — called Lovaza — which contains both DHA and EPA.

Ethyl ester-form omega-3s vs. triglyceride-form omega-3s
Amarin Pharma's omega-3 drug Vascepa contains EPA in the ethyl ester form, which they call “icosapent ethyl”.

The two major types of omega-3 fatty acids in seafood, called DHA and EPA, usually occur in the triglyceride form.

Many — though not all — fish oil supplements deliver DHA and EPA in the ethyl ester form, and most laboratory and clinical studies have used ethyl ester DHA and EPA.

Ethyl-ester omega-3s aren’t quite as well absorbed as triglyceride omega-3s, but they typically cost less and are certainly more than adequate for use in clinical trials.

The chemical process of refining fish oils to remove contaminants results in conversion of DHA and EPA from the natural triglyceride form into the ethyl ester form.

Some brands of refined fish oil supplements — including Vital Choice — choose to reconvert the ethyl ester omega-3s back into their original triglyceride form, to ensure optimal absorption.


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