• Islon Woolf MD

A new fish oil works but shoots itself in the foot

The REDUCE-IT trial concluded this week and returned results in favor of fish oil. It was a randomized placebo controlled trial following 8,000 patients for five years with high cardiac risk and high triglycerides. Those taking fish oil had a whopping 25% reduction in cardiovascular events. It was sponsored by the pharmaceutical company Amarin to test their proprietary fish oil Vascepa. These results are impressive - are they likely to be true?

First, await peer review and publication

After a study is completed, it must be submitted to a journal for peer review and publication. The REDUCE-IT trial has not yet been through this process. Peer review is the most important step in the scientific method. This is where evidence is subjected to critical review from a panel of unbiased peers. The panel is often privileged with data not accessible to the public and looks for oversights, manipulations, and confabulations that may skew the final results. When the paper is finally published, journals invite scientists with opposing views to submit editorials and rebuttals. Journal reputations are staked on their objectivity in this process. The ultimate scar on a journal is the retraction of a fraudulent paper it decided to publish. (there are websites that monitor these retractions)

Medical science is based on the ‘survival of the fittest idea’. Everything must be challenged. Only those that survive running the gauntlet of its peers are worthy of consideration. Please await peer review and publication of this study before rendering judgement.

Consider the results of similar trials

There are mixed results in the scientific literature with respect to fish oil. Some studies showing reductions in cardiac risk and others that do not. The overall impression, however, is that fish oil fails to reduce cardiovascular events. A meta-analysis of the ten best quality trials showed no cardiovascular reduction with fish oil. Recently, the ASCEND trial was published and also showed no benefit of fish oil in 15,000 diabetics. Adding these numbers to the prior meta-analysis would return even more strongly negative results.

Why did Vascepa work and the others did not?

Most fish oil, including over-the-counter preparations and prescription Lovaza, contain a combination of two different omega-3’s - DHA and EPA. Vascepa is almost pure EPA. The one discernible difference between DHA and EPA is that DHA raises bad cholesterol (LDL) levels. EPA does not. This is what prompted Amarin to create a pure EPA product.

In addition, Vascepa is different because of its dosing. It is prescribed at a very high dose - 4,000 mg per day. The typical dose of fish oil for cardiovascular protection is 1,000 mg per day. Translating 4,000 mg of EPA into fish consumption, one would have to eat nearly 40 cans of tuna daily to achieve the same dose. Hence, it is appropriate to call the Vascepa dose supraphysiologic - unattainable naturally, even with a pure fish diet.

Shooting oneself in the foot

If Amarin is correct, and cardiac prevention can only be achieved with pure EPA at supraphysiologic doses, how can we explain the observed cardiac prevention seen in fish eaters? The reason we got excited about fish oil in the first place was the dramatic evidence from observational studies. Populations consuming as little as 1-2 servings of fish per week had a 36% decreased incidence in heart disease. Amarin must concede that this observational evidence cannot be true. Fish eaters can’t possibly get enough EPA to make a difference; not to mention the deleterious effects of the DHA they consume. The hypothesis has essentially shot itself in the foot - refuting one of its premises.

In logic, when an idea shoots itself in the foot it is known as a self-refuting idea. An idea that denies its premise. Another example of a self-refuting idea involving supraphysiologic dose comes from the supplement Reseveratrol. Resveratrol, found in red wine, was hypothesized to be the active ingredient responsible for red wine’s health benefits. Yet, the dosage of Resveratrol needed for even a small effect was enormous. In fact, one would have to drink a few hundred glasses of wine a day to achieve the same levels of Resveratrol as one pill. Unsurprisingly, the initial positive studies were shown to be fraudulent and could not be replicated in larger trials. Eventually the hypothesis was abandoned.

Higher doses require new safety testing

Most of our experience with fish oil supplementation is in the 1000 mg per day range. Potential concerns at this dose include: bleeding, cancer, and contaminants (PCB’s). Higher doses further increase the likelihood of side effects. Thus, we need to determine the long term safety of 4000 mg of EPA.

As illustrated in my last email on Aspirin, determining safety is especially important for primary prevention. The REDUCE-IT trial recruited high cardiac risk patients on statins with high triglycerides, not healthy patients. Even if the results of the trial are true, we must resist the temptation of extrapolating the results to the healthy. The benefit to harm ratio is different. Healthy patients benefit less and consequently rare side effects become unacceptable.


Either EPA, along with other fish oils, does not work, and this single pharmaceutical-sponsored clinical trial achieved statistical significance by misconduct


Only supraphysiologic doses of EPA work, refuting the observational evidence that started the fish oil hypothesis in the first place

This is an inditement of one type of evidence versus another. Clinical trials versus observational evidence. Either clinical trials are rigged and biased, or observational evidence is unreliable. I don’t know the answer.

We should first await peer review and publication. If the study passes peer review unscathed, we should take the hypothesis seriously. We should try replicate the results in another trial - hopeful by an unbiased party. Large long term studies should be conducted in healthy persons before use in primary prevention. And finally, we should await the results of other fish oil trials. There are several in progress testing other products, populations, and dosages.

For now, I agree with the American Heart Association recommendations. Try to get omega 3’s from your diet. Eat fish. If you are healthy and cannot eat fish that’s okay. If you have considerable cardiac risk and cannot eat fish, consider a fish oil supplement. Prescription fish oil is preferred even if your insurance will not cover it. Prescription fish oils are regulated, regularly audited, and quality controlled. Avoid over-the-counter preparations. They have been shown to be impure and oxidized.

#supplements #clinicaltrial #supraphysiologicdose #selfrefutingidea #peerreview #primaryprevention

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