Omega-3 fatty acid supplements failed to lower risk for major CVD events

Michael H. Davidson, MD

The recent meta-analysis in JAMA provides little new information regarding the benefits of omega-3 fatty acids for the prevention of CV events. The conventional explanations for the disparate results between the positive earlier trials (GISSI and JELIS) and the negative later trials (Alpha-Omega and ORIGIN) have been improvements in risk-modifying strategies such as statins and aspirin. However, a much more likely explanation is that a 1-g dose of ethyl ester omega-3s are ineffective in reducing CV events in a population with a high consumption of omega-6 fatty acids, and this dose is also inadequate to effectively lower triglycerides. The only trial to evaluate the correlation of on-treatment omega-3 levels and CV benefit was the JELIS trial, which was conducted in Japan. In this high-risk population taking statins, on-treatment EPA levels correlated with the benefit, and although the triglyceride lowering was only 6% on the 2-g dose in the subset of patients with high triglycerides the relative risk reduction was 55% (compared with 19% overall). One gram of ethyl ester omega-3 administered to a patient in the United States or Western Europe, where the failed trials were conducted, will only increase the omega-3 levels to about one-fourth of the baseline levels in the Japanese patients in the JELIS trial. In Italy, where both GISSI trials were positive with a 1-g dose, the background diet is low in omega-6 fatty acids and high in omega-3 consumption. Therefore, the dose in the failed trials was far too low to achieve a therapeutic effect of either triglyceride reduction or inhibiting the production of arachodonic acid, which is linked to the antiplatelet and anti-inflammatory effects of omega-3s.

The bottom line is that omega-3s in high doses (at least 4 g of ethyl esters) are effective for lowering triglycerides, and in populations with a low intake of omega-3 fatty acids only 1 gram per day is not likely to achieve a significant benefit. Higher-dose omega-3 studies are underway that are far more likely to demonstrate a clinical benefit especially in patients with hypertriglyceridemia.

William P. Castelli, MD

There is no ‘magic bullet’ when it comes to supplements. Most patients do not want to, or cannot, give up the American diet, which is the worst possible diet to eat anywhere in the world. They think that by taking a supplement, they can eat whatever they want, but that is not the case.

The guidelines encourage consumption of fish two to three times per week. I think the minimum should be three to four, given all the health benefits. I always remember Ancel Keys, one of the most important researchers on diet, who taught us the dangers of eating too much saturated fat, cholesterol and refined carbohydrates. Whenever I saw Ancel at the heart meetings, he was eating a can of sardines. He died just a few years ago at 100 years old.

What we do see in this study, however, is that increased levels of omega-3s lowered total deaths from CVD. In my opinion, this study has some key gaps. For example:

1. Duration of the studies. Eleven of the 20 studies included in the meta-analysis were conducted over 1 to 2 years; that’s simply too short a timeframe to draw any conclusions regarding any true clinical outcomes.
2. Dose of the drugs. Fourteen of the 20 trials in this analysis had too low a dose of the fish oils. In the Physicians Health Study, researchers measured the EPA+DHA levels in the blood, and if participants were in the lowest quartile of omega-3s, they had a 10 times higher mortality risk than those in the fourth quartile.
3. Evidence that fish oil works. Populations in two countries that do better than most in life extension are the Greenland Eskimos and the Japanese. What do they have in common? They eat the most fish. The Gissi study fed one tablet of the cleanest fish oil to participants — 840 EPA+DHA, free of PCBs, mercury, lead, etc. This study was conducted in participants in Italy who had an acute MI and were rushed into hospitals; participants were eventually randomized to one fish oil capsule or placebo, and within about 10 days total mortality started to fall for those on the fish oil, and it reached statistical significance in about 90 days.

In the future, we need to focus on studies that are following long-term health outcomes of these types of dietary changes. And, the sample sizes need to be much larger in order to classify the results as significant.

As physicians, we need to counsel patients to eat more fish and get those omega-3s from their diet. Lately, our hamburger heavens have added bacon to the double-burgers with cheese, raising the saturated fat to 17 g. Consider a tuna salad sandwich instead, which would have 1 to 2 g of saturated fat, depending on what kind of mayonnaise was used. Physicians need to talk to their patients about diet and exercise habits. Of course, many physicians are time strapped. But, there are a lot of resources we can direct patients to learn more about eating seafood; I was a part of one this year, GetRealAboutSeafood.com, which has a discussion guide for patients, recipes and many other resources.