Polarized light micrograph of recrystallized docosahexaenoic acid (DHA), one of the principal omega-3 fatty acids thought to have cardiovascular benefits. © Dennis Kunkel Microscopy.

BETHESDA, MD—Leading omega-3 fatty acid researchers are disappointed with the Food and Drug Administration’s most recent ruling on fish oil and heart health, charging the agency with undue conservatism.

Last November, FDA issued a statement that, “the scientific evidence about whether omega-3 fatty acids may reduce the risk of coronary heart disease is suggestive but not conclusive.” The Administration mandated that omega-3 supplement labels not advocate intake exceeding 2 g/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

FDA reviewers acknowledged that, “the weight of the scientific evidence for a claim relating EPA and DHA … and reduced risk of CHD outweighs the scientific evidence against the claim.” But they cited a lack of “significant scientific agreement,” and held that it is, “still unknown what effect omega-3 fatty acids may have or may not have on risk of CHD in the general population.”

This is, in essence, a reiteration of the agency’s 1993 position and it comes on the heels of a similarly conservative statement by the American Heart Association. FDA based its position on a review of 51 published studies, 12 of which—including the four largest intervention trials—weighed in favor of omega-3’s. Many of the smaller studies were inconclusive.

Researchers gathered for the recent International Workshop on Omega-3 Fatty Acids, Diabetes and Cardiovascular Risk, voiced consternation, holding that a powerful preventive health measure is foundering on the rocks of bureaucratic short-sightedness. While there are still unanswered questions and subjects for debate, many attendees argued that a lot of people will die of heart disease before there is scientific agreement on use of what is, essentially, a very safe modality.

William Lands, PhD, senior scientific advisor to the National Institute of Alcohol Abuse and Alcoholism.

“There are some very important primary preventive medicine tactics at our fingertips, not yet fully developed,” said William Lands, PhD, senior scientific advisor to the National Institute of Alcohol Abuse and Alcoholism, who has studied omega fatty acid metabolism for several decades.

He and others hold that CVD and diabetes are two deadly reflections of an American diet almost completely dominated by omega-6 and largely devoid of omega-3 fatty acids. The former derive from land plants and are bioconcentrated in the flesh of cattle, hogs, grain-fed poultry and dairy products; the latter come from the marine food chain, though one of the omega-3’s—linolenic acid—is found in some plants.

Physiologically, omega-3’s and omega-6’s are metabolized via different, somewhat oppositional pathways. Omega-6’s drive synthesis of arachidonic acid, leukotrienes, prostaglandins, and other inflammatory mediators. Omega-3’s produce anti-inflammatory signals. Both are essential, but as with many things in nature, balance is critical.

Dr. Lands contends that in the US, we couldn’t be more out of balance—and it is killing us.

“Disorders of excessive omega-6 eicosanoid actions are many in the US,” he said, pointing to heart attack, thrombotic stroke, arthritis, asthma, colitis, headache, inflammatory diseases, menstrual cramps, metastases of cancer, and osteoporosis.

On a typical American low-fish diet, 80% of the highly unsaturated fatty acid is omega-6. “We’re maxed out—we can’t possibly get more omega-6.” Americans eat very little omega-3, whereas the Japanese eat a lot more omega 3’s, and they have an omega-6/omega-3 tissue balance closer to 1:1.

Until they move to America, that is. Dr. Lands noted that Japanese in America have roughly 74% of their tissue unsaturated fatty acid as omega-6, compared with urban Japanese in Japan who have about 43% omega-6. Greenlanders also eat a lot of omega-3’s. Their tissue balance is roughly 20% omega-6, and 80% omega-3—the mirror image of the US average.

On a population basis, CVD correlates very clearly with elevated omega-6 and diminished omega-3: in the US, it is 200 per 100,000 versus 50 per 100,000 in Japan, and 20 per 100,000 in Greenland. “I believe it (tissue fatty acid balance) is a surrogate clinical outcome; it is an index of the relative intensity of omega-6 eicosanoids.” Dr. Lands developed an omega-3/omega-6 personal dietary calculator called KIM (Keep it Managed), downloadable free-of-charge at: http://intramural.niaaa.nih.gov/eicosanoids/.

Artemis Simopoulos, MD, director of the Center for Genetics, Nutrition and Health, pointed out that since the 1950s, intake of omega-6’s, saturated fats, and trans fatty acids has soared, as has CVD. “In some people, you now see ratios of 25:1 or 30:1 in favor of omega 6’s. This is an enormous imbalance.”

Dr. Simopoulos has been following-up the observations made during the original “Seven Countries” studies, which compared dietary patterns and cardiovascular disease in the US, Crete, Japan, Finland, Italy, Yugoslavia, and Holland in the 1970s. The lowest CVD morbidity and mortality was in Crete.

Cretan people eat a lot of wild plants, fish, and products from free-grazing animals. “No matter what it was, we found omega-3’s throughout their food supply. Their eggs, from grass-fed chickens, had equal amounts of omega-6 to omega-3. The average store-bought egg here has a ratio of 20 to 1.”

Epidemiologic correlations and retrospective analyses are one thing; clinical outcomes are another. The FDA points out that there have been no published primary prevention studies showing increased omega-3, whether from seafood or supplements, reduces CV events. Secondary prevention studies in already-ill individuals are suggestive, though far from unanimous.

	David Siscovick, MD, a cardiovascular researcher at the University of Washington.

David Siscovick, MD, a University of Washington researcher, who has been studying the effect of increasing fish intake on CV incidence, believes the divergent results reflect inconsistencies in design. “In each study, what questions are being asked? The question influences the design, which influences the findings.”

The issue of omega-6 versus omega-3 balance warrants careful attention, said Dr. Siscovick. “We tend to ignore it, but we should be considering the background diets. It could explain a lot of the heterogeneity in the conclusions.” He and others believe the time is right for definitive, large-scale primary prevention trials, especially in high-risk populations like type 2 diabetics.

Roberto Marchioli, MD, one of the leaders of the recently completed GISSI-Prevenzione trial.

Roberto Marchioli, MD, one of the leaders of the recently completed GISSI-Prevenzione trial, agreed. He held that the data from GISSI and other recent studies are already strong enough to advocate, “administration of omega-3 fatty acids as a drug” after myocardial infarction (see p. 13). A primary prevention trial involving diabetics makes a lot of sense. “We know diabetics are at increased risk of CV events, and newly diagnosed type 2’s have a long course before CVD.”

The FDA holds that up to 3 grams of omega-3 daily is, “generally regarded as safe.” But it set the limit on supplement claims at 2 grams, to ensure that people who already get omega-3’s from their diet will not exceed the “safe” limit. The main safety concern is a small increased risk of hemorrhagic stroke due to the omega-3 anti-platelet and anti-thrombotic effects.

But omega-3 advocates argue that given the stunning lack of omega-3 in the average American diet, the prevalence of coronary artery disease, and the role of platelet aggregation in myocardial infarction, the FDA’s logic is questionable. “Any sensible person, aside from bureaucrats, realizes these are safe,” remarked Alexander Leaf, MD, a cardiovascular researcher at Harvard Medical School, who is studying the anti-arrhythmic effects of omega-3’s.

Clemens von Shacky, MD, a University of Munich investigator, whose 1999 study of 223 CHD patients showed reduced infarction and cardiac death rates after 21 months on 3–6 g/d omega-3, insisted that, “there may be side effects but they’re all good.” He called the safety concerns in the recent AHA dietary guidelines, “egregious.”

FDA and the AHA may be moving very slowly, but at least they are moving in the right direction, said William Harris, MD, of St. Luke’s Lipid & Diabetes Research Center, Kansas City. “The FDA’s judgment that 3 g of EPA and DHA appears safe is important to consider. They’ve suggested that it might be helpful for heart disease, and AHA says the same thing.” It may not be fast, but it is progress.