19 November 2018 - Vox.com - Do fish oil supplements work? Science keeps giving us slippery answers

When it comes to natural supplements, nothing beats fish oil. These little capsules of omega-3s, which are made with everything from mackerel, sardines, and anchovies to krill and vat-grown algae, are more popular than glucosamine and probiotics combined.

The millions of Americans who take fish oil supplements have become all too familiar with the intensely fishy burps they cause. But it’s a small price to pay to reduce the risk of heart disease, which remains the nation’s leading cause of death.

The problem is fish oil doesn’t do anything. Or it doesn’t seem to do what we thought it did. What began as a series of groundbreaking nutritional discoveries in the late 1990s has turned into a perplexing drip of null findings.

That’s why the cardiologists, nutritionists, and doctors were paying keen attention the American Heart Association’s Scientific Sessions, held last week in Chicago, where the results of two major fish oil studies, following more than 34,000 subjects, were presented. Harvard’s JoAnn Manson delivered the results of the first study: another null finding. Fish oil supplements, her study found, do little to prevent heart disease. Fifteen minutes later, standing at the same podium, another Harvard scientist, Deepak Bhatt, claimed the opposite. In his study, a purified fish oil intervention reduced the risk of coronary events by an astonishing 25 percent.

These developments in the fish oil story are intriguing, confusing, exciting, and depressing all at once. They show, above all, that the progress of science is not always as linear as we think. As research methods have improved, statistical power has grown, and scientists have tested ever more precise hypotheses, the truth about fish oil remains, like fish itself, slippery.

Exquisitely carnivorous Greenlanders

The fish oil and heart health story begins in 1970, when two Danish scientists traveled to the northwest coast of Greenland to study an indigenous population that had been described as “probably the most exquisitely carnivorous people on earth.” Despite their extremely meaty diet, this community appeared curiously free of diabetes and between 1963 and 1967 experienced a mere three cases of heart disease. The scientists studied 130 local Inuit and made an intriguing discovery: They had blood lipids lower than their Danish counterparts.

It wasn’t genetics. Inuit people who lived in Denmark had blood lipid levels similar to typical Danes. After nearly a decade of further study, the scientists concluded that the difference came down to diet. Specifically, it was the high consumption of fish and marine mammals, whose omega-3 fatty acids were present in the Greenlanders’ blood.

A few years later, the New England Journal of Medicine published a study that examined seafood consumption and coronary heart disease in 852 middle-aged Dutch men over a 20-year span. It found a striking “inverse dose–response relation.”

“Mortality from coronary heart disease,” the authors wrote, “was more than 50 percent lower among those who consumed at least 30 g of fish per day than among those who did not eat fish.”

The fish oil gold rush begins

By 1990, seafood had captured the attention of cardiac researchers. That year, 51 studies were published exploring the link between fish oil and heart disease, up from four a decade earlier. But the research was mainly “observational.” It compared health outcomes of people who ate a lot of fish to those who did not, and by doing so, it uncovered intriguing correlations between eating fish and cardiovascular health. But these studies did not, and could not, prove causation.

Was it the oil in fish that was causing people to have less heart disease? Perhaps. But there were other equally plausible causes. For example, it could be that affluent people tend to eat more fish, and that affluent people, like rugged Greenlanders, also tend to spend more time outside exercising, and that it’s actually exercise that causes people to have less heart disease, which would make fish consumption a marker for less heart disease but not the cause. Or it could be something even simpler: When people eat fish, they have less room in their diet for Big Macs, fried chicken, and candy bars.

What was needed was a large-scale randomized controlled trial (RCT), which is considered the “gold standard” of nutritional research because it can demonstrate cause. That began in 1993, when 11,324 heart attack survivors from across Italy were given fish oil, vitamin E, or nothing. The vitamin E had no effect. The fish oil, by comparison, was astonishing, causing a 10 percent reduction in heart disease.

Another sensational RCT followed almost a decade later. In this one, a fish oil supplement led to a 19 percent reduction in heart disease in 18,645 Japanese subjects. Fish oil, amazingly, could even confer a health benefit to a population at the upper end of seafood consumption.

In 2008, scientists published 114 studies on fish oil and heart disease. As fish oil’s biological importance became further elucidated, particularly its role in reducing inflammation, it became a wellness panacea, offering apparent benefits for everything from blood pressure and triglycerides to pain, vision, and mental health.

An avalanche of null findings

But the good times wouldn’t last. In 2010, the first major null RCT, published in the New England Journal of Medicine, found that fish oil “did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy.”

By 2012, nearly 20 million American adults were using a fish oil supplement of some kind. But among scientists, the relationship was souring, and fast. A big RCT, also published in the NEJM, found that a daily supplement of omega-3 fatty acids “did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events.”

It got worse. The Journal of the American Medical Association published a meta-analysis of fish oil, which examined 20 studies comprising 68,680 subjects. It soberly concluded, “Omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke.” A year later, fish oil research would reach its zenith, with 169 papers published, a high point never again to be reached.

This year was shaping up to be fish oil’s worst to date. In July, another major meta-analysis, this one billing itself as “the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date,” reported that fish oil supplements have “little to no effect on mortality or cardiovascular health.” Its illusory benefits, furthermore, “spring from trials with higher risk of bias.” Scientifically, fish oil looked dead.

And if that wasn’t enough, the final nail in the coffin came last Saturday in Chicago, in the form of JoAnn Mason’s VITAL study, an RCT that followed 25,871 participants over five years. The results indicated that “supplementation with n-3 [omega-3] fatty acids did not result in a lower incidence of major cardiovascular events.”

But wait, is fish oil back?

Except fish oil wasn’t dead. Because within minutes of the VITAL results, Deepak Bhatt announced the results of his REDUCE-IT RCT, results that were so exciting, a roomful of cardiologists gave it a standing ovation. In this study, which followed 8,179 people over four years, fish oil reduced the risk of cardiovascular events by 25 percent, and this in subjects who were already being treated with heart disease drugs like statins. All of a sudden, fish oil was alive and flopping in the bottom of the boat.

All of which raises the question: What the heck is going on? Why would fish oil look healthy, then stop looking healthy, then suddenly look healthy again?

One of those answers is statins. This popular class of cholesterol-lowering drugs didn’t exist when the first fish oil studies were done. It may be that whatever positive effect fish oil once had was made redundant by statins. Statins, in other words, may have eaten fish oil’s lunch. That, of course, doesn’t explain the recent REDUCE-IT results. But that study featured a very large dose.

D’oh, it’s dose

In fact, dose could explain a lot of what’s going on. In the first-ever fish oil RCT, subjects received 1 gram of fish oil. The Japanese study that followed in 2007 featured 1.8 grams. And the recent REDUCE-IT trial featured such a large dose - 2 grams twice daily for a total of 4 grams — it blurs the line between nutritional supplement and pharmaceutical intervention.

Many of the null studies, by comparison, used small - and in some cases, tiny - doses. For example, in that null study published in 2010, subjects consumed about 0.375 grams of fish oil. In the VITAL study, subjects consumed 840 milligrams of omega-3s. Statins wouldn’t work if people didn’t get a sufficiently large dose. So why would a low dose of fish oil work, especially in subjects who are already being treated with statins?

Then again, fish oil’s mixed track record may come down to type. The Japanese study and the recent REDUCE-IT study - the two most dramatic results in the history of fish oil research - did not use standard fish oil. They used EPA, which is one of two major fatty acids found in fish oil. The other is called DHA. Of the two, DHA tends to get more attention because there’s a lot of it in the human brain. But EPA has its own biological importance. It is converted into a family of molecules called “prostaglandins” and “specialized proresolving mediators,” which regulate inflammation, thin the blood, and are believed to lower heart attack risk.

So it might be EPA. But it might be the dose. It might be both EPA and dose. And statins may also play a role.

Then again, the harshest fish oil critics might be right - fish oil might not do anything, and its apparent benefits may be due to nothing more than poor study design or chance, although that seems like a long shot at this point. However, while heart health has been a focus of fish oil research, it is not the only area being studied. There is evidence that fish oil lengthens gestation in pregnant women and improves anxiety. EPA may also have an antidepressant effect.

Finally, it’s possible there is some variable at play that no one has paid adequate attention to - like oxidation. Despite its reputation, fish oil is not inherently fishy. It only smells that way once omega-3 fatty acids begin reacting with oxygen. (Another word for this kind of oxidation is “rancidity.”) And some lipid scientists believe that taking fish oil that has become oxidized does not deliver the same benefits.

Should people stop taking fish oil? Should they start? What about people who never eat fish? And is a high dose of EPA the answer to our problems? After half a century of study, we may not have the answer we want - but we do have better questions. What we need, believe it or not, is more research. As it happens, another major fish oil study is underway. It should be reporting about a year from now.