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When it comes to natural supplements, nothing beats fish oil. These small omega-3 capsules, made from everything from mackerel, sardines and krill anchovies to tank-grown algae, are more popular than glucosamine and probiotics combined.
Millions of Americans who take fish oil supplements have become too familiar with the burps of fish intensely that they cause. But it is a small price to pay to reduce the risk of heart disease, which remains the leading cause of death in the country.
The problem is that fish oil does not do anything. Or it does not seem to do what we thought we did. What began as a series of breakthrough nutritional discoveries in the late 1990s has turned into a disconcerting drip of nil results.
That's why cardiologists, nutritionists, and doctors paid close attention to the American Heart Association's scientific sessions held last week in Chicago, where the results of two important fish oil studies were presented. more than 34,000 subjects. Harvard's JoAnn Manson presented the results of the first study: another nil result. His study revealed that fish oil supplements do little to help prevent heart disease. Fifteen minutes later, Deepak Bhatt, another Harvard scientist, said the opposite. In his study, a purified fish oil intervention reduced the risk of coronary events by 25%.
These developments in the history of fish oil are both intriguing, confusing, exciting and depressing. Above all, they show that the progress of science is not always as linear as we think. As research methods have improved, statistical power has developed and scientists have tested more and more precise hypotheses. The truth about fish oil remains, just like fish, slippery.
Exceptionally carnivorous Greenlandic
The history of fish oil and heart health begins in 1970, when two Danish scientists visit the northwest coast of Greenland to study an indigenous population described as "probably the most carnivorous people." of the planet". The community seemed strangely free of diabetes and, between 1963 and 1967, had only three cases of heart disease. The scientists studied 130 Inuit from the region and made an intriguing discovery: their blood lipids were lower than those of their Danish counterparts.
It was not genetics. Inuit living in Denmark had blood lipid levels similar to those of typical Danes. After nearly a decade of studies, scientists concluded that the difference was in diet. More specifically, it involved the high consumption of fish and marine mammals, of which omega-3 fatty acids were present in the blood of Greenlanders.
A few years later, the New England Journal of Medicine published a study on seafood consumption and coronary heart disease in 852 Dutch men of average age over a 20-year period. He found a striking "inverse dose-response relationship".
The authors wrote: "Mortality from coronary artery disease was more than 50% lower in those who ate at least 30 g of fish a day than those who ate it."
The gold rush of fish oil begins
By 1990, seafood had attracted the attention of cardiology researchers. That year, 51 studies were published on the link between fish oil and heart disease, up from four ten years ago. But the research was mainly "observational". She compared the health outcomes of people who ate a lot of fish to those of others, and in doing so she found fascinating correlations between fish consumption and cardiovascular health. But these studies have not and can not prove causality.
Was it the oil in the fish that was causing do people have less heart disease? Maybe But there were other causes also plausible. For example, affluent people may tend to eat more fish, and these affluent people, such as the robust Greenlanders, also tend to spend more time off of physical exercise and that is actually the physical activity that causes people have less heart disease, which would make fish consumption a marker of 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 chocolate bars.
What was needed was a large-scale randomized controlled trial (RCT), considered the "standard of reference" for nutritional research, because it can demonstrate the cause. It started in 1993 when 11,324 survivors of a heart attack in Italy received fish oil, vitamin E or nothing at all. Vitamin E had no effect. The fish oil, by comparison, was amazing, resulting in a 10% reduction in heart disease.
Another sensational RCT followed almost a decade later. In this one, a fish oil supplement resulted in a 19% reduction in heart disease in 18,645 Japanese subjects. Surprisingly, fish oil could even confer a health benefit to a population at the peak of seafood consumption.
In 2008, scientists published 114 studies on fish oil and heart disease. As the biological importance of fish oil became clearer, particularly its role in reducing inflammation, it became a panacea for well-being, offering apparent benefits for all areas, from blood pressure and triglycerides to pain, vision and mental health.
An avalanche of invalid results
But the good times would not last. In 2010, the first major zero RCT published in the New England Journal of Medicine, found that fish oil "did not significantly reduce the rate of major cardiovascular events in patients with myocardial infarction receiving advanced antihypertensive, antithrombotic and lipid-lowering therapy".
In 2012, nearly 20 million American adults used a fish oil supplement. But among scientists, the relationship was sour and fast. A large TCR, 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 of cardiovascular events".
It's getting worse. the Journal of the American Medical Association published a meta-analysis of fish oil on 20 studies involving 68,680 subjects. He concluded soberly: "Omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or death." One year later, research on fish oil would reach its peak. published documents, climax never to reach.
This year promises to be the worst fish oil to date. In July, another major meta-analysis, this one presenting itself as "the most comprehensive systematic evaluation of the effects of omega-3 fatty acids on cardiovascular health," indicated that oil supplements of fish had "little or no effect on mortality or cardiovascular health. . "Its illusory benefits, furthermore," result from trials involving a higher risk of bias. " Scientifically, fish oil seemed dead.
And as if that were not enough, the last nail of the coffin came last Saturday in Chicago, in the form of the VITAL study by JoAnn Mason, an RCT that followed 25,871 participants for five years. The results indicated that "n-3 supplementation [omega-3] fatty acids have not reduced the incidence of major cardiovascular events. "
But wait, fish oil is back?
Except that fish oil was not dead. Because, just minutes after the results of VITAL, Deepak Bhatt announced the results of its RCT REDUCE-IT, results so exciting that a room full of cardiologists have ovationnée. In this study, which followed 8,179 people for four years, fish oil reduced the risk of cardiovascular events by 25%, and this, in subjects already treated with drugs for heart disease. heart, like statins. Suddenly, the fish oil was alive and falling to the bottom of the boat.
Which raises the question: what the hell is going on? Why would fish oil look healthy, then stop looking healthy, and then suddenly become healthy again?
Statins are one of those answers. This popular class of cholesterol-lowering drugs did not exist at the time of the first fish oil studies. The positive effect of fish oil may have been rendered superfluous by statins. In other words, the statins may have eaten the meal of fish oil. This of course does not explain the recent results of REDUCE-IT. But this study involved a very large dose.
Oh, that's the dose
In fact, the dose could largely explain what is happening. In the first RCT on fish oil, subjects received 1 gram of fish oil. The Japanese study that followed in 2007 presented 1.8 grams. And the recent REDUCE-IT trial had such a high dose – 2 grams twice a day for a total of 4 grams – blurs the line between a nutritional supplement and a pharmaceutical intervention.
In comparison, many of the null studies used small doses – and in some cases, minute doses. For example, in this 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 would not work if people did not take a large enough dose. So, why would a low dose of fish oil work, especially for people already treated with statins?
Again, the mixed history of fish oil can be typed. The Japanese study and the recent REDUCE-IT study – the two most spectacular results in the history of fish oil research – have not used oil standard fish. They used EPA, which is one of the two major fatty acids found in fish oil. The other one is called DHA. Of the two, DHA tends to attract more attention because it contains a lot of it in the human brain. But the EPA has its own biological importance. It is converted into a family of molecules called "prostaglandins" and "resolution mediators", which regulate inflammation, thin the blood and are supposed to reduce the risk of heart attack.
So, it could be EPA's action. But it could be the dose. It could be both the EPA and the dose. And statins can also play a role.
Here again, the most severe critics of fish oil might be right: fish oil might do nothing and its apparent benefits could be due to a study design or a bad luck, although that seems to be a long-term attempt at the moment. However, if fish oil research has been focused on heart health, this is not the only area in the study. There is evidence that fish oil lengthens pregnancy in pregnant women and improves anxiety. The EPA may also have an antidepressant effect.
Finally, it is possible that there are some variables in play that no one has paid enough attention to – such as oxidation. Despite its reputation, fish oil is not inherently fish. This only feels if omega-3 fatty acids start to react with oxygen. (Another word for this type of oxidation is "rancidity.") And some lipid scientists think that taking fish oil that is oxidized does not provide 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 solution to our problems? After half a century of study, we may not have the answer, but we have better questions. Believe it or not, we need more research. As it happens, another major study on fish oil is underway. It should be reported in about a year.
Richard Bazinet is a aAssociate Professor and Canada Research Chair in Lipid Metabolism in the Brain, Department of Nutritional Sciences, University of Toronto.
Mark Schatzker is the author of The Dorito effect and the writer-in-residence at the Modern Nutrition and Physiology Research Center of Yale University.
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