In the beginning, everything was very exciting. In 1971, a team of Danish researchers located on the northwest coast of Greenland found that a local Inuit community has remarkably low rates of diabetes and heart disease. The reason, the researchers I guess, was their diet high in marine fats—in other words, fish oil. The incidence of heart disease, which once affected relatively few Americans, has shot up since the turn of the century and there was clearly a simple solution here. “I remember how exciting these studies were when they first came out,” Marion Nestle, professor emeritus of nutrition and food research at New York University, told me. “The idea that there are populations of people who eat fish and are protected from heart disease seems great.”
The buzz didn’t stop with heart disease. Soon fish oil appeared hailed as a panacea. It can help prevent dementia! depression! Obesity! Crab! News and books repeat these claims. And supplement manufacturers in capital letters. Until 2014, fish oil supplements were a a billion dollar industry. Today, the market continues to grow at an astronomical rate I’m sorry. The growth of science supporting the healing properties of fish oil, meanwhile, has been, shall we say, less astronomical. The first papers that generated the initial enthusiasm were simply observations, meaning they could only establish correlation, not causation. When the randomized control trials eventually began to trickle in, the results were mixed at best.
Tens of thousands of studies later, things haven’t gotten much clearer: We still don’t have anything close to a firm understanding of what fish oil can and can’t do. And lately, things have been getting even weirder.
Most experts agree that fish oil has some modest benefits in certain circumstances. Omega-3, its star nutrient, has been shown to lower levels of fat linked to heart failure, help prevent premature births and improve infant formula. But they are far from the game-changing promise of early studies. That promise has been lost over the years in a tangle of theoretical possibilities, Nestlé told me. Fish oil contains two different types of omega-3, DHA and EPA; perhaps only the former carries the benefit. Or maybe just the last one. Perhaps the benefit comes only from pairing the two. Perhaps neither does anything unless consumed with other parts of the actual fish.
And that’s just the beginning. Perhaps the benefits have less to do with the fish itself and more to do with the fact that if you’re eating fish, you’re probably not eating a hamburger or a pork chop. Maybe they have to do with your overall diet. Maybe they have nothing to do with your diet at all. Maybe it’s just that people who eat fish tend to be wealthier and, not unrelatedly, healthier in the first place. Maybe it’s something else entirely.
For most of the 2010s, one study after another on fish oil came up empty, Richard Bazinet, a nutrition researcher at the University of Toronto, told me — “zero, zero, zero, zero, zero.” And then came REDUCE-IT, a trial funded by the pharmaceutical company Amarin to test its fish oil-based heart drug called Vascepa. the results, introduced in 2018, found that among high-risk adults already receiving another type of cholesterol-lowering treatment, the drug reduced the risk of heart failure and other serious cardiovascular events by an impressive 25 percent. Fish oil seems to be back in business. When the study’s lead author, Harvard cardiologist Deepak Bhatt, presented his findings at the American Heart Association’s annual meeting in Chicago, the crowd gave standing ovation. The following year, the FDA approved the drug for the use studied in REDUCE-IT. (The agency already had approved the drug for a different use in 2013)
However, with triumph came controversy. Even during Bhatt’s presentation, some cardiologists noted that the study’s mineral oil-based placebo — a pill chosen because its color and consistency mimicked that of fish oil but whose use in fish oil studies it is discussed— didn’t seem to be completely neutral. In fact, the placebo looked like this harmful the people. Nothing much came of these concerns at first. Then, last month, a new analysis published in the journal Circulation justified them and then some. It showed, based on increased levels of several biomarkers in blood test results, that the placebo may have increased the risk of heart attack and stroke in the volunteers. Many researchers find these results compelling evidence that Vascepa’s shocking success may be due to a bad placebo rather than a great drug.
“What’s kind of shocking about this paper is that it looks like everything got worse in the placebo group, and the treatment group stayed the same,” Bazinet told me. “You could have given the subjects a glass of water. Everything would be better against this placebo.” Steven Nissen, a cardiologist at the Cleveland Clinic who participated in a different omega-3 study, called Circulation the study’s findings are “extremely disturbing.” Two members of the expert panel that in 2019 recommended that the FDA give the green light even to Vascepa said statisticsMatthew Harper that if they had access to the new data at the time, they may not have voted for approval.
To make things even more confusing, Circulation the study—like the study itself that ignited this controversy—was also funded by Amarin, and one of the study’s 13 authors was Bhatt, REDUCE-IT’s lead author. In a statement, Amarin told me that he “continues to stand behind the results of REDUCE-IT” and was “very surprised” that panel members would make such comments based on Circulation paper. The company stressed that REDUCE-IT’s positive results “could not be explained” by placebo and that the effects found in Circulation the studies were too small to “correlate with any meaningful changes in outcomes.” Bhatt agreed, telling me that he saw the new paper not as undermining REDUCE-IT, but simply as clarifying Vascepa’s biological mechanisms. He defended the use of mineral oil as a placebo, arguing that it alone could not explain the significant reduction in risk seen in the trial.
The lead author of Circulation study, Paul Ridker, declined to comment on the conflicting results. But other experts I spoke to were significantly less optimistic than Bhatt. A few would only say that at this stage the REDUCE-IT results are basically uninterpretable. Nissen, who in the past called REDUCE-IT “almost certainly a false positive study,” went so far as to say that he thought the benefits he found could be “entirely explained by placebo harm” and that Amarin should have known not to use mineral oil. JoAnn Manson, chief of preventive medicine at Brigham and Women’s Hospital in Boston and leader of the largest study of vitamin D and omega-3 pills in healthy adults, was more sympathetic to the idea that Circulation the study findings probably do not account for the full 25 percent risk reduction. But she also raised the possibility that Vascepa, if ineffective, could be dangerous: Some studies show that a high daily dose of fish oil may increase the risk of developing a type of irregular heartbeat. (Amarin called the suggestion that Vascepa might be ineffective and dangerous a “gross distortion of the facts,” saying that “findings from independent, thorough and unbiased scientific and statistical reviews” found that the drug’s benefits for at-risk patients to whom it is intended more than offsets the risks.)
The upshot of all this is that an already murky situation has become much murkier, and there is no end in sight to the gloom. Which is a shame, because, in at least one sense, the stakes are higher now than they were a while ago: REDUCE-IT suggests that Vascepa can legitimately save lives. If it cannot, it is more than a scientific scandal; this is a real human loss. “I’ve never seen anything like it,” Bazinet told me. “In a way, it’s not surprising. The field has been controversial all along, and now we probably have the biggest controversy yet.”
The only way out of this mess, experts said, is to conduct an entirely new study comparing Vascepa (or its generic equivalent, icosapent ethyl) with something everyone agrees is a true placebo—one we can be sure of. , that it does not harm people. Manson led a team that applied for NIH funding to conduct such a study. (She said that Amarin had told her that it was not open to a replication trial and that the company had declined to fund three related studies. When I asked Amarin about this, the company told me that it would not replicate REDUCE-IT because the results “read” and that it does not publicly discuss research proposals from third parties.) The study will also investigate a pair of promising leads discovered by her own basic researchan ongoing project that found that although omega-3s are very small for the general population, they may have significant benefits for blacks and people who don’t eat a lot of fish.
In the meantime, doctors are unlikely to abandon Vascepa, Clifford Rosen, a professor at Tufts University School of Medicine, told me. In the first quarter of 2022, Amarin sold nearly $100 million value of the drug that is his single product. “There is such momentum to use this agent that until the next study comes along, I think there will still be widespread use,” Rosen said. To his point: In 2019, the American Diabetes Association recommended icosapent ethyl for certain patients as part of official standards of care based explicitly on REDUCE-IT results. Since the publication of Circulation paper, the ADA has not taken any action to withdraw this recommendation. (When I asked if the group was considering doing so, its chief scientific and medical officer said only that he was “following the evidence based on what was available at the time.”)
Not that this state of affairs is particularly new. We’ve known for years that fish oil supplements have virtually no benefits for the average healthy person, Peter Cohen, a professor at Harvard Medical School, told me. It hasn’t stopped tens of millions of Americans to take the pills every day. “People just love it take supplementsRosen said. “It’s religiosity … It’s magical thinking.” Vascepa is an FDA-approved drug, not just a supplement, but in some ways the line isn’t so clear. The dosage is certainly higher, the packaging is certainly better, and the rules are certainly stricter. But if you don’t understand the biological mechanism behind the drug or supplement—and scientists don’t—it makes it hard to say with any confidence that they’re fundamentally different.
“If you don’t know how something works – as you know no an idea how it works—it’s hard to tell they’re different!” Bazinet told me. “Because it might just be a little bit more of the same mechanism. Not clear.” When it comes to fish oil, very little.