Through much of the 2010s, one fish-oil study after another came up
empty, Richard Bazinet, a nutrition researcher at the University of
Toronto, told me—“null, null, null, null, null.” 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,
presented in 2018,
found that, among high-risk adults already receiving another type of
cholesterol-lowering treatment, the drug decreased the risk of heart
failure and other serious cardiovascular events by an eye-popping 25
percent. Fish oil, it seemed, was back in business. When the study’s
lead author, the Harvard cardiologist Deepak Bhatt, presented his
findings at the American Heart Association’s annual meeting in Chicago,
the crowd gave a
standing ovation. The following year, the FDA approved the drug for the use studied in REDUCE-IT. (The agency had already
approved the drug for a different use back in 2013.)
With triumph, though, came controversy. Even at the time of Bhatt’s
presentation, some cardiologists noted that the study’s
mineral-oil-based placebo—a pill selected because its color and
consistency mimic those of fish oil, but whose
use in fish-oil studies has been
debated—seemed not to be entirely neutral. In fact, the placebo seemed to be
harming people. Initially, nothing much came of these concerns. Then, last month, a
new analysis published in the journal
Circulation
substantiated them and then some. It showed, based on elevated levels
of several biomarkers in blood-test results, that the placebo may have
increased volunteers’ risk of heart attack and stroke. Many researchers
found these results to be compelling evidence that Vascepa’s eye-popping
success could be due to a bad placebo, not a great drug.
“What’s somewhat shocking about that 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. Anything would have been better against that placebo.” Steven
Nissen, a cardiologist at the Cleveland Clinic who was involved in a
different omega-3 trial, called the
Circulation study’s
findings “extraordinarily disturbing.” Two members of the expert panel
that in 2019 recommended that the FDA green-light Vascepa even
told Stat’s Matthew Herper that, if they’d had access to the new data at the time, they might not have voted to approve.
To make matters more confusing, the
Circulation study—as
in, the very study that ignited this controversy—was also funded by
Amarin, and one of the study’s 13 authors was Bhatt, the lead author on
REDUCE-IT. In a statement, Amarin told me it “continues to stand by the
results of REDUCE-IT” and is “very surprised” that the panel members
would make such comments based on the
Circulation
paper. The company stressed that REDUCE-IT’s positive results “could
not be explained” by the placebo, and that the effects found in the
Circulation study
were too minor to “correlate to any meaningful changes in outcomes.”
Bhatt agreed, telling me he sees 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 risk reductions observed in the trial.
The lead author of the
Circulation study,
Paul Ridker, declined to comment on the controversial results. But
other experts I spoke with were considerably less sanguine than Bhatt.
Several would say only that, at this point, the REDUCE-IT results are
basically uninterpretable. Nissen, who has in the past called REDUCE-IT “
almost certainly a false-positive study,”
went so far as to say that he thinks the benefits it found can be
“entirely explained by the harms of the placebo” and that Amarin should
have known not to use mineral oil. JoAnn Manson, the chief of preventive
medicine at Brigham and Women’s Hospital in Boston and the leader of
the largest-ever study of vitamin D and omega-3 pills in healthy adults,
was more sympathetic to the idea that the
Circulation study’s
findings likely don’t account for the full 25 percent risk reduction.
But she also raised the possibility that the Vascepa, if ineffective,
could be dangerous: Some studies have shown that a high daily dosage of
fish oil can heighten one’s risk of developing a type of irregular
heartbeat. (Amarin called the suggestion that Vascepa could be
ineffective and dangerous “a gross distortion of fact,” saying that “the
findings of independent, thorough, and impartial scientific and
statistical reviews” had determined that the drug’s benefits to the
at-risk patients for whom it is designed more than make up for its
risks.)
The upshot of all this is that an already murky situation has become a
good deal murkier, and there’s no end to the murk in sight. Which is a
shame because, in one sense at least, the stakes are higher now than
they’ve been in some time: REDUCE-IT suggested that Vascepa could
legitimately save lives. If it can’t, that’s more than a scientific
scandal; it’s a real, human loss. “I’ve never seen anything like this,”
Bazinet told me. “In a way, it’s not surprising. The field’s been
controversial all the time, and now we probably have the biggest
controversy.”
The only way out of this mess, experts said, is to run a whole new trial
comparing Vascepa (or its generic equivalent, icosapent ethyl) with
something everyone agrees is a true placebo—one that we can be confident
doesn’t harm people. Manson is leading a team applying for NIH funding
to run such a study. (She said that Amarin told her it was not open to a
replication trial and that the company declined to fund three related
studies. When I asked Amarin about this, the company told me it would
not replicate REDUCE-IT, because the outcomes “read out robustly,” and
that it does not publicly discuss research proposals from third
parties.) The study would also investigate a pair of promising leads
turned up by
her own major study,
an ongoing project that has found that although omega-3 did very little
for the population as a whole, it might have considerable benefits for
Black people and people who don’t eat much fish.