Two months ago, the medical community was all abuzz over a big clinical study that showed a prescription fish-oil supplement could reduce the risk of heart disease. Today, a fuller look at the data presents a more nuanced picture.
Doctors working on the REDUCE-IT trial, which enrolled more than 8,000 people, published the full set of data today in the New England Journal of Medicine (NEJM) and presented it at the American Heart Association conference in Chicago. The big takeaway, which caused cardiologists to do a double-take in September, remains unchanged. The prescription-grade pill, branded Vascepa, reduced the risk of heart attack and stroke by 25 percent in patients who have high levels of triglycerides, a type of fat in the bloodstream.
But with the full data revealed, experts still had several questions about how Vascepa works, how rock-solid that 25 percent reduction level really is, and the pill’s side effects. Shares of Amarin (NASDAQ: AMRN), Vascepa’s owner, fell roughly 14 percent in pre-market trading Monday morning.
Amarin has been selling it for years after the FDA approved it in 2012 for patients with very high triglyceride levels—more than 500 mg per deciliter of blood. But that approval did not give Amarin, of Bedminster, NJ (but headquartered in Ireland for tax purposes), the right to market the drug more broadly or claim that Vascepa would improve health outcomes, which has limited sales of the pill. If the FDA expands Vascepa’s label because of the REDUCE-IT data, Amarin will be able to make those claims. REDUCE-IT marks the first time a fish-oil pill has produced statistically significant health outcomes in a big randomized, blinded study.
“It really opens up a new frontier,” said David Maron, a Stanford University professor and director of preventive cardiology at Stanford Healthcare. “I’ve already started prescribing Vascepa to patients who fit the same profile as those in the trial.” (Maron has no ties to Amarin or the REDUCE-IT trial.)
All the patients in the trial were already diagnosed with cardiovascular disease or diabetes, at high risk for more serious health trouble, and taking standard-of-care statins, which lower the bad form of cholesterol (LDL). Entering the study, their median LDL level was 75 mg/dl. Vascepa, like other forms of fish oil with omega-3 fatty acids, does not lower cholesterol. The pill, consisting of pure eicosapentaenoic acid (EPA), reduces triglycerides, which, like LDL, are linked to bad heart health.
“There Is No Perfect Placebo”
They remain enthusiastic, but Maron and others acknowledge that a deeper look at the data unveiled today raises some important questions.
First, the patients taking a placebo saw a median LDL rise of 10 percent, compared to a 3 percent rise in the Vascepa group, perhaps because REDUCE-IT used mineral oil as a placebo, which might block statin absorption and make the Vascepa results look even better in comparison, as the study authors noted. “If mineral oil in the placebo affected statin absorption in some patients, this might have contributed to differences in outcomes between the groups,” they wrote. Even if it’s true, they said, it wasn’t likely to cause the full 25 percent difference in risk—a point Amarin CEO John Thero echoed in an interview.
“There is no strong evidence we’ve seen of biological activity [of mineral oil],” Thero said. “We think it had a minimal effect, if any. There is no perfect placebo. We think we’ve used the right one for what we’re doing.”
Thero has addressed these questions before. Because mineral oil mimics the color and consistency of EPA, Amarin has used it as the placebo in previous Vascepa trials as well, including the one dubbed MARINE that led to the FDA’s approval in 2012 for patients with high triglycerides. The FDA concluded that other factors, not the mineral oil placebo, were behind the results.
Another notable twist in the new paper: The study’s leaders aren’t sure if the patients who benefited did so because Vascepa lowered their triglycerides, or for other reasons. Despite initial plans to only enroll patients with triglyceride levels over 150 mg/dl, it turns out about 10 percent of the participants had lower levels, down to 135 mg/dl. “That isn’t considered high in anyone’s book,” says Maron.
Because of those patients, “at least some of the effect” may be explained by other means, the study leaders wrote in the NEJM paper. In other words, how Vascepa is working is a mystery.
For many doctors, the results are more important than the drug’s mechanism. “It didn’t seem to matter what level triglycerides patients started and ended at” for them to benefit from the pill, said Norman Lepor of the Cedars-Sinai Heart Institute in Los Angeles, a professor at the University of California, Los Angeles Geffen School of Medicine, and one of many doctors who worked on the REDUCE-IT trial. “Until you can figure out the mechanism of action, it’s hard to generalize the effects to other fish oils. The data were impressive, bottom line.”
Two Side Effects To Watch
For the most part, the Vascepa and placebo groups in REDUCE-IT had similar low rates of serious side effects. But Vascepa patients had higher rates of atrial fibrillation—an irregular heartbeat—and peripheral edema, a swelling of the limbs that can be caused by sitting too long or by a long list of conditions. Atrial fibrillation showed up in 5.3 percent of the Vascepa group versus 3.9 percent in the placebo group; edema in 6.5 percent Vascepa, 5 percent placebo.
Ethan Weiss, a professor and cardiologist at the University of California, San Francisco, called the rates “troublesome”; Lepor of UCLA said they were “something to take into account.” Doctors considering Vascepa will have to weigh the risk versus the marked benefit of reducing the risk of death from heart attack and stroke that the study indicates.
When asked if there’s any hesitation adding Vascepa on top of a patient’s cholesterol-lowering medicine, no one interviewed for this article expressed concerns. (Thero says Amarin has seen no drug-drug interactions with Vascepa.)
Vascepa costs about $280 for a month’s supply without insurance coverage. Sales have climbed from about $50 million in 2014 to $180 million in 2017. But the drug has never taken off, in part because Amarin hasn’t had the proof that the drug can prevent heart disease, something that would set its fish oil pill apart from rival prescription-grade fish oils (like Lovaza) or over-the-counter supplements. (A huge study testing whether a combination of Lovaza and vitamin D can reduce the risk of heart attack, stroke, and cancer is due to report results later today.)
Estimating that new Vascepa prescriptions could come in at a minimum of 10 to 12 million, Amarin is expanding its U.S. sales force from 150 to 400. “It’s been a niche indication,” says Thero. “Now we’ll be widening it up.”
Ben Fidler contributed to this report.