REDUCE-IT: Serum EPA Levels Hold Key to Vascepa's Dramatic CV Benefits

A prescription fish oil pill sharply cut the risk of cardiovascular (CV) events and deaths, but no one understood how.

Until today.

It appears that higher levels of the omega-3 fatty acid eicosapentaenoic acid (EPA) found in the blood after patients took the pill, icosapent ethyl, are the reason why they were less likely to have a CV event, according to findings1 presented in a late-breaking session of the 2020 American College of Cardiology/World Congress of Cardiology Virtual Experience.

The results not only answer questions that have surrounded the purified fish oil pill, sold as Vascepa, but also open doors for new areas of research, said Deepak L. Bhatt, MD, MPH, lead investigator of REDUCE-IT, the study that first revealed the pill’s CV benefits.

“A major missing piece of the puzzle, and what many clinicians want to know, is how icosapent ethyl actually works to produce such dramatic cardiovascular risk lowering,” said Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, in a statement. “On-treatment EPA levels achieved via the drug strongly correlated with lower rates of cardiovascular events, heart attack, stroke, coronary revascularization procedures, unstable angina, sudden cardiac arrest, new heart failure, or death for any reason.”

Today’s findings do more than explain how 1 therapy works. They also suggest that the change in serum EPA is an important biomarker in cardiovascular risk, as it turned out be highly predictive of icosapent ethyl’s success, more so than traditional markers such as changes in cholesterol, apolipoprotein B, or even triglycerides—even though treatment for this last lipid won the drug its original 2012 approval.

Icosapent ethyl is an EPA-only therapy; some fish-oil derived treatments contain docosahexaenoic acid, or DHA, a different omega-3 fatty acid. Besides highlighting how icosapent ethyl works, the new findings show that EPA, not DHA, is responsible for the reduction of CV events. “I think this finding is going to usher in a whole new era of cardiovascular therapies. We are, in a sense, where we were with statins when the first one came out,” Bhatt said.

Since the first results for REDUCE-IT were reported in November 2018,2 investigators have been dogged by the question: How could a fish oil pill so effectively prevent heart attacks, strokes, and even deaths? It was clear that the dramatic benefits—a 30% reduced risk of first and future CV events—could not be explained by a reduction in triglycerides. Based on recent results, in December Amarin gained FDA approval for icosapent ethyl as an add-on therapy for certain patients with established CV disease or diabetes.

Bhatt and the REDUCE-IT investigators looked for potential explanations to the dramatic CV reductions among other biomarkers. The original trial enrolled 8179 patients with elevated CV risk who were already being treated with statins. Initial results showed that a high dose of icosapent ethyl (4 g/day) cut the risk of an initial heart attack, stroke, coronary procedures, hospitalization for unstable angina, or CV death by 25% over 4.9 years. Patients in REDUCE-IT were already being treated with other standard therapies, which drove the conclusion that the fish oil pill was the reason for the drop in CV events.

First, they looked at whether the participants had different levels of serum EPA when they joined the study that could explain the results. They found there was no difference—regardless of baseline EPA level, participants saw the same degree of benefit. Instead, what mattered was achieved EPA levels among those taking the drug. Overall, the drug increased serum EPA levels 386% after the first year compared with placebo; meanwhile, levels of DHA fell by 2.9%, which Bhatt said means that the CV benefits are likely linked to EPA, not DHA.

“The higher the EPA level in their blood, the lower the rates of the different cardiovascular events, cardiovascular deaths, and even total mortality,” Bhatt said.

Bhatt’s recent work shows he is untangling a multilayered explanation for EPA’s benefits. A study presented at the American Heart Association in November 2019 showed that icosapent ethyl drug may slow the advance or coronary plaques that contribute to heart attacks. In a review paper published earlier this week, Bhatt and coauthors wrote, “This clinical benefit likely arises from multiple molecular mechanisms.…Indeed, human plaques readily incorporate EPA, which may render them less likely to trigger clinical events.”

And the effects of EPA may not be limited to prevention of CV events. A 2014 paper by Yagi et al in Nutrition Journal found that low serum EPA concentration is linked with cognitive function in patients with coronary artery disease, “suggesting that a low serum EPA level is a risk factor for cognitive impairment independent of cardiac function, including left ventricular ejection fraction.”

The American Journal of Managed Care® contacted Bhatt by email and asked about icosapent ethyl’s potential to prevent cognitive decline. “That is a very interesting question,” Bhatt wrote. “By virtue of significantly preventing strokes, I would expect that icosapent ethyl would have an impact on that proportion of cognitive decline that is due to strokes, so called vascular dementia, assuming a large enough long-term study was done.”

“Whether there is a broader effect on cognitive decline or dementia is currently being studied,” he said, noting a study by the Veterans Administration with which he is not involved. That is a small study of 150 adults who are randomized 1:1 to take the fish-oil pill or placebo so that researchers can assess the drug’s impact on biomarkers for Alzheimer disease.

Amarin sponsored the study.