Serum EPA levels from pharma-grade EPA drive CV benefits

A substudy of the REDUCE-IT* trial – REDUCE-IT EPA** – presented at the ACC.20/WCC Virtual Meeting shows that the level of eicosapentaenoic acid (EPA) in the blood achieved from the consumption of icosapent ethyl (IE) – a pure, stable EPA ethyl ester – propelled the substantial reductions in cardiovascular (CV) event rates in statin-treated patients.

These findings come on the heels of REDUCE-IT and an exploratory analysis reflecting substantial CV benefits derived from IE. [N Engl J Med 2019;380:11-22; J Am Coll Cardiol 2019;73:2791-2802]

“A major missing piece of the puzzle, and what many clinicians want to know, is how IE actually works to produce such dramatic CV-risk lowering,” said lead author Dr Deepak Bhatt from the Brigham and Women’s Hospital in Boston, Massachusetts, US, in a press release.

REDUCE-IT EPA explored the link between serum EPA levels and CV events achieved with IE. The team used data from REDUCE-IT wherein 8,179 statin-treated patients were randomized 1:1 to receive either IE 4 g daily or placebo and followed for a median of 4.9 years. [ACC.20/WCC, abstract 411-14]

On-treatment analysis showed that derived serum EPA concentrations of IE recipients increased by ~400 percent across the study, which was substantially higher than those who received placebo (median change from baseline, 363.9 percent vs 0.2 percent; p<0.0001).

“[These suggest that] EPA levels achieved via IE strongly correlate with lower rates of CV events, heart attack, stroke, coronary revascularization procedures, unstable angina, sudden cardiac arrest, new heart failure, or death for any reason,” said Bhatt.

Further exploration using a continuous variable model showed that as EPA levels increase, the primary endpoint*** decreased (p<0.001). Similar findings were observed for the key secondary endpoint^#, CV death, and total mortality (p<0.001 for all). “[These] suggest that the higher the on-treatment serum EPA level, the greater the CV benefit observed,” said Bhatt.

However, Bhatt indicated that the findings only apply to this specific IE formulation. “EPA within blood can distribute differentially, potentially resulting in differential downstream tissue distribution.” Moreover, omega-3 fatty acid mixtures contain both EPA and docosahexaenoic acid, which appear to have varying biological effects. “[This] might explain the lack of [CV] benefit in other omega-3 trials.”

“[Taken together,] these data provide a mechanistic underpinning for the large risk reductions seen in multiple endpoints with IE in REDUCE-IT … [Our findings] strongly suggest that achieved EPA levels are a key mechanism of the CV benefit [of IE],” said Bhatt.

While the findings imply that the 4-g dose is optimal in achieving CV efficacy, it remains unclear whether a higher dose would render greater CV benefit, noted Bhatt. “[The 4-g daily dose] is what provided the large degree of risk reduction … As a trialist, that’s what I would stick with. [However, this] is certainly a topic that might be worthy of study … I think there will be more science to come from REDUCE-IT that might be able to answer that question more specifically,” he said.

Diet, supplements

In terms of diet, Bhatt underscored that high consumption of omega-3-containing food may not be sufficient in delivering “natural” EPA levels. “A diet high in fish and seafood will generally lead to higher levels of serum EPA … [However,] people [consuming multiple servings] of fish and seafood and who have the highest levels of EPA one can attain naturally [may] still benefit [from IE].”

Regarding supplements, Bhatt noted that the pill burden one will have to take to get anywhere near the range of EPA achieved in the study would be around 20–30 daily. The potential risk from the other components of the supplement should also be taken into context, he added. “[Oversupplementation] would be unlikely to give these levels of EPA.”