Fish oil cuts triglycerides by 20%, randomized trial suggests

A 12-week treatment regimen with a purified formulation of fish oil led to a greater-than- 20% reduction of elevated triglyceride levels, as well as other favorable lipid changes, in a phase III, randomized, placebo-controlled trial in about 700 patients.

“AMR101, pure eicosapentaenoic acid, at both 4 g/day and 2 g/day significantly reduced triglyceride levels in statin-treated patients with optimized low-density lipoprotein cholesterol levels and persistently elevated triglyceride levels,”it said. The results reported from the Anchor trial came from a group of 702 patients who had high cardiovascular disease risk and were on “optimized” statin therapy, with an LDL cholesterol level of 100 mg/dL or less, but with a triglyceride level of 200-500 mg/dL.

Although the highest dosage of AMR101 tested (4 d/day) produced an average 22% reduction in triglyceride level beyond the placebo effect after 12 weeks of treatment, the clinical benefit from this triglyceride reduction remains uncertain until results accrue from a longer-term study that has clinical end points but is only now starting, he added.

“The key issue is, What does this mean for outcomes?” said the professor of medicine and pediatrics and chief of the section of atherosclerosis and vascular medicine at Baylor College of Medicine in Houston. “Omega-3 fatty acids have proven safe, but the question is, what will be the event reduction? There was prior evidence for efficacy in ... JELIS (Japan EPA Lipid Intervention Study). I think the odds are higher for this working than for many other treatments,” but, he acknowledged, “no one has ever done a trial on patients with elevated triglycerides.”

JELIS enrolled more than 18,000 men and postmenopausal women, both with and without documented coronary artery disease, who had a total cholesterol level of at least 6.5mmol/L (251mg/dL), and an LDL cholesterol level of at least 4.4 mmol/L (171mg/dL). JELIS randomized patients to treatment with either a statin alone or a statin plus 1.8 g/day eicosapentaenoic acid (EPA), purified from omega-3 fatty acids in fish oil. After an average follow-up of 4.6 years, people in the combined statin-plus EPA group had a 2.8% incidence of a major coronary event, compared with a 3.5% rate in those who were treated with a statin only, a 19% relative risk reduction that was statistically significant.

The JELIS result remains the only evidence documenting that treatment with EPA can reduce the incidence of coronary events, although JELIS did not specifically enroll patients with elevated triglyceride levels at baseline.

“There is no evidence” that lowering triglycerides cuts coronary events, agreed director of atherometabolic research at the Utah Foundation for Biomedical Research in Salt Lake City.

“Results from the five fibrate treatment trials were all suggestive that lowering triglycerides led to reduced events. And the JELIS results showed clinical benefit with fish oil and greater benefit in people who entered with high triglycerides and low level of HDL cholesterol. The EPA [that was] used in JELIS was essentially the same drug as AMR101,” a highly purified form of EPA, he said in an interview. “But we won’t know what AMR10l will do for events until we do a study,” the steering committee for the AMR101 clinical trial scheduled to soon begin.

“I think we have a very good chance of showing benefit. It’s very exciting. If any drug can show a statistically significant benefit on top of a statin, it will be a huge step forward.”

In September, Amarin, the company developing AMR10l, announced that it had filed a New Drug Application with the Food and Drug Administration for AMR10l for treating elevated triglyceride levels, based on both the Anchor results and the results of a similarly designed study, the MARINE (Multicenter, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study With an Open Label Extension) trial, which randomized 229 patients with fasting triglyceride levels of at least 500mg/dL (average baseline level, about 680mg/dL) to treatment with either the 4g/day or 2 g/day dosages of AMR10l or placebo.

Results from the MARINE study, published in September, showed that after 12 weeks the 4g/day dosage of AMR101 1ed to an average 45% placebo-corrected cut in triglycerides.

The clinical end point trial — REDUCE-IT (Reduction of Cardiovascular Events With EPA-Intervention Trial) — that Amarin plans for AMR101 will enroll about 8,000 patients with elevated triglycerides and will last for 6 years. However, Amarin announced last August that a Special Protocol Assessment may allow the FDA to approve AMR10l for treating the mixed dyslipidemia patients who are enrolled in Anchor before REDUCE-IT is completed.

The ANCHOR trial ran at 97 U.S. sites, and enrolled patients who were, on average, 61 years old, 61% of whom were men. Their average body mass index was 33 kg/m 2 and 73% had diabetes. Some 63% were on a “medium” efficacy statin regimen, and 7% were on a “high” efficacy regimen, and 7% were on a “low” efficacy statin regimen. The study’s primary end point was the change in triglyceride level, compared with placebo treatment, and the secondary end points included the change in LDL cholesterol, compared with placebo.

The 4g/day dosage produced an average placebo-corrected 21.5% reduction in triglyceride level, an average 6.2% cut in LDL cholesterol, an average 13.6% decrease in non-HDL cholesterol, and an average 4.9% reduction in HDL cholesterol, all statistically significant changes. The 2 g/day dosage produced smaller placebo-corrected reductions, including a 10.1% cut in triglycerides that was statistically significant, and a non-significant 3.6% decrease in LDL cholesterol. The results also showed that triglyceride reductions were larger in patients who started with higher triglyceride levels at baseline.