Novel ω-3 Formulation Reduced Triglyceride Levels in Severe Hypertriglyceridemia

Dariush Mozaffarian, MD

Resulting from interest in novel ω-3 forumations to reduce blood triglyceride (TG) levels, a recent study aimed to close the gap in uncertainties regarding their effects on bioavailability, and lowering of TG levels.

Led by Dariush Mozaffarian, MD, DrPH, Tufts Friedman School of Nutrition Science and Policy, a team of investigators determined the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA).

Mozaffarian and colleagues found that ω-3-PL/FFA showed reduction in TG levels, as well as showed measures of safety and tolerability at 12 and 26 weeks from the pooled results of 2 large trials.

Methods

The TRILOGY 1 (study of CapRe in Lowering Very High Triglycerides) phase 3 study enrolled 242 participants at 71 US centers from January 2013 - November 2019, while TRILOGY 2 enrolled 278 patients at 93 US, Canadian, and Mexican centers from April 2018 - January 2020.

Both studies were double-blind, placebo-controlled randomized clinical trials testing the efficacy and safety of ω-3-PL/FFA, 4 g/d or matched placebo in an adult patient population aged ≥18 years with fasting TG levels from 500 - 1500 mg/dL.

Those who met eligibility criteria were randomized to receive ω-3–PL/FFA, 4 g/d (including 1.24 g/d of EPA and DHA and 2.4g of total PLs) or matched placebos (cornstarch). They were randomized in a 2.5:1.0 ratio in order to increase the ability to assess safety and tolerability over 26 weeks.

Similar to the individual trials, the primary end point for the pooled analysis was the percentage of change from baseline in fasting TG levels at 12 weeks, comparing ω-3–PL/FFA with placebo, while the change at 26 weeks was considered the key secondary outcomes, with others including non-HDL-C, VLDL-C, HDL-C, and LDL-C levels at 12 and 26 weeks.

Findings

From the 520 patients randomized, the mean age was 54.9 years, with 339 men (65.2%) and a mean body mass index of 21.5 (5.1). The baseline mean TG level measured was 701 (222) mg/dL.

At 12 weeks, TG levels were reduced by 26.0% (95% CI, 20.5% - 31.5%) in the ω-3–PL/FFA group and 15.1% (95% CI, 6.6% - 23.5%) in the placebo group, with a mean treatment difference of -10.9% (95% CI, -20.4% to -1.5%).

Then, the reductions persisted at 26 weeks with TG levels reduced by 33.5% (95% CI, 27.2% - 39.8%) in the ω-3–PL/FFA group and 20.8% (95% CI, 11.5% - 30.1%) in the placebo group, at a mean treatment difference of -12.7% (95% CI, -23.1% - -2.4%, P = .02).

For secondary endpoints, ω-3–PL/FFA showed no significant effect at 12 weeks on mean treatment differences for non–HDL-C (−3.2%, 95% CI, −8.0% - 1.6%, P = .18), VLDL-C (−3.8%, 95% CI, −12.2% - 4.7%, P = .38), HDL-C (0.7%, 95% CI, −3.7% - 5.1%, P = .77), or LDL-C (4.5%, 95% CI, −5.9% - 14.8%, P = .40) levels.

The corresponding differences compared to placebo at 26 weeks were -5.8% (95% CI, -11.3% to -0.3%, P = .04) for non-HDL-C levels, -9.1% (95% CI, -21.5% to 3.2%, P = .15) for VLDL-C levels, 1.9% (95% CI, -4.8% to 8.6%, P = .57) for HDL-C levels, and 6.3% (95% CI, -12.4% - 25.0%, P = .51) for LDL-C levels.

Additionally, effects on the primary endpoint tended to be larger among patients taking statins or cholesterol absorption inhibitors at baseline (mean treatment difference, -19.5%, 95% CI, -34.5% to -4.6%, P = .08) and lower baseline EPA and DHA level (-19.5%, 95% CI, -33.8% to -5.3%, P = .08).

Takeaways

“The pooled results of 2 large trials among patients with severe hypertriglyceridemia show that ω-3–PL/FFA, a novel, krill oil–derived mixture of ω-3, reduced TG levels at 12 and 26 weeks and increased the proportion of patients with TG levels of less than 500 mg/dL,” investigators wrote.

The study, “Effectiveness of a Novel ω-3 Krill Oil Agent in Patients With Severe Hypertriglyceridemia: A Randomized Clinical Trial,” was published in JAMA Network Open.