Effectiveness of a Novel ω-3 Krill Oil Agent in Patients With Severe Hypertriglyceridemia: A Randomized Clinical Trial

Abstract

Importance: Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels.

Objective: To determine the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA [CaPre]), measured by fasting TG levels and other lipid parameters in severe hypertriglyceridemia.

Design, setting, and participants: This study pooled the results of 2 identical randomized, double-blind, placebo-controlled trials. TRILOGY 1 (Study of CaPre in Lowering Very High Triglycerides) enrolled participants at 71 US centers from January 23, 2018, to November 20, 2019; TRILOGY 2 enrolled participants at 93 US, Canadian, and Mexican centers from April 6, 2018, to January 9, 2020. Patients with fasting TG levels from 500 to 1500 mg/dL, with or without stable treatment with statins, fibrates, or other agents to lower cholesterol levels, were eligible to participate.

Interventions: Randomization (2.5:1.0) to ω-3-PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks.

Main outcomes and measures: The primary outcome was the mean percentage of change in TG levels at 12 weeks; persistence at 26 weeks was the key secondary outcome. Other prespecified secondary outcomes were effects on levels of non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), HDL-C, and low-density lipoprotein cholesterol (LDL-C); safety and tolerability; and TG level changes in prespecified subgroups.

Results: A total of 520 patients were randomized, with a mean (SD) age of 54.9 (11.2) years (339 men [65.2%]), mean (SD) body mass index of 31.5 (5.1), and baseline mean (SD) TG level of 701 (222) mg/dL. Two hundred fifty-six patients (49.2%) were of Hispanic or Latino ethnicity; 275 (52.9%) had diabetes; and 248 (47.7%) were receiving statins. In the intention-to-treat analysis, 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 at 12 weeks (mean treatment difference, -10.9% [95% CI, -20.4% to -1.5%]; P = .02), with reductions persisting at 26 weeks (mean treatment difference, -12.7% [95% CI, -23.1% to -2.4%]; P = .02). Compared with placebo, ω-3-PL/FFA had no significant effect at 12 weeks on mean treatment differences for non-HDL-C (-3.2% [95% CI, -8.0% to 1.6%]; P = .18), VLDL-C (-3.8% [95% CI, -12.2% to 4.7%]; P = .38), HDL-C (0.7% [95% CI, -3.7% to 5.1%]; P = .77), or LDL-C (4.5% [95% CI, -5.9% to 14.8%]; P = .40) levels; corresponding differences 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% to 25.0%; P = .51) for LDL-C levels. Effects on the primary end point did not vary significantly by age, sex, race and ethnicity, country, qualifying TG level, diabetes, or fibrate use but 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 for interaction) and with lower (less than median) baseline blood eicosapentaenoic acid plus docosahexaenoic acid levels (-19.5% [95% CI, -33.8% to -5.3%]; P = .08 for interaction). ω-3-PL/FFA was well tolerated, with a safety profile similar to that of placebo.

Conclusions and relevance: This study found that ω-3 -PL/FFA, a novel krill oil-derived ω-3 formulation, reduced TG levels and was safe and well tolerated in patients with severe hypertriglyceridemia.

Trial registration: ClinicalTrials.gov Identifiers: NCT03398005 and NCT03361501.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mozaffarian reported serving as a consultant for Acasti Pharma Inc as principal investigator of this trial; receiving research funding from the National Institutes of Health, the Gates Foundation, and the Rockefeller Foundation; personal fees from Barilla, Cleveland Clinic Foundation, Danone SA, and Motif FoodWorks; chapter royalties from UpToDate; serving on the scientific advisory board of Beren Therapeutics PBC, Brightseed, Calibrate, DayTwo (ended June 2020), Elysium Health, Filtricine Inc, Foodome Inc, HumanCo, January, Perfect Day Inc, Season, and Tiny Organics; and holding stock ownership in Calibrate and HumanCo outside the submitted work. Dr Maki reported receiving research grants from and consulting for Acasti Pharma Inc and Matinas BioPharma Holdings Inc, and receiving research funding from Indiana University Foundation, Pharmavite, Novo Nordisk A/S, General Mills Inc, The Kellogg Company, and PepsiCo Inc, and consulting for 89bio Inc, and NewAmsterdam Pharma outside the submitted work. Dr Bays reported receiving research grants from Acasti Pharma Inc. Dr Aguilera reported receiving research grants from Acasti Pharma Inc. Dr Gould reported receiving research grants from Acasti Pharma Inc. Dr Hegele reported receiving research grants from Acasti Pharma Inc and personal fees from Akcea-Ionis, Amgen Inc, Arrowhead Pharmaceuticals, HLS Therapeutics Inc, Novartis International AG, and Pfizer Inc outside the submitted work. Dr Moriarty reported receiving research grants from Acasti Pharma Inc. Dr Robinson reported receiving research grants to the institution from Acasti Pharma Inc, Amarin Corporation, Amgen Inc, Astra-Zeneca, Eli Lilly & Co, Esperion Therapeutics Inc, The Medicines Company, Merck & Co Inc, Novartis International AG, Novo Nordisk A/S, and Regeneron Pharmaceuticals Inc, and consulting fees from COR2ED, Getz Pharma Limited, The Medicines Company, and Novartis International AG. Dr Shi reported consulting for Acasti Pharma Inc for performing statistical analyses on this trial. Dr Tur reported receiving research grants from Acasti Pharma Inc. Dr Lapointe reported owning stock or stock options in Acasti Pharma Inc. Dr Aziz reported owning stock or stock options in Acasti Pharma Inc. Dr Lemieux reported serving chief operating officer/chief strategy officer of Acasti Pharma Inc during the conduct of the study and outside the submitted work and holding a patent for CaPre. No other disclosures were reported.

Figures

Figure 1.. Percentage Changes in Fasting Triglyceride (TG) Levels Between Baseline and Week 26 (N = 520)

The 520 participants received ω-3–phospholipid/free fatty acid (ω-3–PL/FFA), 4 g/d, or placebo. Values are least-square mean differences from baseline, with 95% CIs (error bars) from analysis of covariance, including the main effects of treatment; qualifying TG category (≤750 vs >750 mg/dL); use of statins, cholesterol-absorption inhibitors, and/or proprotein convertase subtilisin/kexin type 9 serine protease inhibitors (yes or no); and baseline TG value as covariates.

Figure 2.. Percentage Change From Baseline in Fasting Triglyceride Levels According to Tertiles of Achieved Concentrations of Plasma Phospholipid Eicosapentaenoic Acid and Docosahexaenoic Acid

Values are least-square mean differences from baseline (circles), with 95% CIs (error bars) from the analysis of covariance, including main effects of treatment; qualifying triglyceride (TG) category (≤750 vs >750 mg/dL); use of statin, cholesterol-absorption inhibitors, and/or proprotein convertase subtilisin/kexin type 9 serine protease inhibitors (yes or no); and baseline TG value as covariates. The ranges of achieved eicosapentaenoic acid plus docosahexaenoic acid concentrations in each tertile, assessed as percent of fatty acids, are as follows: T1, 1.2 to 2.4 (12 weeks) and 1.1 to 2.3 (26 weeks); T2, 2.5 to 3.6 (12 weeks) and 2.4 to 3.5 (26 weeks); T3, 3.7 to 9.0 (12 weeks) and 3.6 to 11.3 (26 weeks).

Figure 3.. Percentage Changes in Fasting Triglyceride (TG) Levels at 12 Weeks Across Prespecified Subgroups

Comparisons were between ω-3–phospholipid/free fatty acid (ω-3–PL/FFA), 4 g/d, or placebo. Values are least-square mean differences from baseline, with P values based on analysis of covariance (ANCOVA), including main effects of treatment; qualifying TG category (≤750 vs >750 mg/dL); use of statin, cholesterol-absorption inhibitors (CAIs), and/or proprotein convertase subtilisin/kexin type 9 serine protease inhibitors; and baseline value as covariates. P value for interaction was tested by including a main effect of subgroup and a treatment-by-subgroup interaction effect within the same ANCOVA model. DHA indicates docosahexaenoic acid; EPA, eicosapentaenoic acid.