Effectiveness of a Novel ω-3 Krill Oil Agent in Patients With Severe Hypertriglyceridemia
Authors: Dariush Mozaffarian, Kevin C. Maki, Harold E. Bays, Fernando Aguilera, Glenn Gould, Robert A. Hegele, Patrick M. Moriarty, Jennifer G. Robinson, Peilin Shi, Josefina F. Tur, Jean-François Lapointe, Sarya Aziz, Pierre Lemieux, Tao Hao, Lubna Mirza, Gaylon Kipp, Wentworth Jarrett, Raymond Little, Hipolito Mariano, Nagapradeep Nagajothi, Kevin Bender, Brian Everhart, Syed Rahman, Lisa Usdan, David Larsen, John McGettigan, Roohi Faiyaz, Jean Foucauld, Calvin Higgins, Fadi Chalhoub, William Freeman, Steven Corse, Stephen Miller, Amol Malanakar, Michael Reschak, Mahendra Jain, Adline Ghazi, Nizar Daboul, Natalia Hegedosh, Mark McKenzie, Marina Raikhel, John Dodd, Leonard Dunn, Stephan Jannach, Stanislaw Sojka, Howard Sherman, James Diener, Barry Horowitz, Marian Shaw, Walter Pharr, John David Lentx, Enrique Hanabergh, Randall Miller, Andres Patron, John Agaiby, Michael Feldman, Gilbert Ledesma, Lidia Rosa Bermudez, Preetham Jetty, Giselle Debs-Perez, Aslam Loya, David Butuk, Amy Cullen, Chris Recknor, Lon Lynn, Lisa Connery, Pedro Ylisastigui, Randall Huling, Marianela Portilla, Humberto Cruz, Roberto Sotolongo, Isaac Dor, Raul Ebran-Gonzalez, Samuel Lederman, Omar Benitez, James Cain, Vivek Awasty, Cindy Martinez, Ramon Hernandez, Michael Dao, Antonio Terrelonge, Jennifer Bellucci Jackson, Robert Busch, Sameul Mujica Trenche, Kim Barbel-Johnson, Carlos Ince, Bernard Garcia, Colby Grossman, George Mitchell Cornett, Faisal Latif, Amer Al-Karadsheh, Robinson Koilpillai, Jorge Alvarez-Moreno, Krista Preston, David Wright, John Eck, Suzanne Fussell, Javier Reyna, Royce Keith Solano, Joseph Raoof, Jean Park, Hayes Williams, Alan Miller, Robert Remler, Miguel Trevino, Charles Harper, Gordon Connor, Nayvis Iglesias, Sashi Makam, Staci Jordan, Suresh Shah, Carl Griffin, Donald Gardner, Oricel Aguiar, Bhola Rama, Luis Zepeda, William French, Matthew Braddock, Joseph Boscia, Oscar Galvez, Bruce Rankin, Stephen Straubing, Cathy Hurley, Jack Rosenfeld, Eric Hogan, Joseph Risser, John Willis, Nabil Andrawis, Khalid Ahmed, Barry Bertolet, Giancarlo Guido, David Erb, Louis Chaykin, James Greenwald, Christin Barlow, Michael Dever, Jorge Santander, John O'Mahony, Naresh Aggarwal, Andre Frechette, Peter Dzongowski, Sam Henein, Dennis O'Keefe, Thomas Ransom, Sudip Datta, Kevin Saunders, Ginette Girard, Daniel Gaudet, Laura Castro Castrezana, Israel Olvera Alvarez, Alberto Esteban Bazzoni Ruiz, Guillermo Antonio, Marco Antonio Alcocer Gamba, Carlos Eduardo, Jose Hector Sanchez Mijangos, Martha Ofelia Pereda Quintero, Carlos  Ramos
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels. <h3>Objective</h3> 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. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> Randomization (2.5:1.0) to ω-3–PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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%];<i>P</i> = .02), with reductions persisting at 26 weeks (mean treatment difference, −12.7% [95% CI, −23.1% to −2.4%];<i>P</i> = .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%];<i>P</i> = .18), VLDL-C (−3.8% [95% CI, −12.2% to 4.7%];<i>P</i> = .38), HDL-C (0.7% [95% CI, −3.7% to 5.1%];<i>P</i> = .77), or LDL-C (4.5% [95% CI, −5.9% to 14.8%];<i>P</i> = .40) levels; corresponding differences at 26 weeks were −5.8% (95% CI, −11.3% to −0.3%;<i>P</i> = .04) for non–HDL-C levels, −9.1% (95% CI, −21.5% to 3.2%;<i>P</i> = .15) for VLDL-C levels, 1.9% (95% CI, −4.8% to 8.6%;<i>P</i> = .57) for HDL-C levels, and 6.3% (95% CI, −12.4% to 25.0%;<i>P</i> = .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%];<i>P</i>= .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%];<i>P</i> = .08 for interaction). ω-3–PL/FFA was well tolerated, with a safety profile similar to that of placebo. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifiers:NCT03398005andNCT03361501