A Head-to-Head Comparison of a Free Fatty Acid Formulation of Omega-3 Pentaenoic Acids Versus Icosapent Ethyl in Adults With Hypertriglyceridemia: The ENHANCE-IT Study

Kevin C. Maki, Harold E. Bays, Christie M. Ballantyne, James A. Underberg, John J. P. Kastelein, Judith B. Johnson, James J. Ferguson

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BACKGROUND: MAT9001 is an omega-3 free fatty acid (FFA) formulation containing mainly eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA). Compared with icosapent ethyl (EPA-ethyl esters [EE]), EPA+DPA-FFA previously showed en-hanced triglyceride lowering and higher plasma EPA when both were administered once daily with a very– low fat diet. This trial compared pharmacodynamic responses and plasma omega-3 levels following twice daily dosing, with meals, of EPA+DPAFFA and EPA-EE in hypertriglyceridemic subjects consuming a Therapeutic Lifestyle Changes diet. METHODS AND RESULTS: This open-label, randomized, 2-way crossover trial, with 28-day treatment periods separated by ≥28-day washout, was conducted at 8 US centers and included 100 subjects with fasting triglycerides 1.70 to 5.64 mmol/L (150– 499 mg/dL) (median 2.31 mmol/L [204 mg/dL]; 57% women, average age 60.3 years). The primary end point was least squares geometric mean percent change from baseline plasma triglycerides. In the 94 subjects with analyzable data for both treatment periods, EPA+DPA-FFA and EPA-EE reduced least squares geometric mean triglycerides from baseline: 20.9% and 18.3%, respectively (P=not significant). EPA+DPA-FFA reduced least squares geometric mean high-sensitivity C-reactive protein by 5.8%; EPA-EE increased high-sensitivity C-reactive protein by 8.5% (P=0.034). EPA+DPA-FFA increased least squares geometric mean plasma EPA, DPA, and total omega-3 (EPA+docosahexaenoic acid+DPA) concentrations by 848%, 177%, and 205%, respectively, compared with corresponding changes with EPA-EE of 692%, 140%, and 165% (all P<0.001). EPA+DPA-FFA increased docosahexaenoic acid by 1.7%; EPA-EE decreased docosahexaenoic acid by 3.3% (P=0.011). Lipoprotein cholesterol and apolipoprotein responses did not differ between treatments. CONCLUSIONS: EPA+DPA-FFA raised plasma EPA, DPA, and total omega-3 significantly more than did EPA-EE. EPA+DPA-FFA also reduced triglycerides and high-sensitivity C-reactive protein without increasing low-density lipoprotein cholesterol. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT04177680.

Original languageEnglish
Article numbere024176
JournalJournal of the American Heart Association
Issue number6
Publication statusPublished - 15 Mar 2022


  • docosapentaenoic acid
  • eicosapentaenoic acid
  • hypertriglyceridemia
  • omega-3 fatty acids
  • triglycerides

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