title: A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial).
abstract: BACKGROUND
  A novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia.
  
  
  OBJECTIVE
  This study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non-HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease.
  
  
  METHODS
  In this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥ 200 mg/dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events.
  
  
  RESULTS
  In the 627 subjects in the intention to treat sample, non-HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (-3.9% and -6.9%, respectively) compared with OO (-0.9%) (both, P < 0.05), as were TG levels (-14.6% and -20.6%, respectively, vs -5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) (P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d.
  
  
  CONCLUSIONS
  OM3-FFA was well tolerated and lowered non-HDL-C and TG levels at both 2- and 4-g/d dosages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental improvements compared with 2 g/d.
authors.affiliation: Biofortis Clinical Research, Addison, Illinois. Electronic address: kevin.maki@mxns.com.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Maki
authors.forename: David G
authors.initials: DG
authors.lastname: Orloff
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Nicholls
authors.forename: Richard L
authors.initials: RL
authors.lastname: Dunbar
authors.forename: Eli M
authors.initials: EM
authors.lastname: Roth
authors.forename: Danielle
authors.initials: D
authors.lastname: Curcio
authors.forename: Judith
authors.initials: J
authors.lastname: Johnson
authors.forename: Douglas
authors.initials: D
authors.lastname: Kling
authors.forename: Michael H
authors.initials: MH
authors.lastname: Davidson
mesh_terms: D000368:Aged; D001682:Biological Availability; D002318:Cardiovascular Diseases / Q000097:blood / Q000517:prevention & control; D008076:Cholesterol, HDL / Q000097:blood; D003131:Combined Modality Therapy; D019587:Dietary Supplements; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015228:Hypertriglyceridemia / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D055118:Medication Adherence; D008875:Middle Aged; D000069463:Olive Oil; D010938:Plant Oils / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: D008076:Cholesterol, HDL; D005230:Fatty Acids, Nonesterified; D015525:Fatty Acids, Omega-3; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069463:Olive Oil; D010938:Plant Oils; D014280:Triglycerides
keywords: LDL-C; hypertriglyceridemia; omega-3 fatty acids; statins; triglycerides