The effect of omega-3 carboxylic acids on apolipoprotein CIII-containing lipoproteins in severe hypertriglyceridemia

J Clin Lipidol. 2016 Nov-Dec;10(6):1442-1451.e4. doi: 10.1016/j.jacl.2016.09.005. Epub 2016 Sep 13.


Background: Lipoprotein subspecies containing apoCIII adversely affect cardiovascular disease (CVD) risk; for example, low density lipoprotein (LDL) with apoCIII is a stronger CVD predictor than LDL without apoCIII. The Epanova for Lowering Very High Triglycerides (EVOLVE) trial showed that Epanova (omega-3 carboxylic acids [OM3-CA]) significantly lowered TG and apoCIII but raised LDL-C. However, it is unknown what subspecies of LDL were affected by treatment.

Objective: To determine how lipoprotein subspecies are affected by omega-3 fatty acid treatment, we studied the effect of OM3-CA on apoCIII concentrations in high density lipoprotein (HDL), LDL, and very low density lipoprotein (VLDL) and on the concentrations of subspecies of HDL, LDL, and VLDL that contain or do not contain apoCIII.

Methods: We analyzed plasma from a subset of subjects from the EVOLVE trial, a 12-week double-blind study of 399 subjects with fasting TG of 500 to 2000 mg/dL who were randomized to OM3-CA 2, 3, or 4 g/d or olive oil (placebo).

Results: OM3-CA significantly reduced plasma apoCIII relative to placebo, as well as apoCIII in HDL, and apoCIII in LDL. Treatment did not significantly affect the concentration of LDL with apoCIII, a subspecies highly associated with CVD risk. OM3-CA increased selectively the concentration of LDL that does not contain apoCIII, a subspecies with a weak relation to coronary heart disease. The reduction in apoCIII was associated with plasma increases in eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid and decreases in linoleic, palmitic, and oleic acids.

Conclusion: Reduction in apoCIII may be a mechanism for the TG-lowering effects of OM3-CA. The increase in LDL-C seen in the EVOLVE trial may not be associated with increased risk of CVD.

Keywords: Apolipoprotein CIII; Diet effects and lipid metabolism; Epanova; Fish oil; Omega-3 fatty acids; Severe hypertriglyceridemia.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apolipoprotein C-III / blood*
  • Apolipoprotein C-III / isolation & purification
  • Cardiovascular Diseases / etiology
  • Docosahexaenoic Acids / blood
  • Double-Blind Method
  • Eicosapentaenoic Acid / blood
  • Fatty Acids, Omega-3 / therapeutic use*
  • Female
  • Humans
  • Hypertriglyceridemia / complications
  • Hypertriglyceridemia / drug therapy*
  • Hypertriglyceridemia / pathology
  • Lipoproteins, HDL / blood*
  • Lipoproteins, LDL / blood*
  • Lipoproteins, VLDL / blood
  • Male
  • Middle Aged
  • Olive Oil / therapeutic use
  • Placebo Effect
  • Risk Factors
  • Severity of Illness Index
  • Triglycerides / blood


  • Apolipoprotein C-III
  • Fatty Acids, Omega-3
  • Lipoproteins, HDL
  • Lipoproteins, LDL
  • Lipoproteins, VLDL
  • Olive Oil
  • Triglycerides
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid