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

Abstract Background: Apolipoprotein CIII, present on some HDL, LDL, and VLDL, promotes dyslipidemia and activates atherogenic processes. Lipoprotein subspecies containing apoCIII adversely affect CVD risk. For example, it has been shown that LDL with apoCIII is a stronger predictor of CVD than LDL without apoCIII, and that HDL with apoCIII is associated with increased CVD. Small studies have suggested that omega 3 fatty acids may reduce plasma total apoCIII in addition to their TG-lowering effects, but there is a lack of detailed analysis in regards to which lipoprotein subtypes are affected by treatment. We studied the effect of omega-3 carboxylic acids on apoCIII concentrations in HDL, LDL, and VLDL; and on the concentrations of subspecies of HDL, LDL, and VLDL that contain or do not contain apoCIII. Methods: We analyzed plasma samples from the EVOLVE trial (EpanoVa fOr Lowering Very high triglyceridEs), a 12 week double-blind study of 399 subjects with fasting TG between 500 mg/dl and 2000 mg/dl who were randomized to Epanova (omega-3 carboxylic acids) 2, 3 or 4 g/d or olive oil (placebo). Our analysis included 273 subjects who were randomized to olive oil, Epanova 2 g/d or Epanova 4 g/d and had a baseline and end of treatment sample. Epanova contains EPA (50-60%) and DHA (15-25%) in free fatty acid form. Results: Epanova decreased plasma total apoCIII, apoCIII in HDL and LDL relative to olive oil, by 11% (2 g) and 17% (4 g)(p=0.01), by 10% (2 g) and 12% (4 g)(p=0.04), and by 13% (2 g) and 31% (4 g)(p=0.007), respectively. Epanova increased selectively the subtype of LDL that does not have apoCIII, a subtype that has a weak relation to CHD, by 10% (2 g) and 15% (4 g)(p=0.006). Importantly, treatment did not increase the concentration of LDL with apoCIII, a subtype of LDL that predicts CHD more strongly than LDL without apoCIII (p=0.58). Epanova decreased fasting TG by 34% (2 g) and 42% (4 g) (p<0.0001) relative to olive oil. Conclusion: Omega-3 carboxylic acids at dosages of 2 and 4 g/d are effective for lowering total plasma apoCIII and apoCIII in HDL and LDL, without raising LDL with apoCIII. The effect of omega-3 carboxylic acids to raise LDL concentration is limited to the LDL subspecies without apoCIII. Reduction in apoCIII may be a mechanism for the TG lowering effects of omega-3 carboxylic acids.