High-Dose DHA Has More Profound Effects on LDL-Related Features Than High-Dose EPA: The ComparED Study

J Clin Endocrinol Metab. 2018 Aug 1;103(8):2909-2917. doi: 10.1210/jc.2017-02745.


Context: Supplementation with high-dose docosahexaenoic acid (DHA) increases serum low-density lipoprotein (LDL) cholesterol (LDL-C) concentrations more than high-dose eicosapentaenoic acid (EPA). The mechanisms underlying this difference are unknown.

Objective: To examine the phenotypic change in LDL and mechanisms responsible for the differential LDL-C response to EPA and DHA supplementation in men and women at risk of cardiovascular disease.

Design, setting, participants, and intervention: In a double-blind, controlled, crossover study, 48 men and 106 women with abdominal obesity and subclinical inflammation were randomized to a sequence of three treatment phases: phase 1, 2.7 g/d of EPA; phase 2, 2.7 g/d of DHA; and phase 3, 3 g/d of corn oil. All supplements were provided as three 1-g capsules for a total of 3 g/d. The 10-week treatment phases were separated by a 9-week washout period.

Main outcome measure: In vivo kinetics of apolipoprotein (apo)B100-containing lipoproteins were assessed using primed-constant infusion of deuterated leucine at the end of each treatment in a subset of participants (n = 19).

Results: Compared with EPA, DHA increased LDL-C concentrations (+3.3%; P = 0.038) and mean LDL particle size (+0.7 Å; P < 0.001) and reduced the proportion of small LDL (-3.2%; P < 0.01). Both EPA and DHA decreased proprotein convertase subtilisin/kexin type 9 concentrations similarly (-18.2% vs -25.0%; P < 0.0001 vs control). Compared with EPA, DHA supplementation increased both the LDL apoB100 fractional catabolic rate (+11.4%; P = 0.008) and the production rate (+9.4%; P = 0.03).

Conclusions: The results of the present study have shown that supplementation with high-dose DHA increases LDL turnover and contributes to larger LDL particles compared with EPA.

Trial registration: ClinicalTrials.gov NCT01810003.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cholesterol, LDL / blood*
  • Cross-Over Studies
  • Dietary Supplements
  • Docosahexaenoic Acids / administration & dosage
  • Docosahexaenoic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Eicosapentaenoic Acid / administration & dosage
  • Eicosapentaenoic Acid / pharmacology*
  • Female
  • Humans
  • Inflammation / blood*
  • Inflammation / diet therapy
  • Male
  • Middle Aged
  • Obesity, Abdominal / blood*
  • Obesity, Abdominal / diet therapy
  • Young Adult


  • Cholesterol, LDL
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid

Associated data

  • ClinicalTrials.gov/NCT01810003