The Effect of E-EPA on Circulating LDL and Plasma Lipid Metabolism (EPA&LDL)

The Effect of Ethyl Eicosapentaenoic Acid on Circulating Low-density Lipoproteins and Plasma Lipid Metabolism in Healthy Volunteers

40-70 healthy volunteers of ages 18 to 65 participate in a E-EPA-diet where 3,9 grams of E-EPA is added to their normal diet and lifestyles for a month. Blood samples will be collected before the study and at weeks 1 and 4 and also, two weeks after finishing the diet. Main study focuses are LDL aggregation susceptibility, lipid composition and proteoglycan binding affinity. In addition, important plasma lipid metabolism enzymes and lipid mediated resolvins are measured as well as several baseline characteristics.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases; Atherosclerosis; Low-density Lipoproteins Aggregation Susceptibility; Low-density Lipoprotein Lipid Composition
• Intervention / Treatment: Dietary supplement: Ethyl-Eicosapentaenoic Acid (E-EPA)

Detailed Description

Four grams of daily E-EPA was found to significantly decrease atherosclerotic cardiovascular diseases in the REDUCE-IT study. In the upcoming study the effect of E-EPA to low-density lipoprotein (LDL) aggregation susceptibility is measured using dynamic light scattering technique to continuously measure particles size while inducing aggregation. LDL Lipid composition is analyzed using electrospray mass spectrometer optimized for lipid measurements. Previously is reported that the aggregation susceptibility is affected by the lipid composition which is modifiable (Ruuth et. al. Eur.H.Journal 2018). Common disease factors such as total cholesterol, LDL, HDL, triglycerides, ApoB-100, ApoA-I, Lp(a) and different modified LDL levels are measured. Also, activities of lipid metabolism enzymes like PON-1, LCAT, CETP, PLTP and lipid mediated resolvins are looked into. Objective is to identify changes and possible pathways that are altered by the increase of E-EPA and to use the data to possibly explain the health benefits of EPA.

Update at study conclusion 17.6.2025. Covid-19 halted our study progression leading to a partial cohort (final n=38). Covid-19 restrictions also prevented us from measuring plasma lipid metabolism enzymes and lipid mediated resolvins. As a results we expanded the lipoprotein lipidomics analysis to consist all three lipoprotein fractions (VLDL, LDL, and HDL) using LC/MS. Finally a clinical cardiovascular risk score assessment was also performed (CERT2/Hertta-test).

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland
    • Wihuri Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy normolipidemic

Exclusion Criteria:

• Prescription of blood thinner medicine
• Circulating Low-density lipoprotein > 5mmol/l, Triglycerides >3mmol/l
• Chronic use of pain medication
• Fish allergy
• Pregnancy
• Breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: E-EPA-diet group; All the study participants will receive the same treatment. 3.9g of E-EPA in capsules, which also include 75µg of D3-vitamin, daily for 28 days.	Dietary supplement: Ethyl-Eicosapentaenoic Acid (E-EPA); 3,9 grams of E-EPA (Icosapent ethyl) is added to participants' normal diet.; Other Names: E-EPA; Icosapent ethyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LDL Aggregation Susceptibility	LDL aggregation susceptibility was induced in vitro by sphingomyelinase and measured using dynamic light scattering. Time-size curves were generated, and the inflection point (EC50)-the midpoint of the most rapid aggregation-was determined by nonlinear regression with a modified Hill equation. A longer time to reach EC50 indicates lower aggregation susceptibility, and thus a lower risk of future cardiovascular events.	28 days
Total Blood Triglycerides	Percentage change in blood triglycerides after IPE-supplementation (day 28) compared to the baseline (day 0). Percentage change was calculated as follows: [(day 28 - day 0) / day 0] x 100.	28 days
EPA Incorporation Into LDL	Total concentration of eicosapentaenoic acid in LDL lipoprotein fraction at baseline (day 0), and after IPE-supplementation (day 28).	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increases in EPA mediated resolvins	Increases in circulating resolvins, derived from EPA	30 days
Changes in lipid metabolizing enzymes	Changes in activities of circulating lipid metabolizing enzymes such as PON-1, LCAT, PLTP and CETP	30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipoprotein Retention	The binding of lipoproteins to aortic proteoglycans, measured ex vivo. At the end of the assay lipoprotein-associated bound cholesterol is measured in each well and compared to control wells to determine the binding probability of LDL particles to aortic proteoglycans.	28 days
Coronary Event Risk Test 2	A clinical risk rest used to assess 10-year Coronary event risk. Based on plasma ceramides and phospholipids. Lower risk score indicates smaller future risk of coronary events. The four risk categories are: 0-3 (Low risk), 4-6 (Moderate risk), 7-8 (High risk), and 9-12 (Very high risk).	28 days

Collaborators and Investigators

• Sponsor: Wihuri Research Institute
• Collaborators: University of Helsinki
• Investigators: Principal Investigator: Katariina Öörni, Professor, Ph.D, Wihuri Research Institute

Publications and helpful links

General Publications

• Ruuth M, Nguyen SD, Vihervaara T, Hilvo M, Laajala TD, Kondadi PK, Gistera A, Lahteenmaki H, Kittila T, Huusko J, Uusitupa M, Schwab U, Savolainen MJ, Sinisalo J, Lokki ML, Nieminen MS, Jula A, Perola M, Yla-Herttula S, Rudel L, Oorni A, Baumann M, Baruch A, Laaksonen R, Ketelhuth DFJ, Aittokallio T, Jauhiainen M, Kakela R, Boren J, Williams KJ, Kovanen PT, Oorni K. Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Eur Heart J. 2018 Jul 14;39(27):2562-2573. doi: 10.1093/eurheartj/ehy319.
• Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10.
• Preprint/ Lauri Äikäs, Petri T. Kovanen, Martina Lorey, Reijo Laaksonen, Minna Holopainen, Hanna Ruhanen, Reijo Käkelä, Matti Jauhiainen, Martin Hermansson, Katariina Öörni. Remodelling of plasma lipoproteins by icosapent ethyl -supplementation and its impact on cardiovascular disease risk markers in normolipidemic individuals. MedRxiv 2024.11.27.24318042; doi: https://doi.org/10.1101/2024.11.27.24318042

Helpful Links

• Preprint of the research article from the study

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2019
• Primary Completion (Actual): June 30, 2024
• Study Completion (Actual): December 31, 2024

Study Registration Dates

• First Submitted: November 1, 2019
• First Submitted That Met QC Criteria: November 1, 2019
• First Posted (Actual): November 5, 2019

Study Record Updates

• Last Update Posted (Estimated): September 22, 2025
• Last Update Submitted That Met QC Criteria: September 2, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Atherosclerosis; Omega-3; Metabolism; Lipidomics; E-EPA; LDL aggregation susceptibility; Fatty acid; Icosapent ethyl; Proteoglycan binding
• Additional Relevant MeSH Terms: Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Atherosclerosis; Platelet Aggregation Inhibitors; Lipid Regulating Agents; eicosapentaenoic acid ethyl ester
• Other Study ID Numbers: E-EPA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared in compliance with EU's General Data Protection Regulation (GDPR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No