European Journal of Preventive Cardiology (2024) 00, 1–10 REVIEW

https://doi.org/10.1093/eurjpc/zwae003 Pharmacology & pharmacotherapy

Omega-3 fatty acids for cardiovascular event

lowering

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Gurleen Kaur1, R. Preston Mason1,2, Ph. Gabriel Steg3, and Deepak L. Bhatt 4
*
1
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2Elucida Research LLC, Beverly, MA, USA; 3Paris Cité University, Public Hospitals of Paris (AP-HP),
Bichat Hospital, Paris, France; and 4Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Received 28 November 2023; revised 28 December 2023; accepted 31 December 2023; online publish-ahead-of-print 3 January 2024

Low-density lipoprotein cholesterol (LDL-C) is the main target for therapeutics aimed at reducing the risk of atherosclerotic cardiovascular disease
(ASCVD) and downstream cardiovascular (CV) events. However, multiple studies have demonstrated that high-risk patient populations harbour
residual risk despite effective LDL-C lowering. While data support the causal relationship between triglycerides and ASCVD risk, triglyceride-
lowering therapies such as omega-3 fatty acids have shown mixed results in CV outcomes trials. Notably, icosapent ethyl, a purified formulation
of eicosapentaenoic acid (EPA), has garnered compelling evidence in lowering residual CV risk in patients with hypertriglyceridaemia and treated
with statins. In this review, we summarize studies that have investigated omega-3-fatty acids for CV event lowering and discuss the clinical
implementation of these agents based on trial data and guidelines.
---------------------------------------------------------------------------------------------------------------------------------------------------------------
Graphical Abstract

.............................................................................................................................................................................................
Keywords omega-3 fatty acids • atherosclerotic cardiovascular disease • icosapent ethyl

* Corresponding author. Tel: +1-212-241-5174, Email: [email protected]

© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,
distribution, and reproduction in any medium, provided the original work is properly cited.
2 G. Kaur et al.

Introduction 1.56–1.90] for individuals with TG values in the top third of the popu-
lation compared with those in the bottom third.6 However, older stud-
Atherosclerotic cardiovascular disease (ASCVD) continues to be the ies have shown this association to be attenuated after adjustment for
leading cause of mortality in the United States (US).1 Lowering low- other lipoproteins, such as high-density lipoprotein cholesterol
density lipoprotein cholesterol (LDL-C) is the predominant focus for (HDL-C).6 Klempfner et al demonstrated that in a cohort of 15 355 pa-
reducing the risk of developing ASCVD and downstream cardiovascular tients from the Bezafibrate Infarction Prevention (BIP) trial, 22-year
(CV) events.2 However, even with effective LDL-C lowering, residual mortality risk for patients with severe hypertriglyceridaemia
risk remains in high-risk patient populations, such as those with type (≥500 mg/dL) was increased by 68% vs. patients with low-normal TG
2 diabetes mellitus, metabolic syndrome, and obesity.3,4 Studies have (<100 mg/dL). This was after adjustment for covariates including
demonstrated that additional apolipoprotein B-containing lipoproteins, HDL-C.23 Additionally, in an observational longitudinal cohort study

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such as triglyceride (TG)-rich lipoproteins, may contribute to the using electronic health record data, patients with ASCVD and statin-
pathogenesis of atherosclerosis via multiple mechanisms.5 High TGs controlled LDL-C were more likely to have non-fatal MI and coronary
can be used as a marker for elevated levels of these TG-rich lipopro- or peripheral revascularization over mean follow-up of 5 years in the
teins, and growing clinical evidence has associated hypertriglyceridae- high TG group.24 In a retrospective administrative claims analysis of
mia with residual ASCVD risk.6–9 Data supporting the causal more than 20 000 statin-treated patients with diabetes and/or
relationship between TG and ASCVD have led to a focus on targeting ASCVD, the cohort with high TG had increased risk of major CV events
hypertriglyceridaemia to incrementally lessen the risk of future CV (HR 1.35, 95% CI 1.225–1.485) along with higher average total health-
events. Yet, lipid-lowering therapies for hypertriglyceridaemia, such as care cost per month and rate of inpatient hospital stay.25 These studies
fibrates and niacin, have not shown benefit in mitigating CV risk support the notion that elevated TG contribute to residual CV risk in
when used in conjunction with statins.10–12 statin-treated patients.
In addition to fibrates and niacin, omega-3 fatty acids can effectively Despite epidemiologic, genetic, and clinical evidence for increased
lower TG levels. Mechanisms include reducing the rate of fatty acid in- CV risk with hypertriglyceridaemia, attempts to reduce this risk using
corporation into very-low-density lipoprotein (VLDL) and stimulating agents that lower TGs, such as fibrates and niacin, have been disap-
activity of lipoprotein lipase.13 Omega-3 fatty acids took centre stage pointing.10,26,27 In the ACCORD (Action to Control Cardiovascular
when several trials showed inconsistent results in lowering CV events. Risk in Diabetes) trial, the combination of fenofibrate and simvastatin
The potential benefit of omega-3 fatty acids in decreasing CV events did not reduce the rate of fatal CV events, non-fatal MI, or non-fatal
may be beyond that of their TG-lowering effects; it has been hypothe- stroke compared with simvastatin alone in a patient population
sized that the pleiotropic effects of omega-3-fatty acids can lead to re- with type 2 diabetes mellitus.10 Similarly, in the AIM-HIGH
duction in atherosclerosis.14 Omega-3 fatty acids exist in several (Atherothrombosis Intervention in Metabolic Syndrome with Low
sources: plant products such as nuts, vegetable oils, chia seeds, walnuts, HDL/High Triglyceride and Impact on Global health Outcomes) trial,
and flax seeds are dietary sources of omega-3 fatty acids in the form of in patients with established CV disease, the combination of niacin and
alpha-linolenic acid (ALA).15 ALA is converted to docosahexaenoic acid LDL-lowering therapy did not reduce CV events; though, niacin
(DHA) via enzymatic steps, which include eicosapentaenoic acid (EPA) showed a trend towards benefit in the subset of patients within the
as an intermediary. EPA and DHA can also exist in dietary sources such highest TG tertile (≥198 mg/dL) in a post hoc analysis.26 However, no
as fish.16 Omega-3 fatty acids are often consumed in the form of fish oil difference in incidence of major vascular events between groups
supplements. Although these supplements have gained popularity, their (15.1 vs. 15.5%) was found among high TG patients in the
impact on mitigating CV risk is limited due to lack of regulation in pro- HPS2-THRIVE (Heart Protection Study 2–Treatment of HDL to
cessing and unclear quality.17 Finally, omega-3 fatty acids exist in highly Reduce the Incidence of Vascular Events) trial, which investigated niacin
concentrated purified formulations, available with prescriptions such as and laropiprant vs. placebo.12 Furthermore, in the PROMINENT
icosapent ethyl, that have been studied in recent major clinical trials. (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing
Past trials of omega-3 fatty acids to improve CV outcomes have been Triglycerides IN patiENts With diabetes) study, randomization of pa-
inconsistent in their results, with potential contributing factors including tients with type 2 diabetes mellitus taking moderate to high intensity
variability in trial design, patient population, and omega-3-fatty acid statins with TG levels 200–499 mg/dL and HDL-C ≤ 40 mg/dL to
composition and dosing. In this review, we summarize the studies pemafibrate—a selective peroxisome proliferator-activated receptor
that have investigated omega-3-fatty acids for CV event lowering and α modulator—did not reduce CV events as compared to placebo,
discuss practical implications of trial data to the clinical setting despite lowering TG levels.28
(Graphical abstract).

Mechanisms of action of
Elevated TGs and CV risk omega-3-fatty acids
Hypertriglyceridaemia is highly prevalent in the US; 21.1% of adults had
high TG levels (≥150 mg/dL) in data from 2015 to 2018.1 Lowering of TGs
Hypertriglyceridaemia can occur due to increased production of Omega-3 fatty acids can lower TG by reducing VLDL production,
triglyceride-rich lipoproteins (TRLs), and therefore TG concentrations increasing VLDL clearance, and stimulating lipoprotein lipase.13
can be considered as a marker of apolipoprotein B (apoB) The MARINE (Multi-centre, plAcebo-controlled, Randomized,
pro-atherogenic lipoproteins.18 Recently, several genetic and genome- double-blINd, a 12-week study with an open-label Extension) trial de-
wide analysis studies have linked plasma TG levels (a modifiable risk monstrated that 4 g/day of icosapent ethyl (a highly purified omega-3
factor) to the development of ASCVD.19,20 In one Mendelian random- fatty acid with >96% EPA) reduced placebo-corrected TG levels by
ization study, one standard deviation increase in TG levels was asso- 33.1% without increasing LDL-C in patients (n = 229) with fasting TG
ciated with a 54% increase in the risk for myocardial infarction >500 mg/dL.29 Furthermore, the ANCHOR [Effect of AMR101
(MI).21,22 Furthermore, data from prospective studies in European (Ethyl Icosapentate) on Triglyceride Levels in Patients on Statins
populations have indicated a significant association between TG levels With High Triglyceride Levels] trial also confirmed the safety of icosa-
and coronary heart disease (CHD) risk, with one meta-analysis demon- pent ethyl and its ability to decrease TG levels in high-risk statin-treated
strating an adjusted odds ratio of 1.72 [95% confidence interval (CI) patients (n = 702) with residual high TG (200–500 mg/dL) despite
Omega-3 fatty acids for cardiovascular event lowering 3

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Figure 1 Differences in eicosapentaenoic acid and docosahexaenoic acid. Eicosapentaenoic acid and docosahexaenoic acid are different in their tis-
sue distributions, effects on membrane structure, and ability to modulate inflammation, oxidative stress, and endothelial dysfunction.

LDL-C < 100 mg/dL. The median placebo-adjusted change in TG levels acid supplements (1 g mixture of EPA and DHA) and demonstrated a
from baseline was 21.5% with 4 g/day of icosapent ethyl.30 TG lowering reduction in the composite outcome of death, non-fatal MI, and stroke
has also been demonstrated in trials of mixed omega-3 fatty acids con- by 10%. However, only 5% of patients were on statins at baseline, mak-
taining both EPA and DHA. In the EVOLVE (EpanoVa fOR Lowering ing it less generalizable to current clinical practice.42 A constellation of
Very high triglyceridEs) trial, TGs were lowered from baseline by subsequent large scale clinical trials failed to show benefit of omega-3
25.5–30.9% with various doses of the mixed omega-3 fatty acid formu- fatty acids. The ORIGIN (Outcome Reduction with an Initial Glargine
lation in patients with TG ≥ 500 mg/dL.31 Of note, LDL-C was signifi- Intervention) trial investigated a population of patients at high risk for
cantly increased (19 vs. 3% in placebo) with 2 and 4 g/day omega-3 CV events who had impaired glucose tolerance or diabetes; randomiza-
fatty acid formulations, but there was no increase in circulating concen- tion of patients to 1 g capsule of ethyl esters of omega-3 fatty acids with
trations of atherogenic lipoprotein particles as evidenced by no change median follow-up of 6.2 years demonstrated a lowering of TG levels by
in apoB concentrations.31 14.5 mg/dL but showed no difference in the primary outcome of death
from CV causes between groups. In this trial, 53% of patients were on a
statin at baseline.43
Mechanisms beyond TG lowering The ASCEND (A Study of Cardiovascular Events in Diabetes)-
The benefits of omega-3- fatty acids extend beyond that of TG lower- Omega 3 trial also investigated patients with diabetes, but its population
ing, and the full range of biological effects remain to be fully investigated. consisted of patients without evidence of ASCVD. Patients were ran-
Current hypotheses include pleiotropic effects mediated by EPA and domized (n = 15 480) to 1 g of omega-3 fatty acids or a placebo of olive
downstream anti-inflammatory and antithrombotic effects. EPA has oil. During a mean follow-up of 7.4 years, there was no difference in the
been shown to diminish markers of inflammation, which is one of the primary endpoint of first serious vascular event, defined as composite
drivers of atherosclerosis. The MARINE and ANCHOR trials of icosa- of MI, stroke, transient ischaemic attack, or vascular death (rate ratio
pent ethyl suggest anti-inflammatory effects with reduction in oxidized 0.97; 95% CI 0.87–1.08). However, in exploratory analyses, there
LDL, lipoprotein-associated phospholipase A2 (Lp-PLA2), and high- were fewer vascular deaths in the fatty acid group vs. placebo (rate ratio
sensitivity C-reactive protein (hsCRP).32 There are also differences be- 0.81; 95% CI 0.67–0.99).44 Another primary prevention trial, VITAL
tween EPA and DHA in their effects on lipid oxidation and endothelial (Vitamin D and Omega-3 Trial), involved 25 871 participants who re-
function,33–35 likely mediated by variations in the way they integrate ceived supplementation with omega-3 fatty acids vs. placebo and found
into the cell membrane36–38 (Figure 1). EPA stabilizes the phospholipid that during a median follow-up of 5.3 years, there was no difference in
bilayer by allowing cholesterol to remain more evenly distributed while incidence of major adverse CV events (HR 0.92; 95% CI 0.8–1.06).
DHA affects membrane fluidity by promoting formation of disordered Although, in secondary endpoint analyses, there was lower incidence
domains, which subsequently disrupts the cell membrane.39 Reducing of total MI (HR 0.72; 95% CI 0.59–0.9) and composite CHD (HR
the cholesterol-rich domains mediated by EPA may alleviate inflamma- 0.83; 95% CI 0.71–0.97).45
tion and improve endothelial dysfunction. Given that atherosclerosis is Other contemporary trials have also been unable to demonstrate CV
the product of endothelial dysfunction and inflammation and is asso- protection with omega-3 fatty acids. For example, in the STRENGTH
ciated with changes in membrane lipid structure with increased perme- (Study to Assess STatin Residual Risk Reduction With EpaNova in
ability, lipid oxidation, and generation of reactive oxygen species, the HiGh CV Risk PatienTs With Hypertriglyceridaemia) trial—comprised
ability to modulate these pathways with EPA is promising.40,41 of 13 078 patients at high CV risk with hypertriglyceridaemia and low le-
vels of HDL-C—4 g/day of omega-3 carboxylic acid (a formulation of
EPA and DHA) did not show any benefit in the primary composite out-
Randomized trials of omega-3 fatty come when compared to a placebo of corn oil.46 Additionally, in the
OMEMI (Omega-3 Fatty acids in Elderly with Myocardial Infarction) trial,
acids which investigated patients with recent acute MI aged 70–82, there was
There have been several randomized clinical trials of omega-3 no reduction in events with 1.9 g of EPA + DHA.47 Data from
fatty acids for CV event lowering (Table 1). The GISSI-P (Gruppo meta-analyses have also been mixed; one study demonstrated no signifi-
Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico- cant association of omega-3 fatty acids with fatal or non-fatal CHD or
Prevenzione) trial randomized patients with recent MI to omega-3 fatty any major vascular events.48 However, in a meta-analysis of 18
 4

Table 1 CV outcomes of trials of mixed omega-3 fatty acids

Trial (year) # of patients Patient population % Baseline statin use Intervention Primary results
...........................................................................................................................................................................................................
GISSI—P (1999) 11, 324 Recent MI (≤3 months) 5% Synthetic α-tocopherol (850–882 mg Composite endpoint of all-cause
EPA + DHA ethyl ester) vs. no death, non-fatal MI, and non-fatal
supplement stroke
RR 10%; 95% CI 1–18; P = 0.048
OMEGA (2010) 3, 851 Admitted for acute MI 94% 1 g omega-3 fatty acid ethyl ester Sudden cardiac death
(460 mg EPA + 380 mg DHA) vs. 1.5 vs. 1.5%; P = 0.84
olive oil placebo
ORIGIN (2012) 12, 536 Impaired fasting glucose or diabetes, 53% 1 g omega-3 fatty acid capsule (465 mg CV mortality
high risk for CV events EPA + 375 mg DHA) vs. olive oil 9.1 vs. 9.3%
placebo HR 0.98; 95% CI 0.87–1.10; P = 0.72
ASCEND 15, 450 With diabetes and no ASCVD 75% 1 g omega-3 fatty acid (EPA + DHA) MACE (vascular death, MI, stroke/TIA)
Omega-3 (2018) vs. olive oil placebo 8.9 vs. 9.2%
Rate ratio 0.97; 95% CI 0.87–1.08
P = 0.55
VITAL (2019) 25, 871 No known CVD 35% 1 g omega-3 fatty acid (EPA + DHA) Major CV events (composite of MI,
vs. olive oil placebo stroke, death from CV causes)
HR 0.92; 95% CI 0.8–1.06; P = 0.24
STRENGTH (2020) 13, 078 High-risk for CV event; on statin for at 100% 4 g omega-3 carboxylic acid (EPA + Composite of CV death, non-fatal MI,
least 4 weeks; LDL <100 or treated 50% high-intensity DHA) vs. corn oil placebo non-fatal stroke, coronary
with maximally tolerated statin; TG revascularization, or UA requiring
180–500 mg/dL hospitalization
12 vs. 12.2%
HR 0.99; 95% CI 0.9–1.09; P = 0.84
OMEMI (2020) 1, 027 Patients age 70 to 82 years with recent 97% 1.8 g omega-3 fatty acid (930 mg EPA Non-fatal acute MI, unscheduled
acute MI (2–8 weeks) + 660 mg DHA) vs. corn oil placebo revascularization, stroke, all-cause
death, heart failure hospitalization
21.4 vs. 20%
HR 1.08; 95% CI 0.82–1.41; P = 0.6

TG, triglyceride; MI, myocardial infarction; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; GISSI-P Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico Prevenzione; RR, relative risk; CI, confidence interval; ORIGIN,
Outcome Reduction with an Initial Glargine Intervention; CV, cardiovascular; HR, hazard ratio; ASCEND, A Study of Cardiovascular Events in Diabetes; ASCVD, atherosclerotic cardiovascular disease; TIA, transient ischaemic attack; VITAL, Vitamin
D and Omega-3 Trial; STRENGTH, Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridaemia; UA, unstable angina; OMEMI, Omega-3 Fatty acids in Elderly with Myocardial Infarction.
G. Kaur et al.

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Omega-3 fatty acids for cardiovascular event lowering 5

randomized controlled trials and 16 prospective studies, there was re- The CV benefits of icosapent ethyl are quite robust, and this was de-
duction with EPA + DHA in CHD in higher-risk populations with ele- monstrated by consistent and significant reductions in CV events as de-
vated TG and LDL-C, though there was no decrease in CHD in the termined by independent, blinded clinical endpoint committee
overall population.49 Another meta-analysis, which did not include adjudication as well as investigator-reported assessments.58 Also, bene-
STRENGTH and OMEMI, found a lower risk of MI, total CHD, and total fit was consistent early on in the study and persisted across pre-
cardiovascular disease (CVD) with omega-3 fatty acids yet there was no specified interim analyses.59 Several investigations from REDUCE-IT
association seen for stroke.50 Furthermore, a meta-analysis of 40 studies have also established the generalizability of the results to various patient
of EPA + DHA supplements showed lower risk of MI (RR 0.87; 95% CI populations. A pre-specified analysis of patients enrolled in the trial in
0.8–0.96) with number needed to treat (NNT) of 272. Nevertheless, the US showed strong risk reductions with no heterogeneity between
there was no association with overall CVD events. There was a US and non-US subgroups, underscoring US patients derive as much

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dose-effect relationship seen with the EPA + DHA formulations; each benefit from the medication as seen in the overall trial.60
additional 1 g/day was associated with risk reduction of 9% in MI,51 Furthermore, while other lipid-lowering therapies may have less effi-
which raises the question of whether one cause of discrepancies in trials cacy and higher adverse events in patients with chronic kidney disease
is the varying concentrations of omega-3 fatty acids utilized. (CKD), icosapent ethyl was shown to reduce ischaemic events across a
Overall, the trials of omega-3 fatty acids have differed considerably in range of estimated glomerular filtration rate (eGFR) and CKD status.
terms of the population studied (primary prevention vs. secondary pre- Tolerability and safety were also consistent. Though bleeding rates
vention) as well as in baseline characteristics, including statin use and and atrial fibrillation/flutter event rates were higher with decreasing
baseline TG levels. Furthermore, all of the trials discussed thus far have eGFR, the relative risks with icosapent ethyl were similar across
included a combination of EPA and DHA, and the meta-analyses above eGFR categories.61
included studies with wide heterogeneity in the composition of omega-3 In addition, the ability of icosapent ethyl to address residual risk for
fatty acids. Given differential effects of EPA and DHA, the formulations CV outcomes after coronary artery bypass grafting (CABG) was de-
used may considerably affect results. Moreover, the threshold concentra- monstrated in a subgroup analysis of patients that showed a decrease
tion of EPA achieved within the trial may be a relevant factor given the in the primary endpoint with absolute risk reduction of 6.2% and
evidence of a dose response; several of these trials had lower-dose pre- NNT of 16 in those with prior CABG (22.5% of trial population).62
parations which may have diluted any potential benefit.52 Similarly, patients who have undergone percutaneous coronary inter-
vention (PCI) are one of the more high-risk groups in danger of subse-
quent CV events. 41.7% of REDUCE-IT participants had prior PCI, and
a post hoc analysis demonstrated a 34% reduction in the primary com-
Randomized trials of EPA posite end point (HR 0.66).63 Another post hoc analysis investigated
While the trials discussed above included combined formulations of benefit in patients with prior MI (45.2% of population) and revealed a
EPA and DHA, the JELIS (Japan EPA Lipid Intervention Study) trial in reduction in the primary endpoint from 26.1% to 20.2% with icosapent
2007 specifically investigated 1.8 g of EPA vs. statin therapy (low-dose ethyl vs. placebo (HR 0.74; 95% CI 0.65–0.85). There was a 35% relative
10 mg pravastatin or 5 mg simvastatin) in a patient population com- risk reduction in total ischaemic events, 34% reduction in MI, 30% re-
prised mostly of those without a history of CVD. There was a 19% rela- duction in CV death, and 20% reduction in all-cause mortality.64,65
tive risk reduction in ASCVD events at a median follow-up of 4.6 years. There were similar reductions in endpoints in those who did or did
The outcome was driven by a statistically significant reduction in hospi- not have a history of prior coronary revascularization.64,65 Proof of
talizations for unstable angina while no other individual endpoints (such benefit in such high-risk populations adds to the growing body of evi-
as non-fatal MI, stroke, revascularization, or CV mortality) were signifi- dence in support of icosapent ethyl.
cantly different. Limitations of this trial include lack of placebo and lack Furthermore, in a pre-specified analysis, there was a reduction in to-
of use of high-intensity statin as comparison. Remarkably, the dimin- tal primary endpoint events (rate ratio 0.70; 95% CI 0.62–0.78), which
ished coronary events seen with EPA were irrespective of reduction highlights the substantial decrease in first, subsequent, and total ischae-
of LDL-C, indicating that other factors influence these beneficial effects. mic events with icosapent ethyl.66 Also, analyses have demonstrated no
Furthermore, EPA was most effective in the high TG (≥150 mg/dL) and difference in outcomes based on baseline TG levels.67 This benefit
low HDL (<40 mg/dL) group of patients, in which there was a 52% re- across ischaemic endpoints regardless of baseline TG levels further sub-
duction in ASCVD events.53,54 stantiates the hypothesis that the benefit from icosapent ethyl stems
Building off of the results of JELIS, REDUCE-IT (Reduction of from mechanisms of action beyond TG lowering. In REDUCE-IT
Cardiovascular Events with Icosapent Ethyl–Intervention Trial), evalu- REVASC, a sub-analysis, reduction was demonstrated in elective, ur-
ated 2 g twice daily of icosapent ethyl (purified stable ethyl ester of gent, and emergent coronary revascularization along with a decrease
EPA) vs. placebo in 8179 patients with CVD or diabetes and CVD in the need for PCI and CABG.68 This emphasizes the impacts of
risk factors. The population consisted of patients with median LDL of EPA on direct atherothrombotic burden.
75 mg/dL and TG of 135–500 mg/dL.55 The trial demonstrated risk re- The results of REDUCE-IT have garnered controversy due to lack of
duction by 25% in CVD events, including death, MI, stroke, revascular- benefit seen in other contemporary trials of high-dose omega-3 fatty
ization, or hospitalization for unstable angina (17.2% in intervention vs. acids, such has the STRENGTH trial. Postulations include clinical signifi-
22% in placebo, HR 0.75; 95% CI 0.68 to 0.83, P < 0.001) with a median cance of the different placebos used between the two trials. There have
follow-up of 4.9 years.56 The total utilized dose of 4 g daily was a higher been theories regarding whether the positive results of icosapent ethyl
dose than prior trials, and the formulation of a highly purified EPA ethyl may be due to theoretical negative effects of the mineral oil placebo
ester also differed from prior trials that had failed to show benefit with used in REDUCE-IT, given that net change in LDL-C was –1.2% in those
omega-3 fatty acids. In comparison, JELIS had used a lower dose of ico- allocated to icosapent ethyl compared to 10.9% in those in the mineral
sapent ethyl—1.8 g. Nevertheless, there were equivalent plasma EPA oil group.56 Notwithstanding, other studies have provided no evidence
levels seen in JELIS as with the 4 g of icosapent ethyl used in that mineral oil affects absorption of other medications (e.g. sta-
REDUCE-IT.56 In terms of safety, there were more hospitalizations tins).14,69 Additionally, no difference in progression of total plaque
for atrial fibrillation and atrial flutter in the intervention group in and total non-calcified plaque volume by coronary computed tomog-
REDUCE-IT, though rates were overall low.57 There was also a trend raphy angiography (CCTA) has been reported in mineral oil placebo
towards higher difference overall rates of serious adverse bleeding participants compared to non-mineral oil placebo participants.70 The
events with icosapent ethyl (2.7 vs. 2.1%, P = 0.06).56 consistent benefit seen for icosapent ethyl across different statin types,
6 G. Kaur et al.

including hydrophilic and hydrophobic statins, further argues against an composition in a trial of 80 patients. The primary endpoint of
interaction between mineral oil and statin absorption.71 low-attenuation plaque—a component of vulnerable plaque—was sig-
The differing results in REDUCE-IT and STRENGTH are unlikely to nificantly reduced with icosapent ethyl compared with placebo. This
be due to placebo alone, but rather stem from the inherent biological reduction in plaque progression without significant difference in
differences in the omega-3 fatty acid formulations used. The carboxylic LDL-C or TG further supports the pleiotropic and non-lipid effects
acid used in STRENGTH has variable absorption depending on dietary of omega-3 fatty acids.82,83 However, there were no significant differ-
fat content compared to the ethyl ester of EPA used in REDUCE-IT. ences in the Agatston score progression rates, so it was unclear if ico-
Icosapent ethyl also has 25% more EPA per dose than the omega-3 car- sapent ethyl modified calcified plaque volume.83 Notably, Bittner et al.
boxylic acid used in STRENGTH, which explains the 61% higher blood showed in a study of 71 patients that low levels of omega-3-fatty acids
levels of EPA in REDUCE-IT vs. STRENGTH.72 The fundamental differ- (EPA + DHA) had significant inverse association with early onset of

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ences in EPA as compared to DHA may also explain the differential re- coronary artery calcium.84 While EVAPORATE specifically investi-
sults. EPA is known to have more potent antioxidant effects as gated plaque burden, a recent sub-study utilizing data from the trial
compared to DHA and can also decrease macrophage accumulation demonstrated that icosapent ethyl also led to significant benefits in
and inflammatory markers, all of which modulate atheroscler- coronary physiology compared with placebo. Improvement in frac-
osis.14,73,74 EPA treatment of endothelial cells has shown anti- tional flow reserve (FFR), derived from CCTA, was seen at 9 months
inflammatory and cytoprotective cellular changes.75 Likewise, data and sustained at 18-month follow-up.85
from a meta-analysis of randomized controlled trials of omega-3 fatty
acids confirm this difference between EPA monotherapy and EPA
and DHA combinations. In this analysis, there was higher relative risk
reductions in CV mortality, non-fatal MI, CHD events, and revascular- Clinical perspective and practical
ization with EPA monotherapy.76 Overall, the anti-inflammatory and
antithrombotic effects of EPA along with modulation of endothelial
implications
dysfunction may contribute to reducing the development of athero- While REDUCE-IT and its sub analyses provide compelling evidence for
sclerosis and stabilizing atherosclerotic plaque.73,77 An in vitro study de- the benefit of icosapent ethyl in lowering residual CV risk, the next chal-
monstrated that EPA significantly inhibited LDL oxidation by 75% while lenge is the implementation of the medication in daily clinical practice.86
DHA, in comparison, exhibited lower antioxidant activity.78 However, Food and Drug Administration (FDA) approval of the medication was
the exact causal mechanisms to explain the benefit detected in initially for severe hypertriglyceridaemia (>500 mg/dL) but expanded
REDUCE-IT still remain uncertain. A sub-study of REDUCE-IT indi- to include indications for CVD risk reduction after REDUCE-IT.87
cated that icosapent ethyl had minimal effects on biomarkers associated Now, it is approved as an adjunct to maximally tolerated statin therapy
with atherosclerosis (homocysteine, oxidized-LDL-C, interleukin-6, in patients with fasting or non-fasting TG >150 mg/dL and established
Lp-PLA2, hsCRP, interleukin-1β) though there were small absolute in- CVD or diabetes and more than two CVD risk factors. There are no
creases in certain biomarkers, including hsCRP, in patients in the min- particular criteria for LDL-C levels, as icosapent ethyl provides CV
eral oil placebo group over time.79 However, an experimental model benefit regardless of baseline LDL-C.
showed that neither mineral nor corn oil affected LDL oxidation.78 Several studies have placed the trial in the context of real-world clinical
The aforementioned trials investigated icosapent ethyl in a mixed pri- practice. In one study of 2 424 865 adults in Ontario with hypertriglyceridae-
mary and secondary prevention population. In contrast, the RESPECT- mia and controlled LDL-C, 25% of the cohort potentially qualified for icosa-
EPA (Randomized trial for Evaluation in Secondary Prevention Efficacy pent ethyl.88 Similarly, a study from the CLARIFY (ProspeCtive observational
of Combination Therapy—Statin and Eicosapentaenoic Acid) trial specif- LongitudinAl RegIstry oF patients with stable coronary arterY disease) regis-
ically examined the utility of icosapent ethyl in a secondary prevention try supported the generalizability of REDUCE-IT; 15% of patients with estab-
population; 2506 Japanese patients with stable coronary artery disease lished coronary artery disease were eligible for the medication.89 Also, in a
and EPA/arachidonic acid ratio below 0.4 were randomized to 1.8 g ico- large contemporary Canadian cohort of patients with a history of CABG
sapent ethyl plus statin or to statin therapy alone. Rate of the primary end- and currently on statin, 26.4% would be eligible for icosapent ethyl according
point of CV death, non-fatal MI, non-fatal cerebral infarction, unstable to REDUCE-IT and FDA criteria.90 In another study applying the results of
angina, and coronary revascularization was the same across groups at REDUCE-IT to patients hospitalized for MI in France, it was demonstrated
two years of follow-up, but there was a trend towards benefit with icosa- that 12.5% of patients could benefit from icosapent ethyl.91 Furthermore,
pent ethyl at six years in the primary endpoint (10.9 vs. 14.9%, HR 0.785; icosapent ethyl was seen as cost effective in an economic evaluation analysis
95% CI 0.616–1.001, P = 0.055) and a nominally significant reduction in from REDUCE-IT. Treatment yielded more quality-adjusted life years than
the secondary endpoint of sudden cardiac death, MI, unstable angina, or standard care and was projected to cost save over a lifetime with a 58.4%
coronary revascularization (8 vs. 11.3%, P = 0.031).80 Despite being probability of costing less and being more effective.92
underpowered, the trial adds to existing evidence showing benefit of Following the results of REDUCE-IT and its several sub studies,
EPA in decreasing coronary events regardless of the placebo group. guidelines have incorporated icosapent ethyl into their recommenda-
Several imaging studies have confirmed the benefit of EPA formula- tions. The 2020 American Diabetes Association guidelines state that
tions in regards to atherosclerosis. The CHERRY (Combination for patients on statins with well-controlled LDL-C and TG 135–
Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary 499 mg/dL, addition of icosapent ethyl can be considered to reduce
Plaque Regression Evaluated by Integrated Backscatter Intravascular CV risk (level A recommendation).93 However, the 2018 American
Ultrasonography) trial consisted of 193 patients in Japan who had College of Cardiology/American Heart Association guidelines were
undergone PCI; icosapent ethyl in combination with pitavastatin from before REDUCE-IT and therefore do not have any statement re-
showed significant reduction in atheroma volume (assessed via intravas- garding icosapent ethyl. They do have a class IIa, B-NR recommendation
cular ultrasound) compared to pitavastatin alone. The baseline TG le- in adults with persistent severe hypertriglyceridaemia (>500 mg/dL) to
vels in this trial were not high (mean TG of 110 mg/dL in adhere to low-fat diet and consume omega-3 fatty acids.94 In the 2019
intervention group), further proving that EPA can stabilize plaques.81 European Society of Cardiology (ESC)/European Atherosclerosis
Furthermore, in the EVAPORATE (Effect of Vascepa on Improving Society guidelines for dyslipidemias, there is a Class IIa, LOE B for ico-
Coronary Atherosclerosis in People With High Triglycerides Taking sapent ethyl 2 g twice per day in combination with a statin in patients
Statin Therapy) trial, 4 g/day of icosapent ethyl decreased rates of pla- with TG levels 135–499 mg/dL despite statin therapy.95 Furthermore,
que progression using CCTA and affected plaque volume and the 2021 ESC Prevention Guidelines recommend icosapent ethyl in
Omega-3 fatty acids for cardiovascular event lowering 7

high-risk patients if TG levels still elevated (>135 mg/dL) despite being Novartis, Regeneron, Eli Lilly, Novo Nordisk, and AstraZeneca; has received
on statins and adopting lifestyle measures (class IIb).96 Similarly, the fees for serving on critical event committees from Bristol Myers Squibb and
National Lipid Association guidelines also recommend icosapent ethyl Pfizer; has received fees for serving as chair of a data monitoring committee
in patients older than 45 with clinical ASCVD or older than 50 with dia- from Servier; and has received fees for serving as chair of a registry from
betes and more than 1 risk factor with TG 135–499 mg/dL on maximal- Servier. D.L.B. discloses the following relationships—Advisory Board:
ly tolerated statin (class I, level B-R).97 Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific,
Other considerations for prescribing high-dose omega-3 fatty acids Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex,
include the risk of atrial fibrillation, which was seen in REDUCE-IT McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo
(rate 5.3 vs. 3.9%, P = 0.003) and STRENGTH (new onset rate 2.2 vs. Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American
1.3%, HR 1.69; 95% CI 1.29–2.21, P < 0.01). The rate of hospitalization Heart Association New York City, Angiowave (stock options), Bristol

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for atrial fibrillation or flutter was also higher in patients taking icosa- Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock);
pent ethyl (3.1 vs. 2.1%, P = 0.004) in REDUCE-IT. Therefore, in pa- Consultant: Broadview Ventures, Hims, SFJ, Youngene; Data Monitoring
tients with poorly controlled atrial fibrillation or flutter the drug Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris,
should likely be avoided. Baim Institute for Clinical Research (formerly Harvard Clinical Research
In addition, patients may inquire about dietary sources of omega-3- Institute, for the PORTICO trial, funded by St. Jude Medical, now
fatty acids and fish oil supplements. In a prospective longitudinal study Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic,
with ST-elevation MI patients, elevated marine omega-3-fatty acids Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research
(EPA) was inversely related to MACE and CV-hospital re-admission. Institute, Mayo Clinic, Mount Sinai School of Medicine (for the
Vegetable omega-3 (ALA) was also inversely related to all-cause mor- ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial,
tality.98 The findings support that consumption of foods rich in omega-3 funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical),
fatty acids may be an effective strategy. However, in regards to fish oil Novartis, Population Health Research Institute; Rutgers University (for
supplements, the results from trials such as REDUCE-IT do not apply, the NIH-funded MINT Trial); Honoraria: American College of Cardiology
as these supplements generally contain less omega-3 fatty acids than (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC
claimed and often have other types of saturated or oxidized fats that Accreditation Oversight Committee), Arnold and Porter law firm (work re-
may interfere with potential benefits.99 lated to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute
for Clinical Research (formerly Harvard Clinical Research Institute;
RE-DUAL PCI clinical trial steering committee funded by Boehringer
Conclusion and future directions Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir
Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical
Patients treated with statins may have residual CV risk despite achieve- and Surgical Knowledge Translation Research Group (clinical trial steering
ment of LDL-C goals. Hypertriglyceridaemia is a target for reducing this committees), CSL Behring (AHA lecture), Cowen and Company, Duke
persistent CV risk. While trials of mixed omega-3 fatty acids have failed Clinical Research Institute (clinical trial steering committees, including for
to exhibit CV event lowering, REDUCE-IT rigorously demonstrated the the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global
efficacy of a high-dose EPA preparation (icosapent ethyl) in patients (Editor in Chief, Journal of Invasive Cardiology), Journal of the American
with hypertriglyceridaemia on maximally tolerated statin with CVD or College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair,
with diabetes and CVD risk factors. Given that the benefit of icosapent interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME
ethyl extends beyond its TG-lowering effects, further work is needed to steering committees), MJH Life Sciences, Oakstone CME (Course
understand the molecular mechanisms and pleiotropic actions. Next steps Director, Comprehensive Review of Interventional Cardiology), Piper
will also involve implementation of icosapent ethyl into the real-world set- Sandler, Population Health Research Institute (for the COMPASS opera-
ting and both identifying and addressing barriers to its clinical use. The fu- tions committee, publications committee, steering committee, and USA na-
ture of utilizing omega-3 fatty acids in CV event lowering is also dependent tional co-leader, funded by Bayer), WebMD (CME steering committees),
on upcoming studies designed to evaluate the effect of icosapent ethyl in Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor);
specific populations and identify which patients derive the most benefit. Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to
Brigham and Women’s Hospital who assigned to Lexicon; neither I nor
Brigham and Women’s Hospital receive any income from this patent);
Author contribution Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine,
Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer
G.K. and D.L.B. contributed to the conception or design of the work. G.K. Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera,
drafted the manuscript. All authors contributed to the acquisition, analysis, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon,
or interpretation of data for the work. All authors critically revised the Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories,
manuscript. All gave final approval and agree to be accountable for all as- Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen,
pects of work ensuring integrity and accuracy. Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed,
Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma,
Funding Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys,
Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier
None. Amarin paid the journal open access charges.
(Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott,
Conflict of interest: G.K. has no disclosures. R.P.M. has received re- Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now
search funding or consulting from Amarin, Lexicon, Esperion, and HLS Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee:
Therapeutics. Ph.G.S. has received grant support from Bayer/Janssen, American College of Cardiology; Unfunded Research: FlowCo.
Merck, Sanofi, Amarin, and Servier; has received fees for serving on a steer-
ing committee or executive steering committee from Bayer/Janssen,
Amarin, Novartis, Boehringer Ingelheim, and Idorsia; has received lecture References
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consulting fees from Sanofi, Amarin, Amgen, Bristol Myers Squibb, Circulation 2022;145:e153–e639.
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