Evolution of Omega-3

F a t t y A c i d T h e r a p y an d
C u r re n t an d F u t u re R o l e i n t h e
Management of Dyslipidemia
Lane B. Benes, MDa, Nikhil S. Bassi, MDb,
Mohamad A. Kalot, MDc, Michael H. Davidson, MDa,*

KEYWORDS
 Omega-3 fatty acids  Omega-3 icosapent ethyl  Omega-3 carboxylic acids  Hypertriglyceridemia
 Residual risk  Dyslipidemia

KEY POINTS
 Newer omega-3 fatty acid formulations have improved bioavailability and triglyceride-lowering
efficacy.
 Omega-3 fatty acids have been shown to reduce cardiovascular risk in certain high-risk subgroups.
 Omega-3 fatty acids provide cardiovascular protection through multiple mechanisms, including
lipid-lowering and non–lipid-altering pathways.
 Although there is no evidence of significant harm, data to suggest significant benefit in event reduc-
tion rates with omega-3 fatty acids are lacking.
 Ongoing large, randomized, controlled trials in high-risk patients are highly anticipated.

INTRODUCTION armamentarium for the treatment of hypertrigly-

The benefits of omega-3 fatty acids have been
recognized since the beginning of the 20th cen-
tury; however, the first US Federal Drug Adminis-
tration (FDA)–approved formulation was not
available until 2004. Since that time, newer for-
mulations consisting of omega-3 carboxylic acids
or pure eicosapentaenoic acid (EPA) ethyl esters
have been developed. Omega-3 fatty acids
are most recognized for their ability to reduce
serum triglycerides; however, there has been
debate regarding their role in the medical
ceridemia or other forms of dyslipidemia. The
most recent recommendations from the Amer-
ican College of Cardiology/American Heart Asso-
ciation (ACC/AHA) guidelines on cholesterol
management1 published in 2013 do not suggest
a major role of omega-3 fatty acid therapy in
the treatment of dyslipidemia. This diminished
role is predominantly because large trials study-
ing nonstatin cholesterol-lowering medications
showed lack of significant benefit. Subgroup an-
alyses of those trials looking at subjects with
elevated triglycerides and low high-density

Disclosures: Dr M.H. Davidson was the Chief Medical Officer of Omthera until June 2015; omega-3 carboxylic
cardiology.theclinics.com

acids were developed by Omthera Pharmaceuticals. L.B. Benes, N.S. Bassi, and M.A. Kalot have nothing to
disclose.
a
Section of Cardiology, The University of Chicago Medicine, 5841 South Maryland Avenue, MC 6080, Chicago,
IL 60637, USA; b Section of Cardiology, University of California – Los Angeles, UCLA Cardiovascular Center
(Westwood), 100 UCLA Medical Plaza, Suite 630, Los Angeles, CA 90095, USA; c Department of Medicine,
American University of Beirut, Riad El Solh, Beirut 1107 2020, Lebanon
* Corresponding author.
E-mail address: mdavidso@bsd.uchicago.edu

Cardiol Clin 36 (2018) 277–285

https://doi.org/10.1016/j.ccl.2017.12.009
0733-8651/18/Ó 2017 Elsevier Inc. All rights reserved.
278 Benes et al
lipoprotein cholesterol (HDL-C), an unfavorable
pattern of dyslipidemia, suggest there may in
fact be a benefit. Current trials are ongoing with
newer omega-3 fatty acid formulations to deter-
mine if patients at increased risk for atheroscle-
rotic cardiovascular disease derive benefit from
therapy. This article discusses the evolution of
omega-3 fatty acid therapy as well as its current
and future role in the treatment of dyslipidemia.
AVAILABLE OMEGA-3 FATTY ACID
FORMULATIONS
The first omega-3 fatty acid formulation, omega-3
acid ethyl esters, was approved by the FDA in
2004 under the trade name Omacor (Reliant Phar-
maceuticals, Liberty Corner, NJ) for the treatment
of triglyceride levels of 500 mg/dL or more. It was
renamed to Lovaza in 2007 (GlaxoSmithKline,
Brentford, UK); however, Omacor is still available
outside of the United States. Icosapent ethyl (Vas-
cepa, Amarin Pharmaceuticals, Bedminster, NJ)
was approved in 2012 for the treatment of severe
hypertriglyceridemia (triglycerides of 500 mg/dL).
Icosapent ethyl differed from the initial omega-3
fatty acid formulation by containing pure EPA ethyl
esters rather than both EPA and docosahexaenoic
acid (DHA). In 2014, omega-3 carboxylic acids
(Epanova, AstraZeneca, Wilmington, DE) gained
approval for the treatment of severe hypertriglyceri-
demia (triglycerides of 500 mg/dL). Omega-3 car-
boxylic acids consist of free fatty acids rather than a
prodrug form; they have improved bioavailability
and can be taken independently of meals because
they are not reliant on hydrolysis by pancreatic
lipase for absorption.
Momentum for the development of supple-
mental omega-3 fatty acids came in part from
the Gruppo Italiano per lo Studio della Sopravvi-
venza nell’Infarto miocardico (GISSI)-Prevenzione
trial published in 19992 and further encouraged
by the Japan EPA Lipid Intervention Study (JELIS)
published in 2007.3 The GISSI-Prevention trial
showed that, in an Italian population, the adminis-
tration of 1 g/d of polyunsaturated fatty acids to
patients who experienced a myocardial infarction
in the past 3 months reduced the primary endpoint
of death, nonfatal myocardial infarction, and
stroke by 10% to 15% at a follow-up of 3.5 years.
The reduction in the primary endpoint was largely
driven by a reduction in deaths.2 JELIS suggested
a benefit of adding omega-3 fatty acids to a statin,
because there was a decrease in major adverse
cardiovascular events (MACE) with a 19% risk
reduction in those taking both compared
with those only taking a statin over 5 years of
follow-up, with more benefit seen in those on
therapy for secondary prevention.3 More recently,
the EpanoVa fOr Lowering Very high triglyceridEs
(EVOLVE) trial has demonstrated the triglyceride-
lowering ability of the omega-3 carboxylic acids,
with a 25.5% to 30.9% reduction after 12 weeks
compared with 4.3% in controls given olive oil
in patients with severe hypertriglyceridemia
(triglycerides of 500 mg/dL).4
Of the available formulations within the United
States, omega-3 acids ethyl esters have been
the most widely prescribed, in part because of
their longer time on the market and generic op-
tions. In the last few years, studies comparing
the ethyl esters and newer formulations suggest
that greater benefit can be expected from
the newer forms owing to their improved bio-
availability. The Epanova compared to Lovaza
in a pharmacokinetic single-dose evaluation
(ECLIPSE) study demonstrated that omega-3 car-
boxylic acids, which are already in the free fatty
acid form, result in about a 4-fold increase in
bioavailability compared with omega-3 acid ethyl
esters when taken with a low-fat meal.5 ECLIPSE
II similarly demonstrated greater EPA and DHA
serum levels with omega-3 carboxylic acid use
compared with omega-3 acids ethyl esters while
on a low-fat diet over a longer observation period
of 14 days.6 Greater triglyceride-lowering ability
was found with omega-3 carboxylic acids.
OMEGA-3 FATTY ACIDS’ BENEFITS AND
MECHANISM OF ACTION
Omega-3 fatty acids are best known for their
triglyceride-lowering ability. Earlier formulations
of EPA and DHA demonstrated about a 20%
reduction,7,8 whereas EVOLVE found closer to
a 30% reduction in serum triglycerides with
omega-3 carboxylic acids.4,5 There are numerous
proposed mechanisms to account for these find-
ings, which include decreased hepatic very low-
density lipoprotein (VLDL) synthesis and increased
triglyceride clearance from the serum. One such
mechanism is a decrease in VLDL triglyceride
synthesis by altering transcription factors
such as sterol regulatory element-binding proteins
and peroxisome proliferator-activated receptors
involved in triglyceride synthesis in the hepato-
cyte.9,10 It is possible that EPA serves as a poor
substrate for VLDL triglycerides, leading to
lipid-poor VLDL rather than triglyceride-rich VLDL
secretion into the serum.11,12 Omega-3 fatty acids
also increase serum clearance of triglyceride-rich
lipoproteins by increased lipoprotein lipase
activity.10
As demonstrated most recently in EVOLVE,
omega-3 fatty acids induce favorable changes in
 Evolution of Omega-3 Fatty Acid Therapy 279

other lipoproteins, including a reduction in non–
HDL-C, VLDL, and remnantlike particle choles-
terol.4 EVOLVE showed significant reductions in
lipoprotein-associated phospholipase A2 (Lp-
PLA2) and arachidonic acid levels, suggesting a
decrease in inflammation and platelet activation.4
Omega-3 fatty acids may lead to an increase in
low-density lipoprotein cholesterol (LDL-C); how-
ever, it decreases the amount of small, dense
LDL-C and is not accompanied by an increase in
apolipoprotein B, suggesting that this represents
a shift in LDL-C particle size instead of a true in-
crease in LDL-C.4,7,8,13,14 Table 1 further details
changes in lipid parameters observed in EVOLVE.
It is presently debated how much of the cardio-
protection observed in some studies is due to the
triglyceride-lowering effect versus other mecha-
nisms. In JELIS, the cardioprotective benefits
seen in the group taking EPA was not associated
with changes in triglycerides, total cholesterol,
HDL-C, or LDL-C, indicating the presence of
non–lipid-altering pathways.3 This may be due
in part to cardiac arrhythmia suppression,15,16
leading to decreased sudden cardiac death.
Omega-3 fatty acids are incorporated into
myocardial cell membranes and, therefore, may
change ion channel properties.17,18 Studies look-
ing at arrhythmia suppression with omega-3 fatty
acid administration have been mixed; however,
there seems to be more evidence of benefit in pa-
tients with ischemia-driven arrhythmias.10 A meta-
analysis published in 2009 consisting of 3 trials
looking at ventricular arrhythmias and death in pa-
tients with implantable cardioverter-defibrillators
and a prior history of ventricular tachycardia or
ventricular fibrillation found no difference in the
rates of appropriate implantable cardioverter-
defibrillator therapy; however, a trend toward
lower arrhythmia rate in those with a history of cor-
onary artery disease (hazard ratio, 0.79; 95% con-
fidence interval 0.60–1.06) taking omega-3 fatty
acids.19
Omega-3 fatty acids improve endothelial func-
tion and modestly lower blood pressure.20,21
Studies looking at peripheral artery flow-
mediated dilatation, a clinical marker of improved
endothelial function, show benefit with ther-
apy.22,23 A recent in vitro model using a proteomic
approach found an upregulation of glutathione and
a downregulation of vascular cell adhesion mole-
cule 1 with endothelial cell exposure to EPA, sup-
porting prior evidence that omega-3 fatty acids
improve endothelial function and have antiinflam-
matory properties.24 Similar to the Lp-PLA2
lowering found with omega-3 carboxylic acid use
in EVOLVE, the Multi-center, plAcebo-controlled,

Table 1
Median percent change from baseline in lipid levels in patients with severe hypertriglyceridemia
(triglycerides ‡500 mg/dL) in the EVOLVE study

OM3-CA 2 g/d OM3-CA 4 g/d Placebo (Olive Oil) 4 g/d

Percent Percent Percent
Baseline (mg/dL) Change Baseline (mg/dL) Change Baseline (mg/dL) Change
TG 717 25.9b 655 30.9c 682 4.3
Non-HDL-C 205 7.6a 225 9.6b 215 2.5
HDL-C 27.3 7.4 28.7 5.8 28.1 1.9
Total C 241 5.4a 254 7.5b 246 3.2
LDL-C 77.3 19.2b 90.3 19.4c 78.2 3.0
VLDL 123 26.6b 126 33.0c 125 8.5
RLP-C 44.5 20.7a 43.0 27.5c 52.3 3.4
Apo AI 130 0.0b 134 0.9b 131 5.9
Apo B 114 3.8 118 3.8 110 0.9
Apo CIII 24.5 10.9a 24.5 14.4c 24.0 1.6
Lp-PLA2 266 14.9c 249 17.2c 258 1.9

Abbreviations: Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein choles-
terol; Lp-PLA2, lipoprotein-associated phospholipase A2; OM3-CA, omega-3 carboxylic acids; RLP-C, remnant-like particle
cholesterol; TG, triglycerides; Total-C, total cholesterol; VLDL, very low-density lipoprotein cholesterol.
a
P<.05 significantly different from placebo.
b
P<.01 significantly different from placebo.
c
P<.001 significantly different from placebo.
Data from Kastelein JJ, Maki KC, Susekov A, et al. Omega-3 free fatty acids for the treatment of severe hypertriglycer-
idemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. J Clin Lipidol 2014;8(1):94–106.
280 Benes et al
Randomized, double-blINd, 12-week study with
an open-label Extension (MARINE) and Effect of
AMR101 (Icosapent Ethyl) on Triglyceride Levels
in Patients on Statins with High Triglyceride Levels
(ANCHOR) studies found a reduction in inflamma-
tory markers including Lp-PLA2 with icosapent
ethyl use.25
Given the multitude of cardiovascular changes
associated with omega-3 fatty acid use, the path-
way(s) responsible for cardioprotection are difficult
to delineate.
DYSLIPIDEMIA SUBGROUPS WITH THE
GREATEST ANTICIPATED BENEFIT
Trials consisting of nonstatin therapies aimed at
treating hypertriglyceridemia have failed to show
a reduction in cardiovascular events. Most of
these studies used fibrates in the treatment arm,
including the Veterans Affairs HDL Intervention
Trial (VA-HIT),26 the Bezafibrate Infarction Preven-
tion (BIP) study,27 the Fenofibrate Intervention and
Event Lowering in Diabetes (FIELD) study,28 and
the Action to Control Cardiovascular Risk in Dia-
betes (ACCORD) Lipid trial.29 Subgroup analyses
of these studies found that those in the highest
group of baseline triglycerides with or without
low HDL-C had a significant reduction in event
rates. The unfavorable pattern of dyslipidemia
consisting of hypertriglyceridemia and low HDL-
C is common, especially in diabetic patients.30,31
As discussed elsewhere in this article, outcome tri-
als looking at newer formulations of omega-3 fatty
acids are ongoing and may help to elucidate
whether those with this unfavorable pattern of dys-
lipidemia or other markers of increased cardiovas-
cular risk benefit from omega-3 fatty acid therapy.
Given that omega-3 fatty acids have similar
triglyceride-lowering efficacy as fibrates in addi-
tion to other cardiovascular benefits as described,
it can be hypothesized that these studies will
demonstrate benefit.
RESIDUAL RISK DESPITE STATIN THERAPY
Several studies have shown an association be-
tween increased triglycerides and cardiovascular
disease.32–34 Most patients with hypertriglyceride-
mia, defined as triglycerides of 150 mg/dL or
greater, also have an indication for a statin, for
which there is well-demonstrated cardiovascular
benefit. Fortunately, statins provide a dose-
dependent reduction in triglycerides, with an ex-
pected reduction of about 5% to 20%.35 This
means that patients with mildly increased triglyc-
erides may achieve a triglyceride level of less
than 150 mg/dL with statin therapy; however, as
demonstrated in a metaanalysis by Nicholls and
colleagues,35 only 0% to 24% of those with base-
line triglyceride levels of greater than 300 mg/dL
will achieve a level under the target of 150 mg/dL
with a statin. Therefore, for many patients treated
with a statin, residual risk remains.
Prior studies have demonstrated benefit of com-
bination statin and omega-3 fatty acid therapy.
The 2007 Combination of prescription Omega-3
Simvastatin (COMBOS) study36 showed signifi-
cant reductions in triglycerides and VLDL levels
in those on combination therapy compared with
simvastatin alone. The ANCHOR study followed
in 2012,37 demonstrating that when omega-3 ico-
sapent ethyl was added to a statin there was
greater reduction in triglycerides, LDL-C, apolipo-
protein B, VLDL, Lp-PLA2, and C-reactive protein
compared with placebo plus statin in diabetic pa-
tients. Similarly, the Epanova Combined with a
Statin in Patients with Hypertriglyceridemia to
Reduce non-HDL Cholesterol (ESPRIT) study
showed similar benefits in 2013 when omega-3
carboxylic acid therapy was added to a statin,
resulting in significant reductions in triglycerides,
VLDL, arachidonic acid, and non–HDL-C.38 This
finding was true when analyzed by statin type
when looking at the 3 most commonly prescribed
statins: rosuvastatin, atorvastatin, and simvastatin
(Fig. 1). All 3 of these trials included patients with
baseline triglycerides between 200 and 500 mg/
dL. See Table 2 for trends observed in the COM-
BOS, ANCHOR, and ESPRIT trials.
Omega-3 fatty acids and statins have different
mechanisms of action; therefore, the benefits
provided by their combination may simply be
additive from different pathways and/or owing
to compensatory benefits. For example, statins
have been shown to increase proprotein conver-
tase subtilisin/kexin type 939 and arachidonic
acid levels,40 whereas omega-3 fatty acids lower
them.38,41 As discussed, JELIS found a
decrease in MACE rates when omega-3 fatty
acids were added to a statin; however, this
change was independent of lipoprotein levels.3
Therefore, although statins provide a large net
benefit, the addition of omega-3 fatty acids
might counteract the paradoxic effects while
providing additional independent pathways of
benefit, accounting for the further decrease in
event rates observed.
CURRENT AND FUTURE ROLE OF OMEGA-3
FATTY ACID THERAPY
Approximately 31% of the United States’ popula-
tion has hypertriglyceridemia with a level of
150 mg/dL or greater and 16% have triglyceride
 Evolution of Omega-3 Fatty Acid Therapy 281

Fig. 1. Median percent change in triglycerides after adding omega-3 carboxylic acids to 3 commonly prescribed
statins. For all 3 statins, the addition of omega-3 carboxylic acids at either 2 or 4 g/d led to a significant reduction
in serum triglycerides in the ESPRIT study, which included patients with severe hypertriglyceridemia (triglycerides
of 500 mg/dL).

levels of 200 mg/dL or greater.42 The 2013
ACC/AHA guidelines on cholesterol management1
do not provide specific recommendations on the
treatment of hypertriglyceridemia, but rather refer-
ence the AHA 2011 guidelines on triglyceride man-
agement.42 The 2011 AHA guidelines recommend
achieving a triglyceride level of less than
100 mg/dL through diet (including dietary
omega-3 fatty acids) and exercise and to consider
medical therapy if levels remain greater than
500 mg/dL. Recently, the AHA published an advi-
sory on omega-3 fatty acid use in different patient
populations based on the currently available data.
For all populations studied, there was no evidence
of significant harm. For most populations, there
was either lack of data or lack of convincing
benefit. Exceptions found were the use of
omega-3 fatty acids as secondary prevention for
patients with prevalent coronary heart disease to
reduce coronary heart disease–related death

Table 2
Percent change in lipid parameters with the addition of omega-3 fatty acids to statin therapy in
patients with hypertriglyceridemia (triglycerides 200–500 mg/dL) in the COMBOS, ANCHOR, and
ESPRIT trials

COMBOS (N 5 256) ANCHOR (N 5 702) ESPRIT (N 5 647)

Ethyl Esters Icosapent Ethyl Carboxylic Acids
Lipid Parameter % 4 g/d D Placebo (Corn 4 g/d D Placebo (Mineral 4 g/d D Placebo (Olive
Change from BL Statin Oil) D Statin Statin Oil) D Statin Statin Oil) D Statin
TGs 29.5a 6.3 17.5a 5.9 21b 6
Non-HDL-C 9a 2.2 5a 9.8 7b 1
LDL-C 0.7 2.8 1.5a 8.8 1.3 1.1
Apo-B 4.2a 1.9 2.2a 7.1 2.1b 0.3
HDL-C 3.4a 1.2 1a 4.8 3 2

Abbreviations: Apo, apolipoprotein; BL, baseline; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipo-
protein cholesterol; TG, triglycerides; VLDL, very low-density lipoprotein cholesterol.
a
P<.05 significantly different from placebo.
b
P<.01 significantly different from placebo.
Data from Refs.36–38
282 Benes et al
(class IIa recommendation) and in patients with
heart failure with reduced ejection fraction (ejec-
tion fraction of <40%) to reduce death and hospi-
talizations (class IIa recommendation).43 The
authors of this 2017 advisory note that with the
exception of JELIS, the omega-3 fatty acids used
in the randomized controlled trials were low doses.
Large, randomized, controlled trials using higher
omega-3 fatty acid doses and newer formulations
are currently underway to assess the effects on clin-
ical outcomes. The Reduction of Cardiovascular
Events with EPA-Intervention Trial (REDUCE-IT) is
looking at 8000 patients with an increased risk of
cardiovascular disease who are considered to
have controlled LDL-C on statin therapy, but have
persistent hypertriglyceridemia (available at:
https://clinicaltrials.gov/ct2/show/NCT01492361).
The omega-3 formulation used in REDUCE-IT is
icosapent ethyl at a dose of 4 g/d. Trial results are
anticipated towards the end of 2018. The Outcomes
Study to Assess Statin Residual Risk Reduction
with Epanova in High CV Risk Patients with Hyper-
triglyceridemia (STRENGTH; available at: https://
clinicaltrials.gov/ct2/show/NCT02104817) enrolled
approximately 13,000 patients at high risk of cardio-
vascular disease with hypertriglyceridemia and low
HDL-C levels. The trial is designed to assess for a
difference in MACE between statin and omega-3
carboxylic acid combination therapy versus statin
alone. Estimated completion is the end of 2019.
These 2 trials are highly anticipated because prior
trials used older omega-3 fatty acid formulations
at lower doses in patients who were at lower cardio-
vascular risk. The newer formulations are expected
to demonstrate greater benefit given higher
bioavailability and/or triglyceride lowering. Further-
more, because subgroup analyses of prior trials
looking at triglyceride lowering showed benefit in
those with higher baseline triglycerides with or
without low HDL-C, it is welcomed that these higher
risk patients will be studied in greater number. A
Study of Cardiovascular Events in Diabetes
(ASCEND) began enrollment in 2005 to study the
rate of cardiovascular events in patients with dia-
betes given aspirin 100 mg/d for primary prevention
versus placebo with or without omega-3 ethyl es-
ters (available at: https://clinicaltrials.gov/ct2/show/
NCT00135226). The trial is completed and results
will be reported in 2018. If it demonstrates a reduc-
tion in MACE rates with omega-3 fatty acid use, it
would be the first to show more convincing benefit
for those with diabetes.
Given the lack of harm, the major limitation of
stronger endorsement of omega-3 fatty acids
has been unconvincing benefit; the results from
these trials may very well change that. If a reduc-
tion in event rates is indeed found, greater
emphasis can be placed on triglyceride lowering
with omega-3 fatty acids in patients with any level
of hypertriglyceridemia. This measure will help to
reduce the residual risk that remains for patients
on statin therapy. Additionally, some patients
with hypertriglyceridemia do not have an indica-
tion for or tolerate a statin; omega-3 fatty acids
may help to fill the void of cardiovascular risk
reduction for such patients.
RISKS OF OMEGA-3 FATTY ACID THERAPY
Omega-3 fatty acids are generally well tolerated
and felt to be safe. The most common adverse ef-
fect is gastrointestinal disturbance, including diar-
rhea, nausea, and eructation, seen at a rate of
19% to 27% compared with 7% in the placebo
arm in EVOLVE.4 There has been concern for
increased minor bleeding with omega-3 fatty
acid; however, no significant increased rates of
major bleeding have been reported. Given the
lack of evidence of significant risk of omega-3 fatty
acid use, the AHA 2017 advisory reports no
perceived harm with treatment.43
SUMMARY
In previous cardiovascular outcome trials with
fenofibrate (ACCORD)29 and niacin (AIM-HIGH),44
the population with both elevated triglycerides
paired with low HDL-C had a high residual risk
despite statin therapy and there was a suggestion
of benefit with triglyceride-lowering therapy. The
ACCORD trial is especially relevant, finding that
fenofibrate reduced major adverse cardiac events
by 31% in the prespecified subgroup in the upper
tertile of triglycerides (TG > 203 mg/dL) and the
lower tertile of HDL-C (HDL-C < 32 mg/dL), but
the P value for an interaction was .06 (not signifi-
cant). Omega-3 fatty acids containing both EPA
and DHA or EPA alone in combination with statins
lowers triglycerides and non–HDL-C. The non–
HDL-C reduction in patients with mixed dyslipide-
mia (triglycerides between 200 and 500 mg/dL) is
due to a decrease in VLDL and remnant choles-
terol with a modest decrease, neutral effect, or
slight increase in LDL-C (depending on baseline
LDL-C levels). Omega-3 fatty acids containing
DHA also shift small dense LDL-C to large LDL-C
and modestly improves HDL-C. The potential
cardiovascular benefits of these compositional
cholesterol changes are being tested in 2 large
outcome trials, REDUCE-IT and STRENGTH. In
addition, Omega-3 fatty acids are thought to pro-
vide cardioprotection via additional mechanisms
beyond triglyceride lowering, and also may help
to combat the paradoxic effects of statins such

as increases in proprotein convertase subtilisin/
kexin type 9 and arachidonic acid levels. There-
fore, if the cardiovascular outcome trials with novel
omega-3 fatty acids prove successful, there will be
a significant shift in therapy from statin monother-
apy to combination treatment for the management
of patients with mixed dyslipidemia with high re-
sidual risk.
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