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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-


ceridemia or other forms of dyslipidemia. The
The benefits of omega-3 fatty acids have been most recent recommendations from the Amer-
recognized since the beginning of the 20th cen- ican College of Cardiology/American Heart Asso-
tury; however, the first US Federal Drug Adminis- ciation (ACC/AHA) guidelines on cholesterol
tration (FDA)–approved formulation was not management1 published in 2013 do not suggest
available until 2004. Since that time, newer for- a major role of omega-3 fatty acid therapy in
mulations consisting of omega-3 carboxylic acids the treatment of dyslipidemia. This diminished
or pure eicosapentaenoic acid (EPA) ethyl esters role is predominantly because large trials study-
have been developed. Omega-3 fatty acids ing nonstatin cholesterol-lowering medications
are most recognized for their ability to reduce showed lack of significant benefit. Subgroup an-
serum triglycerides; however, there has been alyses of those trials looking at subjects with
debate regarding their role in the medical 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 therapy for secondary prevention.3 More recently,
pattern of dyslipidemia, suggest there may in the EpanoVa fOr Lowering Very high triglyceridEs
fact be a benefit. Current trials are ongoing with (EVOLVE) trial has demonstrated the triglyceride-
newer omega-3 fatty acid formulations to deter- lowering ability of the omega-3 carboxylic acids,
mine if patients at increased risk for atheroscle- with a 25.5% to 30.9% reduction after 12 weeks
rotic cardiovascular disease derive benefit from compared with 4.3% in controls given olive oil
therapy. This article discusses the evolution of in patients with severe hypertriglyceridemia
omega-3 fatty acid therapy as well as its current (triglycerides of 500 mg/dL).4
and future role in the treatment of dyslipidemia. Of the available formulations within the United
States, omega-3 acids ethyl esters have been
AVAILABLE OMEGA-3 FATTY ACID the most widely prescribed, in part because of
FORMULATIONS their longer time on the market and generic op-
tions. In the last few years, studies comparing
The first omega-3 fatty acid formulation, omega-3 the ethyl esters and newer formulations suggest
acid ethyl esters, was approved by the FDA in that greater benefit can be expected from
2004 under the trade name Omacor (Reliant Phar- the newer forms owing to their improved bio-
maceuticals, Liberty Corner, NJ) for the treatment availability. The Epanova compared to Lovaza
of triglyceride levels of 500 mg/dL or more. It was in a pharmacokinetic single-dose evaluation
renamed to Lovaza in 2007 (GlaxoSmithKline, (ECLIPSE) study demonstrated that omega-3 car-
Brentford, UK); however, Omacor is still available boxylic acids, which are already in the free fatty
outside of the United States. Icosapent ethyl (Vas- acid form, result in about a 4-fold increase in
cepa, Amarin Pharmaceuticals, Bedminster, NJ) bioavailability compared with omega-3 acid ethyl
was approved in 2012 for the treatment of severe esters when taken with a low-fat meal.5 ECLIPSE
hypertriglyceridemia (triglycerides of 500 mg/dL). II similarly demonstrated greater EPA and DHA
Icosapent ethyl differed from the initial omega-3 serum levels with omega-3 carboxylic acid use
fatty acid formulation by containing pure EPA ethyl compared with omega-3 acids ethyl esters while
esters rather than both EPA and docosahexaenoic on a low-fat diet over a longer observation period
acid (DHA). In 2014, omega-3 carboxylic acids of 14 days.6 Greater triglyceride-lowering ability
(Epanova, AstraZeneca, Wilmington, DE) gained was found with omega-3 carboxylic acids.
approval for the treatment of severe hypertriglyceri-
demia (triglycerides of 500 mg/dL). Omega-3 car- OMEGA-3 FATTY ACIDS’ BENEFITS AND
boxylic acids consist of free fatty acids rather than a MECHANISM OF ACTION
prodrug form; they have improved bioavailability
and can be taken independently of meals because Omega-3 fatty acids are best known for their
they are not reliant on hydrolysis by pancreatic triglyceride-lowering ability. Earlier formulations
lipase for absorption. of EPA and DHA demonstrated about a 20%
Momentum for the development of supple- reduction,7,8 whereas EVOLVE found closer to
mental omega-3 fatty acids came in part from a 30% reduction in serum triglycerides with
the Gruppo Italiano per lo Studio della Sopravvi- omega-3 carboxylic acids.4,5 There are numerous
venza nell’Infarto miocardico (GISSI)-Prevenzione proposed mechanisms to account for these find-
trial published in 19992 and further encouraged ings, which include decreased hepatic very low-
by the Japan EPA Lipid Intervention Study (JELIS) density lipoprotein (VLDL) synthesis and increased
published in 2007.3 The GISSI-Prevention trial triglyceride clearance from the serum. One such
showed that, in an Italian population, the adminis- mechanism is a decrease in VLDL triglyceride
tration of 1 g/d of polyunsaturated fatty acids to synthesis by altering transcription factors
patients who experienced a myocardial infarction such as sterol regulatory element-binding proteins
in the past 3 months reduced the primary endpoint and peroxisome proliferator-activated receptors
of death, nonfatal myocardial infarction, and involved in triglyceride synthesis in the hepato-
stroke by 10% to 15% at a follow-up of 3.5 years. cyte.9,10 It is possible that EPA serves as a poor
The reduction in the primary endpoint was largely substrate for VLDL triglycerides, leading to
driven by a reduction in deaths.2 JELIS suggested lipid-poor VLDL rather than triglyceride-rich VLDL
a benefit of adding omega-3 fatty acids to a statin, secretion into the serum.11,12 Omega-3 fatty acids
because there was a decrease in major adverse also increase serum clearance of triglyceride-rich
cardiovascular events (MACE) with a 19% risk lipoproteins by increased lipoprotein lipase
reduction in those taking both compared activity.10
with those only taking a statin over 5 years of As demonstrated most recently in EVOLVE,
follow-up, with more benefit seen in those on omega-3 fatty acids induce favorable changes in
Evolution of Omega-3 Fatty Acid Therapy 279

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


an open-label Extension (MARINE) and Effect of colleagues,35 only 0% to 24% of those with base-
AMR101 (Icosapent Ethyl) on Triglyceride Levels line triglyceride levels of greater than 300 mg/dL
in Patients on Statins with High Triglyceride Levels will achieve a level under the target of 150 mg/dL
(ANCHOR) studies found a reduction in inflamma- with a statin. Therefore, for many patients treated
tory markers including Lp-PLA2 with icosapent with a statin, residual risk remains.
ethyl use.25 Prior studies have demonstrated benefit of com-
Given the multitude of cardiovascular changes bination statin and omega-3 fatty acid therapy.
associated with omega-3 fatty acid use, the path- The 2007 Combination of prescription Omega-3
way(s) responsible for cardioprotection are difficult Simvastatin (COMBOS) study36 showed signifi-
to delineate. cant reductions in triglycerides and VLDL levels
in those on combination therapy compared with
DYSLIPIDEMIA SUBGROUPS WITH THE simvastatin alone. The ANCHOR study followed
GREATEST ANTICIPATED BENEFIT in 2012,37 demonstrating that when omega-3 ico-
sapent ethyl was added to a statin there was
Trials consisting of nonstatin therapies aimed at greater reduction in triglycerides, LDL-C, apolipo-
treating hypertriglyceridemia have failed to show protein B, VLDL, Lp-PLA2, and C-reactive protein
a reduction in cardiovascular events. Most of compared with placebo plus statin in diabetic pa-
these studies used fibrates in the treatment arm, tients. Similarly, the Epanova Combined with a
including the Veterans Affairs HDL Intervention Statin in Patients with Hypertriglyceridemia to
Trial (VA-HIT),26 the Bezafibrate Infarction Preven- Reduce non-HDL Cholesterol (ESPRIT) study
tion (BIP) study,27 the Fenofibrate Intervention and showed similar benefits in 2013 when omega-3
Event Lowering in Diabetes (FIELD) study,28 and carboxylic acid therapy was added to a statin,
the Action to Control Cardiovascular Risk in Dia- resulting in significant reductions in triglycerides,
betes (ACCORD) Lipid trial.29 Subgroup analyses VLDL, arachidonic acid, and non–HDL-C.38 This
of these studies found that those in the highest finding was true when analyzed by statin type
group of baseline triglycerides with or without when looking at the 3 most commonly prescribed
low HDL-C had a significant reduction in event statins: rosuvastatin, atorvastatin, and simvastatin
rates. The unfavorable pattern of dyslipidemia (Fig. 1). All 3 of these trials included patients with
consisting of hypertriglyceridemia and low HDL- baseline triglycerides between 200 and 500 mg/
C is common, especially in diabetic patients.30,31 dL. See Table 2 for trends observed in the COM-
As discussed elsewhere in this article, outcome tri- BOS, ANCHOR, and ESPRIT trials.
als looking at newer formulations of omega-3 fatty Omega-3 fatty acids and statins have different
acids are ongoing and may help to elucidate mechanisms of action; therefore, the benefits
whether those with this unfavorable pattern of dys- provided by their combination may simply be
lipidemia or other markers of increased cardiovas- additive from different pathways and/or owing
cular risk benefit from omega-3 fatty acid therapy. to compensatory benefits. For example, statins
Given that omega-3 fatty acids have similar have been shown to increase proprotein conver-
triglyceride-lowering efficacy as fibrates in addi- tase subtilisin/kexin type 939 and arachidonic
tion to other cardiovascular benefits as described, acid levels,40 whereas omega-3 fatty acids lower
it can be hypothesized that these studies will them.38,41 As discussed, JELIS found a
demonstrate benefit. decrease in MACE rates when omega-3 fatty
acids were added to a statin; however, this
RESIDUAL RISK DESPITE STATIN THERAPY change was independent of lipoprotein levels.3
Therefore, although statins provide a large net
Several studies have shown an association be- benefit, the addition of omega-3 fatty acids
tween increased triglycerides and cardiovascular might counteract the paradoxic effects while
disease.32–34 Most patients with hypertriglyceride- providing additional independent pathways of
mia, defined as triglycerides of 150 mg/dL or benefit, accounting for the further decrease in
greater, also have an indication for a statin, for event rates observed.
which there is well-demonstrated cardiovascular
benefit. Fortunately, statins provide a dose- CURRENT AND FUTURE ROLE OF OMEGA-3
dependent reduction in triglycerides, with an ex- FATTY ACID THERAPY
pected reduction of about 5% to 20%.35 This
means that patients with mildly increased triglyc- Approximately 31% of the United States’ popula-
erides may achieve a triglyceride level of less tion has hypertriglyceridemia with a level of
than 150 mg/dL with statin therapy; however, as 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 500 mg/dL. Recently, the AHA published an advi-
ACC/AHA guidelines on cholesterol management1 sory on omega-3 fatty acid use in different patient
do not provide specific recommendations on the populations based on the currently available data.
treatment of hypertriglyceridemia, but rather refer- For all populations studied, there was no evidence
ence the AHA 2011 guidelines on triglyceride man- of significant harm. For most populations, there
agement.42 The 2011 AHA guidelines recommend was either lack of data or lack of convincing
achieving a triglyceride level of less than benefit. Exceptions found were the use of
100 mg/dL through diet (including dietary omega-3 fatty acids as secondary prevention for
omega-3 fatty acids) and exercise and to consider patients with prevalent coronary heart disease to
medical therapy if levels remain greater than 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 emphasis can be placed on triglyceride lowering
heart failure with reduced ejection fraction (ejec- with omega-3 fatty acids in patients with any level
tion fraction of <40%) to reduce death and hospi- of hypertriglyceridemia. This measure will help to
talizations (class IIa recommendation).43 The reduce the residual risk that remains for patients
authors of this 2017 advisory note that with the on statin therapy. Additionally, some patients
exception of JELIS, the omega-3 fatty acids used with hypertriglyceridemia do not have an indica-
in the randomized controlled trials were low doses. tion for or tolerate a statin; omega-3 fatty acids
Large, randomized, controlled trials using higher may help to fill the void of cardiovascular risk
omega-3 fatty acid doses and newer formulations reduction for such patients.
are currently underway to assess the effects on clin-
ical outcomes. The Reduction of Cardiovascular RISKS OF OMEGA-3 FATTY ACID THERAPY
Events with EPA-Intervention Trial (REDUCE-IT) is
looking at 8000 patients with an increased risk of Omega-3 fatty acids are generally well tolerated
cardiovascular disease who are considered to and felt to be safe. The most common adverse ef-
have controlled LDL-C on statin therapy, but have fect is gastrointestinal disturbance, including diar-
persistent hypertriglyceridemia (available at: rhea, nausea, and eructation, seen at a rate of
https://clinicaltrials.gov/ct2/show/NCT01492361). 19% to 27% compared with 7% in the placebo
The omega-3 formulation used in REDUCE-IT is arm in EVOLVE.4 There has been concern for
icosapent ethyl at a dose of 4 g/d. Trial results are increased minor bleeding with omega-3 fatty
anticipated towards the end of 2018. The Outcomes acid; however, no significant increased rates of
Study to Assess Statin Residual Risk Reduction major bleeding have been reported. Given the
with Epanova in High CV Risk Patients with Hyper- lack of evidence of significant risk of omega-3 fatty
triglyceridemia (STRENGTH; available at: https:// acid use, the AHA 2017 advisory reports no
clinicaltrials.gov/ct2/show/NCT02104817) enrolled perceived harm with treatment.43
approximately 13,000 patients at high risk of cardio-
vascular disease with hypertriglyceridemia and low SUMMARY
HDL-C levels. The trial is designed to assess for a
difference in MACE between statin and omega-3 In previous cardiovascular outcome trials with
carboxylic acid combination therapy versus statin fenofibrate (ACCORD)29 and niacin (AIM-HIGH),44
alone. Estimated completion is the end of 2019. the population with both elevated triglycerides
These 2 trials are highly anticipated because prior paired with low HDL-C had a high residual risk
trials used older omega-3 fatty acid formulations despite statin therapy and there was a suggestion
at lower doses in patients who were at lower cardio- of benefit with triglyceride-lowering therapy. The
vascular risk. The newer formulations are expected ACCORD trial is especially relevant, finding that
to demonstrate greater benefit given higher fenofibrate reduced major adverse cardiac events
bioavailability and/or triglyceride lowering. Further- by 31% in the prespecified subgroup in the upper
more, because subgroup analyses of prior trials tertile of triglycerides (TG > 203 mg/dL) and the
looking at triglyceride lowering showed benefit in lower tertile of HDL-C (HDL-C < 32 mg/dL), but
those with higher baseline triglycerides with or the P value for an interaction was .06 (not signifi-
without low HDL-C, it is welcomed that these higher cant). Omega-3 fatty acids containing both EPA
risk patients will be studied in greater number. A and DHA or EPA alone in combination with statins
Study of Cardiovascular Events in Diabetes lowers triglycerides and non–HDL-C. The non–
(ASCEND) began enrollment in 2005 to study the HDL-C reduction in patients with mixed dyslipide-
rate of cardiovascular events in patients with dia- mia (triglycerides between 200 and 500 mg/dL) is
betes given aspirin 100 mg/d for primary prevention due to a decrease in VLDL and remnant choles-
versus placebo with or without omega-3 ethyl es- terol with a modest decrease, neutral effect, or
ters (available at: https://clinicaltrials.gov/ct2/show/ slight increase in LDL-C (depending on baseline
NCT00135226). The trial is completed and results LDL-C levels). Omega-3 fatty acids containing
will be reported in 2018. If it demonstrates a reduc- DHA also shift small dense LDL-C to large LDL-C
tion in MACE rates with omega-3 fatty acid use, it and modestly improves HDL-C. The potential
would be the first to show more convincing benefit cardiovascular benefits of these compositional
for those with diabetes. cholesterol changes are being tested in 2 large
Given the lack of harm, the major limitation of outcome trials, REDUCE-IT and STRENGTH. In
stronger endorsement of omega-3 fatty acids addition, Omega-3 fatty acids are thought to pro-
has been unconvincing benefit; the results from vide cardioprotection via additional mechanisms
these trials may very well change that. If a reduc- beyond triglyceride lowering, and also may help
tion in event rates is indeed found, greater to combat the paradoxic effects of statins such
Evolution of Omega-3 Fatty Acid Therapy 283

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