European Journal of Clinical Nutrition (2011) 65, 110–116

& 2011 Macmillan Publishers Limited All rights reserved 0954-3007/11

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ORIGINAL ARTICLE
Prospective randomized comparison between
omega-3 fatty acid supplements plus simvastatin
versus simvastatin alone in Korean patients with
mixed dyslipidemia: lipoprotein profiles and
heart rate variability
Sang-Hyun Kim1,2,5, Min-Kyung Kim1,3,5, Hae-Young Lee1,4, Hyun-Jae Kang1,4, Yong-Jin Kim1,4 and
Hyo-Soo Kim1,4

1
Division of Cardiology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea;
2
Cardiovascular Center, Seoul Metropolitan Boramae Hospital, Seoul, South Korea; 3Healthcare System Gangnam Center, Seoul
National University Hospital, Seoul, South Korea and 4Cardiovascular Center, Seoul National University Hospital,
Seoul, South Korea

Background: This study was designed to evaluate the effects of omega-3 fatty acids supplements and simvastatin on lipoproteins
and heart rate variability (HRV), a surrogate parameter of cardiac autonomic function, in patients with mixed dyslipidemia.
Methods: This study was a prospective, randomized, open-label study. Among the 171 patients screened, 62 who met the
inclusion criteria after 6 weeks on a strict diet therapy were randomized into two treatment groups. The inclusion criteria were
mixed dyslipidemia with a high triglyceride level (200–499 mg per 100 ml) and a total cholesterol level 4200 mg per 100 ml.
After a run-in period of 6 weeks, the patients were randomized into two groups and given a combination treatment with 4 g of
omega-3 fatty acids (four 1 g Omacor (eicosapentaenoic acid, 465 mg; docosahexaenoic acid, 375 mg; other omega-3 fatty
acids, 60 mg; others 100 mg, Gun-il Pharmacy, Seoul, Korea)) and 20 mg of simvastatin daily or a monotherapy of 20 mg
simvastatin for 6 weeks. In the combination therapy group, seven patients dropped out, and in the simvastatin alone therapy
group, five patients dropped out during the study period.
Results: After 6 weeks of drug treatment, triglyceride levels decreased by 41.0% in the combination treatment group and
13.9% in the simvastatin monotherapy group (from 309.2±95 mg per 100 ml to 177.7±66 versus 294.6±78 mg per 100 ml to
238.3±84 mg per 100 ml, respectively, P ¼ 0.0007). No significant changes in the HRV parameters were observed in either
group.
Conclusion: The combination of omega-3 fatty acids plus simvastatin, which achieved a significantly greater reduction of
triglycerides without adverse reactions, should be considered as an optimal treatment option for patients with mixed dyslipidemia.
European Journal of Clinical Nutrition (2011) 65, 110–116; doi:10.1038/ejcn.2010.195; published online 29 September 2010

Keywords: omega-3 fatty acid; statin; lipoproteins; heart rate variability

Introduction fatty acids stabilize atheromatous plaque (Thies et al.,

Omega-3 fatty acids has an important role in the prevention
and treatment of coronary artery disease, because omega-3
Correspondence: Professor Hyo-Soo Kim, Division of Cardiology, Department
of Internal Medicine, Cardiovascular Center, Seoul National University
Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, South Korea.
E-mail: hyosoo@snu.ac.kr
5 1997).
These authors contributed equally to this work.
Received 16 April 2010; revised 1 August 2010; accepted 11 August 2010;
published online 29 September 2010
2003) and lower the risk of fatal ischemic heart disease in
older adults (Lemaitre et al., 2003). Furthermore, omega-3
fatty acids are considered beneficial to autonomic cardio-
vascular function. Heart rate variability (HRV), a surro-
gate marker for cardiac autonomic tone, was improved in
the platelets of survivors of myocardial infarction using
increasing levels of docosahexaenoic acid (Christensen et al.,
In patients with elevated baseline low-density lipo-
protein (LDL) cholesterol (hypercholesterolemia or mixed

dyslipidemia), omega-3 fatty acids decrease LDL cholesterol
when the saturated fatty acid content is decreased or when
they are used at high doses. However, in the patients with
very low baseline LDL cholesterol and/or very high triglycer-
ides (type IV and V dyslipidemia), omega-3 fatty acids
slightly increase LDL cholesterol (Harris, 1997; Calabresi
et al., 2000). Omega-3 fatty acids lower the serum triglyceride
levels of normal subjects (Goyens and Mensink, 2006) and of
patients with diabetes (Kabir et al., 2007), or with hyper-
triglyceridemia (Calabresi et al., 2004). The effect of omega-3
fatty acids on high-density lipoprotein (HDL) cholesterol
varies from having no effect to slightly increasing it (Harris,
1997; Calabresi et al., 2000, 2004; Kabir et al., 2007). The
HDL cholesterol concentration generally increases during
omega-3 therapy in subjects with hypertriglyceridemia, but
it may remain unchanged or even decline slightly in subjects
without hypertriglyceridemia. Recently, as the target goals of
LDL-cholesterol and triglycerides became tougher, a combi-
nation therapy of omega-3 fatty acids and statins would be a
reasonable option for high-risk patients with combined or
mixed dyslipidemia. We designed a study to evaluate the
effects of omega-3 fatty acids administered with or without
simvastatins on lipoprotein levels and HRV parameters in
patients with mixed dyslipidemia, specifically in Koreans
with a high carbohydrate intake showing a high prevalence
of hypertriglyceridemia.
Materials and methods
Patient enrollment
This study was a prospective, randomized, open label, two-
center trial that was performed in two general hospitals, the
Seoul National University Hospital and the Seoul Metropo-
litan Boramea Hospital of Korea. Patients who had mixed
dyslipidemia with high triglyceride levels (200–499 mg per
100 ml) and a total cholesterol level of over 200 mg per
100 ml were enrolled. From June 2006 to March 2008,
171 patients who initially met the inclusion criteria were
kept on a strict diet therapy for 6 weeks. Among them,
62 patients who still met the criteria after the diet therapy
were randomized into two treatment groups. All of the
participants were instructed to follow a low cholesterol diet
during the entire study period. All of the participants gave
their written consent before entering the study, in accor-
dance with a protocol approved by the Institutional Review
Board of the Seoul National University Hospital and the
Seoul Metropolitan Boramea Hospital. This study was also
performed in accordance with the principles set forth in the
Guidelines for Good Clinical Practice and the Declaration of
Helsinki and its amendments.
Study protocol
After a run-in period of 6 weeks, eligible patients were
randomly assigned to two groups using a randomization
Omega-3 fatty acid plus simvastatin versus simvastatin
Hyo-Soo Kim et al
111
table. One group of patients received a combination
treatment with 4 g of omega-3 fatty acids (two 1 g Omacor
tablets (eicosapentaenoic acid, 465 mg; docosahexaenoic
acid, 375 mg; other omega-3 fatty acids 60 mg; others
100 mg, Gun-il Pharmacy) twice a day) and 20 mg of
simvastatin daily; the other group underwent a monother-
apy with 20 mg of simvastatin for 6 weeks (Figure 1). After
randomization, the study processes were not blinded.
The primary objective was to compare the change in
triglyceride levels in the two groups from the baseline
with week 6. The secondary objectives were to examine the
changes of other lipoprotein profiles, high sensitivity
C-reactive protein (hsCRP), and HRV parameters. The total
cholesterol, triglycerides, LDL and HDL cholesterols, and
apolipoprotein B and A1 concentrations were determined
from blood samples collected just before the randomization
and at the 6 week of follow-up visit. The levels of serum
creatine kinase, hepatic transaminases and creatine phos-
phokinase, as well as hsCRP concentrations and differential
blood counts were also measured.
HRV analysis
A 24-h Holter recording was obtained from each patient
using a three-channel tape recorder at the baseline (visit 2)
and again at the 6-week follow-up visit (visit 3). An
investigator who was fully blinded to the treatment alloca-
tion and the study phase independently analyzed the HRV
data.
We defined the following standard time domain measures
of HRV: (1) the standard deviation of all normal RR intervals
(SDNN), (2) the standard deviation of the means of all
normal RR intervals during each 5-min segment of
the recording (SDANN) and (3) the root mean square of the
differences of the successive RR intervals. In addition, the
Assessed for eligibility
N = 121
Excluded 109
• Not meeting inclusion criteria 90
• Refused to participate:15
• Follow-up lost: 2
• Other reasons: 2
Randomization
N = 62
Simvastatin + Omega-2 fatty acid Simvastatin
N = 30 N = 32
Excluded 1
• 1 refused consent
ITT analysis ITT analysis
N = 30 N = 31
Figure 1 Trial profile. Abbreviation: ITT, intention to treat.
European Journal of Clinical Nutrition
 Omega-3 fatty acid plus simvastatin versus simvastatin
Hyo-Soo Kim et al
112
following frequency domain indexes were obtained using
the supine 5-min recording: (1) high-frequency (HF) power
(0.15–0.4 Hz), (2) low-frequency (LF) power (0.004–0.15 Hz),
(3) normalized HF power, (4) normalized LF power and
(5) ratio of LF/HF.
Statistical analysis
The sample size was calculated based on the primary
objective of the trial, in which we detected 10% of the mean
difference in triglyceride levels between the combination
therapy with omega-3 fatty acids plus simvastatin versus the
simvastatin only group, with a power of 80% and a two-sided
significance level of Po0.05. We adjusted the sample size for
an estimated follow-up loss rate of 3%, which resulted in 29
patients in each group. Data analyses were carried out
according to the intention-to-treat population.
Non-normally distributed variables were analyzed using
the Mann–Whitney U-test. Normally distributed data were
presented as the mean±s.d. Categorical variables were
expressed as percentages, and the w2 test was used
for comparison. The significance of any temporal changes
in clinical, laboratory data, and HRV indexes as a result of
therapy were evaluated with the paired t-test or Wilcoxon’s
signed rank test for both normal and non-normal data.
All statistical tests were two-sided; values of Po0.05 were
considered significant. All analyses were performed with
SPSS 12.0 software (SPSS Inc., Chicago, IL, USA).
Results
Patients, adverse events and compliance
Of the 30 patients randomized to the simvastatin plus
omega-3 fatty acids treatment, two were withdrawn
from the study because of patient intolerance; one had a
gastrointestinal disturbance and the other was withdrawn
after a non-specific skin rash. No other subjects experienced
any significant adverse effects in either group. Of the 31
patients randomized to the simvastatin only group, one
patient was excluded because of the patient’s refusal.
Compliance, as assessed by counting capsules during the
follow-up visit, was 92% (simvastatin) and 91% (omega-3
fatty acid) in the omega-3 fatty acids plus simvastatin group
and 87% in the simvastatin only group. The clinical and
demographic characteristics of the participants are given in
Table 1. More female patients were allocated to the
simvastatin only group (P ¼ 0.014). Patients receiving the
combination treatment with omega-3 fatty acids and
simvastatin had a higher alcohol use, but the difference
was not statistically significant (P ¼ 0.097). These clinical
parameters are known to related to triglyceride levels, but a
baseline laboratory test showed no difference in baseline
triglyceride levels, so we assumed that the differences were
negligible.
Triglycerides and other lipoprotein profiles
The concentrations of the lipid parameters at the baseline
and at 6 weeks after treatment are shown in Table 2. Percent
changes from the baseline for the main lipid variables are
presented in Figure 2. There was significant reduction in
triglyceride levels after both treatments. Triglyceride levels
decreased 41.0% with the combination treatment and 13.9%
in the simvastatin monotherapy group (from 309.2 to
177.7 mg per 100 ml in the combination treatment group,
from 294.6 to 238.3 mg per 100 ml in the simvastatin
monotherapy group). The percent change from the baseline
in triglyceride levels, the primary outcome variable, was
significantly greater with omega-3 fatty acids plus simvasta-
tin than with simvastatin alone (P ¼ 0.0007). There were
significant reductions in the total or LDL cholesterol levels

Table 1 Baseline characteristics of the intention-to-treat population

Statistic Omega-3 fatty acids plus Simvastatin P

simvastatin (n ¼ 30) (n ¼ 31)

Male N (%) 17 (56.7%) 8 (25.8%) 0.014*

Age (year) Mean±s.d. 56.7±13.0 59.4±10.3 0.380
Median 60.5 59
Range (min–max) 31.0–76.0 35.0–79.0
Hypertension N (%) 23 (76.7%) 19 (61.3%) 0.195
Diabetes mellitus N (%) 3 (10.0%) 6 (19.4%) 0.473
History of smoking N (%) 5 (16.7%) 3 (9.7%) 0.473
History of drinking N (%) 17 (56.7%) 11 (35.5%) 0.097
Ischemic cardiovascular disease N (%) 2 (6.7%) 3 (9.7%) 0.999
b-Blocker N (%) 7 (23.3%) 12 (38.7%) 0.195
BMI (kg/m2) Mean±s.d. 25.90±3.11 25.74±3.36 0.848
Median 25.86 25.44
Range (min–max) 20.31–35.63 19.15–38.67

Abbreviation: BMI, body mass index.

Values are number (percentage).
*Po0.05.

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 Omega-3 fatty acid plus simvastatin versus simvastatin
Hyo-Soo Kim et al
113
Table 2 Fasting lipids and apolipoproteins at the baseline and 6 weeks after treatment with omega-3 fatty acids plus simvastatin versus simvastatin alone

Lipoproteins (mg/dl) Omega-3 fatty acids plus simvastatin (n ¼ 30) Simvastatin (n ¼ 31)

Baseline 6 Weeks Differences P Baseline 6 Weeks Differences P

TC 238±28 170±30 68±29 (28±10%) o0.001 233±26 180±28 53±33 (22±13%) o0.001
TG 309±95 178±66 131±78 (41±20%) o0.001 295±78 238±84 55±113 (14±39%) 0.009
HDL-C 39±7 41±10 2 ±6 (4±15%) 0.193 41±9 43±10 2±6 (6±15%) 0.068
LDL-C 148±32 95±32 52±30 (35±19%) o0.001 139±31 99±26 40±32 (27±21%) o0.001
Non-HDL-C 197±31 193±22 4±32 (0.1±16%) 0.762 194±32 199±29 5±34 (4.5±20%) 0.339
ApoA1 123±27 128±23 5±24 (5±18%) 0.278 133±31 134±27 1±19 (2±14%) 0.909
ApoB 122±20 86±20 35±22 (28±16%) o0.001 118±18 86±18 31±23 (26±19%) o0.001
ApoE 7±1 5±1 2±1 (30±14%) o0.001 8 ±2 5 ±2 2±2 (27±20%) 0.001

Abbreviations: ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; ApoE, apolipoprotein E; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density
lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides.
Values are shown as means±s.d.s. No differences between groups were statistically significant.

groups (Table 3). There were no cases of clinically significant

Figure 2 Mean percent change in triglycerides (TG), total
cholesterol (TC), HDL-cholesterol (HDL-C), and LDL-C from the
baseline to the end of treatment in the intention-to-treat population.
Values are means±s.d.s.; the percent change from the baseline in
the TG level was significantly greater with omega-3 fatty acids plus
simvastatin than with simvastatin alone (P ¼ 0.0007). There were no
significant differences in the changes of LDL, HDL or TC levels.
after both treatments. The HDL cholesterol level was not
affected by either the combination therapy or by simvastatin
alone. Significant reductions in apolipoprotein B and
apolipoprotein E levels were observed in both treatment
groups. Between the two groups, however, there was no
significant difference in the changes of the LDL, HDL or total
cholesterol levels.
Blood pressure and laboratory findings
The mean baseline systolic/diastolic blood pressure was
128/84 mm Hg in the combination treatment group, and
128/82 mm Hg in the simvastatin alone group. The changes
in hsCRP were not significantly different between the two
increases in hepatic transaminase levels (42.0  the upper
limit of normal) in either group. There was a numerically
higher, but statistically insignificant, incidence of mildly
elevated aspartate aminotransferase levels in the group that
received omega-3 fatty acids plus simvastatin compared with
the group that received simvastatin only (6.67% (2/30)
versus 0% (0/31), respectively; P ¼ 0.317). Thus, the mean
aspartate aminotransferase level was increased after 6 weeks
of treatment with omega-3 fatty acids plus simvastatin
(26.0–29.8 IU/l, P ¼ 0.009). No significant differences were
observed in the serum creatine phosphokinase levels be-
tween the two groups. The mean fasting glucose level was
increased after 6 weeks in the group that received omega-3
fatty acids and simvastatin. However, the incidence of an
elevated fasting glucose level (4110 mg per 100 ml) after 6
weeks was the same in both groups (3.33% (1/31) versus
3.33% (1/31), baseline and 6 weeks after treatment).
Heart rate variability
As shown in Table 3, heart rates, SDNN, SDANN and RMSDD
were not different before and after treatment in either group.
The LF, HF and LF/HF ratio showed similar values before and
after treatment (all P ¼ NS).
Discussion
Efficacy and usefulness of omega-3 fatty acids plus simvastatin in
patients with mixed dyslipidemia
In this study, the efficacy and safety of 4 g of omega-3 fatty
acids plus 20 mg simvastatin combination therapy were
evaluated in Korean patients with mixed dyslipidemia. After
6 weeks of treatment, the triglyceride levels decreased by
41.0% in the combination treatment group and 13.9% in
the simvastatin monotherapy group. These findings were
consistent with previous studies in Western countries
(Durrington et al., 2001; Davidson et al., 2007; Maki et al.,

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 Omega-3 fatty acid plus simvastatin versus simvastatin
Hyo-Soo Kim et al
114
Table 3 Temporal changes in clinical, biochemical, and heart rate variability indices

Omega-3 fatty acid plus simvastatin (n ¼ 30) Simvastatin (n ¼ 31)

Baseline 6 Weeks Differences P Baseline 6 Weeks Differences P

SBP (mm Hg) 128±14 125±12 3±14 0.234 129±16 125±12 –4±14 0.117
DBP (mm Hg) 84±11 81±10 3±9 0.097 82±11 81±9 2±9 0.367
Heart rate 73±10 69±9 4±12 0.117 73±8 71±9 1±6 0.211
AST 26±7 30±12 4 ±7 0.009 24±7 24±7 1±5 0.795
ALT 30±14 35±21 5±15 0.054 25±11 27±11 2±10 0.363
CPK 102±57 100±47 2±38 0.790 94±39 87±34 7±28 0.162
fasting glucose 103±15 109±17 6±11 0.003 108±22 108±25 0±9 0.985
hsCRP 0.19±0.19 0.34±0.6 0.16±0.58 0.398 0.24±0.33 0.16±0.21 0.08±0.37 0.056

Time domain indices

SDNN (ms) 129±30 128±33 2±23 (0±19%) 0.652 122±25 126±34 3±23 (3±19%) 0.469
SDANN (ms) 119±30 117±32 2±23 (0±20%) 0.674 114±21 115±32 2±23 (2±20%) 0.789
RMSSD (ms) 22±6 22±5 0±5 (4±24%) 0.772 24±8 24±9 1±7 (3±30%) 0.883

Frequency domain indices

LF power (ms2) 231±140 222±128 26±425 0.863 215±129 298±267 114±331 0.407
HF power (ms2) 80±40 73±30 13±68 0.413 81±45 78±41 30±99 0.766
LF power (nu) 87±75 168±276 23±189 0.378 89±98 103±112 13±142 0.218
HF power (nu) 30±12 31±13 3 ±7 0.067 35±15 36±14 0±8 0.688
LF/HF ratio 2.83±0.95 2.69±1.53 1±6 (45±206%) 0.567 2.51±1.92 2.36±1.39 0±5 (48±148%) 0.611

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; DBP, diastolic blood pressure; HF, high frequency;
hsCRP, high-sensitivity C-reactive protein; LF, low frequency; RMSSD, root mean square of differences of successive RR intervals; SBP, systolic blood pressure;
SDANN, standard deviation of the means of all normal RR intervals during each 5-min segment of the recording; SDNN, standard deviation of all normal RR intervals.

2008). Durrington et al. (2001) found that omega-3 fatty
acids (4 g) and simvastatin (10–40 mg) decreased serum
triglyceride levels significantly more than treatment with
simvastatin alone (24 versus þ 11% at a 12-week follow-up,
Po0.005). Maki et al. (2008) reported that omega-3 fatty
acids (4 g) plus simvastatin (20 mg) treatment for 6 weeks
decreased triglyceride levels significantly more than treat-
ment with a placebo plus simvastatin (44 versus 29%) in
mixed dyslipidemia patients. The combination of prescrip-
tion omega-3 with simvastatin trial (Davidson et al., 2007)
evaluated the efficacy of omega-3 fatty acids added to stable
statin therapy in subjects with persistent hypertriglyceride-
mia. There was significantly greater reduction in the
triglyceride levels in simvastatin 40 mg plus omega-3 fatty
acids (4 g) per day versus simvastatin only (40 mg) after
8 weeks of treatment (29.5 versus 6.3%).
To summarize the results of the previous studies and this
study, the reduction of triglycerides by omega-3 fatty acids
(4 g) plus variable doses of simvastatin ranges from 25 to
45%, depending on the duration and potency of the
treatment as well as the baseline lipid profile. There was a
trend of a greater reduction in triglycerides with longer
treatment periods (Durrington et al., 2001). The dosage is
also an important determinant. In the Japan Eicosapentae-
noic Acid Lipid Intervention Study, with 1.8 g of eicosapen-
taenoic acid per day plus 10 mg of pravastatin or 5 mg of
simvastatin, relatively smaller doses than in this study,
triglyceride levels were decreased by 18% at the 5-year
follow-up (Yokoyama et al., 2007). Finally, the patient subset
is also a factor in determining efficacy. In general, 3–4 g of
omega-3 fatty acids can reduce triglycerides by 25% in
normal subjects and by 34% in hypertriglyceridemic patients
(Harris, 1997). The combination therapy did not have any
undesirable effects on LDL cholesterol in the current study or
in the previous studies. In this, LDL cholesterol levels
significantly decreased with a combination of omega-3 fatty
acids plus simvastatin (148±32 to 95±32 mg per 100 ml,
Po0.001), which was comparable with the simvastatin
monotherapy (139±31 to 99±26 mg per 100 ml, Po0.001).
When cholesterol synthesis was blocked by simvastatins,
the unwanted effects of omega-3 fatty acids on total
cholesterol and LDL cholesterol levels were kept under
control in mixed dyslipidemia patients. In contrast to the
potential serious side effects of combinations of statins with
fibrate, a combination therapy of omega-3 fatty acids and
simvastatin showed few adverse events. Thus, it could be
considered as good therapeutic choice for patients with
mixed dyslipidemia, lowering triglycerides by 40% without
mitigating LDL cholesterol reduction by statins.
Changes in inflammatory markers with omega-3 fatty acids plus
simvastatin treatment in patients with mixed dyslipidemia
Simvastatin were known to lower hsCRP (Madsen et al.,
2001; Plenge et al., 2002; Meredith et al., 2007). However,
this study showed no significant improvement in hsCRP
levels with the use of combination therapy or simvastatin
alone. In this study, in which high-risk patients were
excluded, the baseline hsCRP level (0.2 mg per 100 ml) was
lower than that (1.1–2.8 mg per 100 ml) of previous studies

European Journal of Clinical Nutrition


(Madsen et al., 2001; Plenge et al., 2002; Meredith et al.,
2007). This difference may explain why there were no
changes in the hsCRPs in either group of this study.
Indices of HRV during combination therapy of omega-3 fatty acids
plus simvastatin
We evaluated HRV changes after the omega-3 fatty acids plus
simvastatin combination. Depressed HRV, an indicator of
autonomic nervous system impairment, has been shown to
be a powerful predictor of sudden cardiac death in post-
myocardial infarction patients (Kleiger et al., 1987; Perkiö-
mäki et al., 1997; La Rovere et al., 1998). Lower HRV indices
were reported in obese subjects (Chen et al., 2008), in post-
myocardial infarction patients (Kleiger et al., 1987; La Rovere
et al., 1998), and in patients with decreased left ventricular
systolic function (Szabo et al., 1995). Depressed HRV has
been well correlated with a decreased left ventricular ejection
fraction and functional capacity (Szabo et al., 1995). In US
adults, consumption of fish and omega-3 fatty acids was
associated with specific HRV components, including higher
root mean square successive differences of normal-to-normal
intervals (P ¼ 0.001), higher normalized HF power
(P ¼ 0.008), and a lower ratio of LF/HF (P ¼ 0.03; Mozaffarian
et al., 2008). However, in this study, omega-3 fatty acids did
not significantly change HRV, such as measures of circadian
variation (SDNN), indices of vagal activity (normalized HF),
and measures that reflect combined sympathetic and para-
sympathetic influences on baroreceptor function (normal-
ized LF, LF/HF ratio). To avoid possible confusion with the
short term (5 or 20 min recording) electrocardiograms of
some previous studies, we collected 24-h Holter recordings at
the baseline and at week 6 for analyses of the HRV
parameters. Our patients had normal HRV indices; the
baseline SDNN was 4120 ms, which indicated normal
circadian variation. Thus, the beneficial effects of omega-3
fatty acids on HRV could not be found significant in subjects
with normal HRV indices. This result is consistent with a
previous report from Europe (Geelen et al., 2003). To our
knowledge, this is the first prospective study that reports that
omega-3 fatty acids plus simvastatin combination therapy
has no impact on indices of HRV in mixed dyslipidemia
patients who do not have cardiovascular diseases and have
normal HRV indices, especially in Asians.
There was also no significant change in the HRV of the
patients receiving simvastatin only. This finding is consistent
with some previous studies (Gentlesk et al., 2005; Riahi et al.,
2006), although others have reported increased HRV para-
meters after statin therapy in hypercholesterolemia patients
(Pehlivanidis et al., 2001). The pleiotropic effect of statins on
autonomic nervous function was still undetermined, requir-
ing further investigation in several disease subsets.
Limitation
The lack of blinding and placebo controls for the omega-3
fatty acids are limitations of this study. We cannot exclude
Omega-3 fatty acid plus simvastatin versus simvastatin
Hyo-Soo Kim et al
115
bias without blinding or placebos. There are also issues
regarding the low statistical power of detecting differences
between groups for variables other than triglycerides. LDL
cholesterol levels significantly decreased with a combination
of omega-3 fatty acids plus simvastatin and also with
simvastatin monotherapy. Considering the potential serious
side effects from the combination of statin plus fibrate, a
combination therapy of omega-3 fatty acids and simvastatin
is good therapeutic strategy for patients with mixed
dyslipidemia. A combination therapy of omega-3 fatty acids
and simvastatin showed low adverse events, and it did not
alter LDL cholesterol reduction by statin.
Conclusion
The combination therapy with omega-3 fatty acids plus
simvastatin produced a greater reduction in triglyceride
levels than simvastatin monotherapy in Korean mixed
dyslipidemia patients. Along with the reduction of triglycer-
ides, LDL cholesterol was also controlled with the combina-
tion therapy without adverse events. Thus, a combination
therapy of omega-3 fatty acids plus simvastatin would be
considered an optimal treatment option for patients with
mixed dyslipidemia.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
This work was supported by the Innovative Research
Institute for Cell Therapy (IRICT) and the Clinical Research
Center for Ischemic Heart Disease (0412-CR02-0704-0001).
Dr Hyo-Soo Kim is a professor of Molecular Medicine &
Biopharmaceutical Sciences, Seoul National University spon-
sored by World Class University Program from the Ministry
of Education, Science, and Technology, Korea.
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