Asia Pac J Clin Nutr 2021;30(3):424-435

424

Original Article

Low dose red yeast rice with monacolin K lowers LDL
cholesterol and blood pressure in Japanese with mild
dyslipidemia: A multicenter, randomized trial
Takuya Minamizuka MD, PhD1,2, Masaya Koshizaka MD, PhD1,2, Mayumi Shoji MD,
PhD1,2, Masaya Yamaga MD, PhD2, Aiko Hayashi MD, PhD1,2, Kana Ide MD, PhD2,
Shintaro Ide MD, PhD2, Takumi Kitamoto MD, PhD2, Kenichi Sakamoto MD, PhD2,
Akiko Hattori MD, PhD2, Takahiro Ishikawa MD, PhD1,2,3, Junji Kobayashi MD, PhD1,2,
Yoshiro Maezawa MD, PhD1,2, Kazuki Kobayashi MD, PhD2, Minoru Takemoto MD,
PhD2,4, Masaru Inagaki MS5,6, Akira Endo PhD7,8, Koutaro Yokote MD, PhD1,2
1

Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital,
Chiba, Japan2
Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of
Medicine, Chiba, Japan
3
Geriatric Medical Center, Chiba University Hospital, Chiba, Japan
4
Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, International University of
Health and Welfare, Chiba, Japan
5
Core Technology Laboratories, Asahi Group Holdings, Ltd., Ibaraki, Japan
6
Laboratory of Exercise Physiology, Graduate School of Health and Sports Science, Juntendo University,
Chiba, Japan
7
Biopharm Laboratory, Ltd., Tokyo, Japan
8
University Research Administration Center, Tokyo University of Agriculture and Technology, Tokyo, Japan
Background and Objectives: Red yeast rice contains monacolin K, an inhibitor of cholesterol synthesis, andgamma-aminobutyric acid, a neurotransmitter. The daily dose of red yeast rice and monacolin K in previous studies
was relatively high; therefore, there were safety concerns. We aimed to examine the effects of low daily dose red
yeast rice on arteriosclerosis in patients with mild dyslipidemia. Methods and Study Design: Eighteen patients
without known cardiovascular disease and unsatisfactory low-density lipoprotein cholesterol (3.96±0.19 mmol/L)controlled only by diet therapy were randomly allocated to receive low dose red yeast rice (200 mg/day) containing
2 mg monacolin K or diet therapy alone for 8 weeks. The primary outcome was the absolute change in low-density
lipoprotein cholesterol. Secondary outcomes included total cholesterol, apolipoprotein B, and blood pressure. Results: Low-density lipoprotein cholesterol decreased significantly in the red yeast rice group than in the diet therapy
group (median [interquartile range]: control −0.20 [−0.62, 1.19] mmol/L vs. red yeast rice −0.96 [−1.05, −0.34]
mmol/L, p=0.030). The red yeast rice group also exhibited significant decreases in total cholesterol, apolipoprotein
B, and blood pressure. No severe treatment-related adverse effects on muscles, liver, or renal function were observed. Conclusions: We found that patients in the red yeast rice group exhibited significant reductions in lowdensity lipoprotein cholesterol, total cholesterol, apolipoprotein B, and blood pressure without any recognised adverse effect. This suggests that low daily dose red yeast rice could reduce cardiovascular risk in patients withdyslipidemia.

Key Words: cardiovascular risk, gamma-aminobutyric acid, hypertension, low-density lipoprotein cholesterol,
Monascus purpureus

Corresponding Author: Dr Masaya Koshizaka, Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital and Department of Endocrinology, Hematology, and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan.
Tel: +81-43-226-2092; Fax: +81-43-226-2095
Email: overslope@chiba-u.jp

Manuscript received 26 July 2021. Initial review completed 29
July 2021. Revision accepted 15 August 2021.
doi: 10.6133/apjcn.202109_30(3).0009

Low dose red yeast rice reduces risk

INTRODUCTION
Cardiovascular disease is a major cause of death worldwide.1 A high LDL cholesterol is a well-established risk
factor for cardiovascular disease. Therefore, a reduction inblood LDL cholesterol can reduce the risk of cardiovascular disease.2,3 Although hydroxymethylglutaryl-CoA(HMG-CoA) reductases (statins) are the first choice for patients with dyslipidemia, some patients hesitate to use
statins due to nocebo effects4 and negative coverage by the
media.5 Some patients without a history of cardiovasculardiseases prefer to avoid medication therapy and continue
diet and exercise therapy. However, these therapies have
only moderate reducing effects on LDL cholesterol, andbetter options that can be incorporated into daily life areneeded. Supplements are widespread, with a market penetration of approximately 50% in the United States6-8 and
10–40% in Japan.9,10 Supplements could be accepted bythose who perceive the use of medicines negatively. However, there is insufficient evidence to support the healthbenefit claims of many food supplements.11
Red yeast rice, made by fermenting rice with the fungus
Monascus purpureus, is a popular traditional food supplement in East Asian countries. This food component has
been used to make tofu, wine, and vinegar. Notably, redyeast rice contains monacolins, pigments, and organic acids, and amino acids. Monacolins, including monacolin K,
a low dose of lovastatin, a type of statin,12,13 and gammaaminobutyric acid (GABA), a neurotransmitter, has antihyperlipidemic effects. Moreover, red yeast rice also includes stigmasterol, which also has an anti-hyperlipidemic
impact. Supplementation with this dietary component has
reduced LDL cholesterol and blood pressure in various
countries worldwide.14-16
However, few randomized controlled studies of the effects of red yeast rice in patients with dyslipidemia havebeen conducted in Japan. The daily dose of red yeast riceand monacolin K in previous studies performed in othercountries was relatively high; therefore, there were safetyconcerns.17-20 Moreover, some reports also noted that its effect as anti-hypertension is controversial.21 Therefore, thisstudy aimed to examine the ability of low daily red yeast
rice dose to improve the quality of life and clinical outcomes as a supplement to diet therapy in Japanese patientswith dyslipidemia.
METHODSThis was a multicenter, prospective, open-label, controlled
study conducted in five facilities in Japan. This study

425

protocol was approved by the Institutional Review Board(IRB) of Chiba University Hospital (ID number: G23073),
which assessed all the participating study sites and served
as a centralized IRB (ID numbers: N26010, N26011,
N26012, N26013). Participants in this study were enrolledfrom May 2012 to October 2016, and all of them provided
signed written informed consent. The study was conductedin full compliance with the articles of the Declaration of
Helsinki and was registered with the University Hospital
Medical Information Network (UMIN) Clinical Trials
Registry (UMIN-ID: UMIN 000007694; Website athttps://upload.umin.ac.jp/cgi-openbin/ctr_e/ctr_view.cgi?recptno=R000009074). Based on
previous reports,14,22 a sample size calculation showed that
16 patients were needed to establish an LDL cholesterol
reduction of 0.65 mmol/L in the red yeast rice group thanin the control group (power: 0.80, significance level: 0.05).
Patients were screened for eligibility at the first visit.
The following eligibility criteria were applied to the potential subjects: LDL cholesterol between 3.62 mmol/L and
4.65 mmol/L, no history of cardiovascular diseases, age
between 20 and 80 years, compliance with diet therapy,
and an understanding of the study and provision of written
informed consent. Additionally, patients who met the following criteria were excluded: familial hypercholesterolemia; LDL cholesterol <3.62 mmol/L after diet therapy; triglyceride (TG) ≥4.52 mmol/L; administration of a statin
within 4 weeks or of a probucol within 8 weeks to avoid
carry-over effects; type 1 diabetes; current glycated hemoglobin (HbA1c) >63.9 mmol/mol; severe liver, kidney, or
heart disease; allergy to food, including rice; excessive alcohol intake; pregnancy or lactation, or the possibility orscheduling of pregnancy; and other determination of inappropriateness for participation by a physician. Subsequently, diet therapies were conducted in line with theAmerican Heart Association Step One diet, which allows≤30%, 50-60%, and 10-20% of total daily calories as fat,carbohydrates, and protein, respectively (Table 1), during
the run-in period for 4 weeks.
After the run-in period, the eligible patients were randomized using an allocation table. The patients were randomly assigned to either the red yeast rice group or thecontrol group based on the following two allocation factors:
man or woman and LDL cholesterol ≥4.14 or <4.14mmol/L. Following allocation, the patients either began theintake of red yeast rice or continued the existing diet therapy. The changes in the run-in period between the twogroups showed no significant difference (Table 2).

Table 1. Nutrient composition of diet during the run-in and study periods
Nutrient
Total fat
Saturated fatty acids
Polyunsaturated fatty acids
Cholesterol
Carbohydrates
ProteinMonacolin K‡†

Percentage of total daily calories†
<30
<10
≤10
<300 (daily intake, mg)
50-60
10-20
0

Except cholesterol, data are expressed as percentage of total daily calories. Cholesterol are expressed as daily intake.
Basically, all patients were not recommended to take monacolin K from background diet. The patients in red yeast rice group take monacolin
K only from red yeast rice supplement.
‡

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Table 2. Absolute changes during the run-in period
Parameter†
ΔBody weight (kg)
ΔBMI (kg/m2)
ΔWaist circumference (cm)ΔTC (mmol/L)
ΔTG (mmol/L)
ΔLDL-C (mmol/L)
ΔHDL-C (mmol/L)
ΔNon-HDL-C (mmol/L)
ΔHbA1c (mmol/mol)
ΔSBP (mmHg)
ΔDBP (mmHg)
ΔbaPWV (cm/s)
ΔABI

Control groupn=8
0.0 (-0.3, 0.2)
0.0 (-0.1, 0.1)
0.1 (-5.1, 2.0)
-0.02±0.14-0.19±0.23-0.02±0.14-0.10±0.05-0.13 (-0.27, -0.05)
0.55±2.26-4.2±4.6-1.2±4.2-89.5 (-169, 80)-0.1±0.1

Red yeast rice groupn=10
0.1 (-0.1, 0.7)
0.0 (0.0, 0.3)
1.1 (-1.9, 2.0)
0.07±0.13
0.08±0.20
0.07±0.13
0.02±0.05-0.04 (-0.21, 0.05)
0.30±1.00
2.4±3.5-2.5±3.2
4.75 (-56.3, 402)
0.0±0.0

p-value‡
0.555
0.623
0.592
0.646
0.391
0.646
0.726
0.197
0.881
0.274
0.805
0.377
0.255

Δ: absolute change; TC: total cholesterol; TG: triglyceride; LDL-C: LDL cholesterol; HDL-C: HDL cholesterol; HbA1c: glycated hemoglobin; SBP: systolic blood pressure; DBP: diastolic blood pressure; baPWV: brachial-ankle pulse wave velocity; ABI: ankle brachial pressureindex.
†
Absolute changes were calculated by subtracting the values at the start from the values at the end of the run-in period. Data are shown as
mean±standard deviation or median values and interquartile range.
‡
p-values indicate differences between the control and red yeast rice groups.

Patients in both groups continuously received diet therapy according to the American Heart Association Step One
diet described above. Daily cholesterol intake was limited
to <300 mg. Patients in the red yeast rice group orally consumed processed foods containing 200 mg/day red yeast
rice (Asahi Group Holdings, Ltd., Tokyo, Japan), whichcontained 2 mg monacolin K, once a day with water after
dinner, for 8 weeks in addition to diet therapy.
The primary outcome was the absolute change in the
LDL cholesterol from the baseline to 4 and 8 weeks after
the start of the intervention. This absolute change was described as ΔLDL cholesterol and was calculated by subtracting baseline values from the values at 4 or 8 weeks.
LDL cholesterol was calculated using the Friedewald
equation:
LDLcholesterol = totalcholesterol(TC) − [(TG/5) × (HDL cholesterol)]. From the results ofprevious studies,14,22 the LDL cholesterol in the red yeast
rice group was expected to decrease by 0.78 mmol/L, andthe LDL cholesterol in the control group was expected todecrease by 0.13 mmol/L. Therefore, a difference of 0.65
mmol/L was set as a significant difference between the twogroups. The following secondary outcomes were also investigated: absolute changes in sitting blood pressure
measured using automated blood pressure devices in theclinic after five minutes rest, body weight, waist circumference, TC, HDL cholesterol, fasting TG, non-HDL cholesterol, apolipoprotein B (ApoB), HbA1c, ankle brachialpressure index (ABI), and brachial-ankle pulse wave velocity (baPWV). The ABI and baPWV were measured using an automated oscillometric device (form PWV/ABI,
BP-203RPE; Nippon Colin, Aichi, Japan). Blood examination was carried out on patients after more than 12 hoursof fasting.
Statistical analyses were performed using JMP Pro 13(SAS, Cary, NC, USA). Some variables were normally distributed, while others were not. Therefore, the Student’s ttest or the Wilcoxon signed-rank test was used for statistical comparisons of the diet therapy and red yeast ricegroups, as appropriate. Pearson’s correlation analysis wasused to analyze correlations between different variables.

Differences were considered statistically significant at
p<0.05.
RESULTS
Thirteen patients were excluded from the study during the
run-in period because they failed to meet the inclusion criteria due to LDL cholesterol amelioration by diet therapy
or other reasons. Finally, 19 patients were enrolled and randomly assigned to the study groups (Figure 1). Subsequently, one patient did not visit the hospital after randomization and was withdrawn from the study. Because there
were no significant changes between the two groups during
the run-in period, the cholesterol- and blood pressure-lowering effects were determined to have not been caused by
the diet therapy. The baseline characteristics of the patientsare shown in Table 3. As indicated, there were no significant differences between the control group and the red
yeast rice group at baseline. Therefore, it was not adjustedwith age, sex, and body mass index.
Diet therapy was performed in both groups. There wasno difference in compliance in both groups. Absolutechanges in the clinical parameters after 4 and 8 weeks fromthe baseline were measured in both groups and are presented in Table 4. In particular, the reductions in LDL cholesterol (mean change±standard deviation: control
0.34±0.41 mmol/L vs red yeast rice −0.57±0.58 mmol/L,
p=0.002 at 4 weeks; median [interquartile range]: −0.20[−0.64, 1.19] mmol/L vs −0.96 [−1.05, −0.34] mmol/L,
p=0.030 at 8 weeks), TC (0.31±0.15 mmol/L vs.
−1.10±0.42 mmol/L, p<0.001 at 4 weeks; 0.00±0.75
mmol/L vs −0.92±0.57 mmol/L, p=0.014 at 8 weeks), nonHDL cholesterol (0.19±0.13 mmol/L vs −0.65±0.12mmol/L, p< 0.01 at 4 weeks, −0.28 [−0.66, 0.56] mmol/Lvs −0.98 [−1.16, −0.82] mmol/L, p=0.023 at 8 weeks), and
ApoB (0.05 [−0.01, 0.11] g/L vs −0.11 [−0.26, −0.01] g/L,
p=0.015 at 4 weeks; 0.03±0.16 g/L vs −0.18±0.11 g/L,
p=0.011 at 8 weeks) were significantly greater in the red
yeast rice group than in the control group at both time
points. Similarly, the reductions in systolic blood pressure(4.9±10.8 mmHg vs −6.8±11.2 mmHg, p=0.040) and dias-

Low dose red yeast rice reduces risk

427

Figure 1. CONSORT diagram for this study.

Table 3. Baseline characteristics
Characteristic†Age (years)
Man (%)
Body weight (kg)BMI (kg/m2)
Waist circumference (cm)TC (mmol/L)
TG (mmol/L)
LDL-C (mmol/L)
HDL-C (mmol/L)
Non-HDL-C (mmol/L)
HbA1c (mmol/mol)
SBP (mmHg)
DBP (mmHg)
baPWV (cm/s)
ABI
Type-2 diabetes, n (%)
Anti-hypertensive treatment, n (%)

Control groupn=856.0±16.2
3 (37.5)
62.0 (56.9, 73.1)
24.4 (22.7, 27.8)
87.5 (80.0, 96.5)
6.12±0.19
1.50±0.78
3.93±0.19
1.51± 0.51
4.61±0.15
43.5±7.8122±18.4
70.5±8.91335±284
1.1±0.1
3 (37.5)
1 (12.5)

Red yeast rice groupn=10
59.6±14.8
4 (40.0)
63.0 (59.0, 66.8)
25.1 (21.9, 28.1)
86.3 (84.4, 102)6.29±0.30
1.84±0.90
3.99±0.19
1.46±0.33
4.83±0.1344.7±8.3
130±16.0
71.5±7.51510±295
1.2±0.1
7 (70)
2 (20)

p-value‡
0.629
0.958
0.894
0.965
0.884
0.421
0.401
0.477
0.778
0.277
0.562
0.339
0.799
0.251
0.076
0.198
0.731

TC: total cholesterol; TG: triglyceride; LDL-C: LDL cholesterol; HDL-C: HDL cholesterol; HbA1c: glycated hemoglobin; SBP: systolicblood pressure; DBP: diastolic blood pressure; baPWV: brachial-ankle pulse wave velocity; ABI: ankle brachial pressure index.
†
Data are shown as mean ± standard deviation, median values and interquartile range, numbers, and percentages.
‡
p-values indicate differences between the control and red yeast rice groups.

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Table 4. Baseline characteristics
Parameters†

At week

ΔBody weight (kg)

4
8
4
8
4
8
4
8
4
8
4
8
4
8
4
8
4
8
4
8
4
8
8
8

ΔWaist circumference (cm)ΔTC (mmol/L)
ΔTG (mmol/L)
ΔLDL-C (mmol/L)
ΔHDL-C (mmol/L)
ΔNon-HDL-C (mmol/L)
ΔApoB (g/L)
ΔHbA1c (mmol/mol)
ΔSBP (mmHg)
ΔDBP (mmHg)
ΔbaPWV (cm/s)
ΔABI

Control groupn=80.1±1.3-0.1±2.3-1.0±2.2-2.5±2.3
0.31±0.15
0.00±0.75-0.33±0.54-0.05 (-0.38, 0.19)
0.34±0.41-0.20 (-0.64, 1.19)
0.12±0.09
0.03±0.14
0.19±0.13-0.28 (-0.66, 0.56)
0.05 (-0.01, 0.11)
0.03±0.16
0.11±1.31-0.33±2.68-1.5±11.8
4.9±10.8
4.5±10.9
7.9±10.4
18.5 (-22.3, 40.5)
0.0±0.1

Red yeast rice groupn=10
0.3±1.9-0.0±1.6-0.8±4.3-1.1±3.0-1.10±0.42-0.92±0.57-0.18±0.79
0.24 (-0.56, 0.40)-0.57±0.58-0.96 (-1.05, -0.34)-0.05±0.05-0.13±0.21-0.65±0.12-0.98 (-1.16, -0.82)-0.11 (-0.26, -0.01)-0.18±0.11
0.82±2.14
2.88±6.11-9.1±10.4-6.8±11.2-3.3±5.1-2.4±5.8-85.8 (-296, 39.1)
0.0±0.1

p-value‡
0.793
0.981
0.933
0.314
<0.001
0.014
0.665
0.505
0.002
0.030
0.038
0.082
<0.001
0.023
0.015
0.011
0.715
0.111
0.167
0.040
0.061
0.018
0.128
0.123

Δ: absolute change; TC: total cholesterol; TG: triglyceride; LDL-C: LDL cholesterol; HDL-C: HDL cholesterol; ApoB: apolipoprotein B;
SBP: systolic blood pressure; DBP: diastolic blood pressure; baPWV: brachial-ankle pulse wave velocity; ABI: ankle brachial pressureindex.
†
Data are shown as mean ± standard deviation or median values and interquartile range.
‡
p-values indicate differences between the control and red yeast rice groups.

tolic blood pressure (7.9±10.4 mmHg vs −2.4±5.8 mmHg,
p=0.018) were significantly greater in the red yeast ricegroup than in the control group after 8 weeks. Although thedifference between the groups was not significant, the red
yeast group exhibited greater reductions in baPWV (18.5[−22.3, 40.5] cm/s vs −85.8 [−296, 39.1] cm/s, p=0.128)
after 8 weeks.
We also investigated whether the blood pressure-lowering effect by red yeast rice was associated with its LDL
cholesterol-lowering effect. Figure 2 presents the results ofa Pearson’s correlation analysis. The ΔbaPWV was shownto correlate with the Δsystolic blood pressure (r = 0.65,
p=0.006; Figure 2A) but not with the ΔLDL cholesterol(Figure 2B). No correlations were observed between the
ΔLDL cholesterol and Δsystolic blood pressure (Figure
2C).

No severe treatment-related adverse events were observed. Laboratory analyses revealed that the red yeast rice
had no adverse effects on muscles, liver, or renal function(Table 5).
DISCUSSION
This study investigated the effects of supplementation withlow daily dose red yeast rice on absolute changes of LDL
cholesterol in Japanese patients with mild dyslipidemia
without previous cardiovascular diseases. The strength of
our study is the use of a supplement for diet therapy insteadof drug therapy. Modification of lifestyle is important because excessive intake of cholesterol and saturated fatty
acids leads to increased serum LDL cholesterol.23 The
main advantage of supplements is its acceptance by those
who view the use of medicine negatively due to nocebo
effects and concerns regarding the chemical nature of

Table 5. Adverse events
Adverse event†
Skin rash
Muscle pain
ΔCK (IU/L)
ΔAST (IU/L)
ΔALT (IU/L)
ΔCre (μmol/L)
Termination

Control group0/8
0/8-16.3±29.8-0.9±2.4-1.9±4.1
0.0±8.8
0/8

Red yeast rice group
0/10
0/10
-1.9±42.6-0.9±3.6-2.1±5.2
0.0±8.8
0/10p-value‡
N/A
N/A
0.432
0.987
0.922
0.353
N/A

Δ: absolute change; N/A: not available; CK: creatine phosphokinase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; Cre:creatinine.
†
Data are shown as mean ± standard deviation or numbers.
‡
p-values indicate differences between the control and red yeast rice groups.

Low dose red yeast rice reduces risk

429

Figure 2. Correlations between the change in baPWV and the change in SBP or LDL-C. Closed and open diamonds represent the control
group and the red yeast rice group, respectively. baPWV, brachial-ankle pulse wave velocity; Δ: change; LDL-C: low-density lipoproteincholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure.

drugs imparted by negative media coverage. However, thelack of evidence regarding their health effects is one of themain problems associated with supplements. The real addon value of this randomized controlled study is the evidence showing that lower daily dose red yeast rice containing 2 mg monacolin K can simultaneously reduce LDLcholesterol, blood pressure, and several secondary outcomes in Japanese patients with dyslipidemia. The reduction of ApoB, which reflects the total number of circulating
atherogenic particles,24 was greater in the red yeast ricegroup. Although the reduction in baPWV was not significant, there was an amelioration tendency in the red yeast
rice group.
In a previous meta-analysis, subjects treated with red
yeast rice exhibited a greater reduction in LDL cholesterol(1.02 mmol/L) than those treated with a placebo.14 Anothermeta-analysis reported a 5.62 mmHg greater reduction insystolic blood pressure among patients treated with red
yeast rice than those who received conventional therapy.16
Consistent with these findings, we observed reductions inboth LDL cholesterol and blood pressure in the red yeast
rice group.
While a meta-analysis of 20 randomized control studies
with 6653 participants (follow-up between 2 months and3.5 years) and a monacolin K dose varying from 4.8 to 24
mg per day showed that red yeast rice supplementation
lowered LDL cholesterol than the placebo (−1.02mmol/L).14 However, since monacolin K is structurally
identical to lovastatin, there are safety concerns related tosome side effects commonly associated with the treatment
with statins.17,18 Table 6 summarized similar randomized
control trials that evaluated the lipid-lowering effects of

red yeast rice. Even in studies with a low monacolin K, alowering effect on LDL cholesterol and TC was observed.
The correlation coefficient of the content of red yeast rice,monacolin K, and ΔLDL cholesterol, ΔTC, ΔApoB, Δsystolic blood pressure, and Δdiastolic pressure of these studies have been evaluated (Table 7). The correlation coefficients were found low. Red yeast rice and monacolin K are
not dose-dependent. Therefore, for the patients with mild
dyslipidemia, low dose monacolin K administration ispreferable. In our study, the patients were treated with alower dose of monacolin K, 2 mg per day, than in previous
studies. However, the LDL cholesterol lowering effect was
not so different from the previous high-dose monacolin K
treatment. Our study shows that the low daily dose monacolin K treatment is effective and safe.
As described above, red yeast rice contains a low doseof lovastatin and monacolin K, which is likely responsible
for the observed reductions in TC, non-HDL-cholesterol,and LDL cholesterol by inhibiting HMG-CoA reductase.57,58 However, red yeast rice contains complex nutrients; therefore, other nutrients may have a lipid-lowering
effect.
In a study with Japanese adults regarding the management of elevated cholesterol in primary cardiovascular disease prevention, patients treated with pravastatin exhibited
an approximately 18% reduction in LDL cholesterol and a
33% reduction in the incidence of cardiovascular disease.59
In our study, red yeast rice supplementation was associatedwith a 24% reduction in the LDL cholesterol, suggestingthat this supplement can reduce the risk of cardiovasculardisease.
Blood pressure reduction effects are an additional bene-

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T Minamizuka, M Koshizaka, M Shoji, M Yamaga, A Hayashi, K Ide et al

Table 6. Randomized control trials that evaluated the effects of red yeast rice
StudyReferences

Year

Country

Main eligibility criteria

Minamizuka
Guerrero-Bonmatty25
Cicero26
Iskandar27
Nafrialdi28
Domenech29
Mazza30

2021
2021
2020
2020
2019
2019
2019

Japan
Spain
Italy
Indonesia
Indonesia
Spain
Italy

Pirro31
Mazza32
Derosa33
Spigoni34
Cicero35
Cicero36
D'Addato37
Heinz38
Verhoeven39
Moriarty40
Ogier41
Barrat42
Barrat43
Karl44
Lee45
Higashikawa46
Affuso47
CCSPS48
Becker49

2018
2018
2018
2017
2017
2017
2017
2016
2015
2014
2013
2013
2012
2012
2012
2012
2010
2010
2009

Italy
Italy
Italy
Italy
Italy
Italy
Italy
Germany
Belgium
USA and China
FranceFranceFranceUSA
Taiwan
Japan
Italy
China
USA

CCSPS50
Hu51
Lin52
Zhao53Zhao54
Keithley55
Heber56

2008
2006
2005
2004
2003
2002
1999

China
China
Taiwan
China
China
USA
USA

LDL-C 3.62-4.65 mmol/L, TG <4.52 mmol/LTC ≥5.17 mmol/L
LDL-C 2.97-4.91 mmol/L, TG <4.52 mmol/L
TC 5.69-6.18 mmol/L, LDL-C 2.59-4.11 mmol/L
LDL-C 3.36-4.65 mmol/L
TC >5.69 mmol/L, LDL-C >2.97 mmol/L
TG >3.88 mmol/L, HDL-C <1.03 mmol/L (man), <1.29 mmol/L (woman) with MetS, in primaryprevention for CVDs
LDL-C >2.97 mmol/L with HIV-1 infection
TC ≥5.17 mmol/L and LDL-C 3.36-4.91 mmol/L
TC 5.17-6.21 mmol/L, TG <4.52 mmol/L
non-HDL-C ≥4.14 mmol/L
LDL-C 3.36-4.91 mmol/L and TG 1.69-4.52 mmol/L with MetS, in primary prevention for CVDs
LDL-C 2.97-4.14 mmol/L
LDL-C 2.97-4.65 mmol/L, TC 5.17-6.72 mmol/L, TG <2.82 mmol/L
LDL-C 4.14-5.69 mmol/L
TG >1.69 mmol/L, HDL-C <1.03 mmol/L (man), <1.29 mmol/L (woman) with MetS
TC ≥6.21 mmol/L, LDL-C 4.14-5.69 mmol/L and TG <4.52 mmol/L
TC >5.69 mmol/L
LDL-C 3.28-5.79 mmol/L, TG ≤2.48 mmol/L and HDL-C ≥1.03 mmol/L
LDL-C 3.28-5.79 mmol/L, TG ≤2.48 mmol/L and HDL-C ≥1.03 mmol/L
man 20-80 years of age and postmenopausal woman 55-80 years of age
TG >1.69 mmol/L, HDL-C <1.03 mmol/L (man), <1.29 mmol/L (woman) with MetS
TG 1.35-2.26 mmol/L
TC >5.69 mmol/L and LDL-C >3.36 mmol/L
TC 4.40-6.47 mmol/L and TG ≤4.52 mmol/L with previous MI and HT
LDL-C 2.59-5.43 mmol/L, TG <4.52 mmol/L, dyslipidemia and history of discontinuation of statin
therapy due to myalgias
TC 4.40-6.47 mmol/L and TG ≤4.52 mmol/L with previous MI
MI and/or AP
TC ≥6.21 mmol/L, LDL-C ≥4.14 mmol/L and TG ≤4.52 mmol/L
MI and/or AP
MI and/or CHD
TC >5.17 mmol/L, LDL-C >3.36 mmol/L and TG >1.52 mmol/L with HIV-1 infection
LDL-C >4.14 mmol/L and TG <1.29 mmol/L

Number ofpatient
18
39
85
76
49
40
104

Number ofintervention
10
21
43
40
25
20
52

Number ofcontrol
8
18
42
36
24
20
52

30
60
80
39
30
50
130
142
50
116
39
100
45
45
96
55
50
2704
62

15
30
40
30
30
25
44 / 42
70
26
78
19
50
30
23
52
28
25
1363
31

15
30
40
9
30
25
44
72
24
38
20
50
15
22
44
27
25
1341
31

4870
50
79
50
50
12
83

2429
25
39
25
25
6
42

2441
25
40
25
25
6
41

LDL-C: LDL cholesterol; TG: triglyceride; TC: total cholesterol; HDL-C: HDL cholesterol; MetS: metabolic syndrome; MI: myocardial infarction; HT: hypertension; AP: angina pectoris; Δ: absolute change; ApoB:
apolipoprotein B; SBP: systolic blood pressure; DBP: diastolic blood pressureLow dose red yeast rice reduces risk

431

Table
Table6.6.Randomized
Randomizedcontrol
controltrials
trialsthat
thatevaluatedevaluatedthe
theeffects
effectsof
ofredredyeast
yeastricerice(cont.)(cont.)
StudyReferences
StudyReferences
Minamizuka
Minamizuka
GuerreroBonmatty25
GuerreroBonmatty
Cicero26 25
26 27
CiceroIskandarIskandarNafrialdi2728
28 29
Nafrialdi
Domenech
30 29
Mazza
Domenech
Pirro3130
Mazza
31 32
Mazza
Pirro
3233
DerosaMazza
3334
Spigoni
Derosa34
Cicero35
Spigoni
36
35
CiceroCicero36 37
D'Addato
CiceroD'Addato37
Heinz3838
Heinz
Verhoeven3939
Verhoeven
Moriarty4040
Moriarty
Ogier4141
Ogier
Barrat42
Barrat4342
BarratKarl44 43
Barrat45
Lee
Karl4446
Higashikawa
Lee45
47
AffusoHigashikawa46
48
CCSPS
Affuso47
49
BeckerCCSPS48
50
CCSPS
Becker49
51
Hu
CCSPS50
52
Lin
Hu51
53
Zhao
Lin52
54
Zhao
Zhao5355
Keithley
Zhao5456 55
Heber
Keithley
Heber56

Mean
ΔSBP (mmHg)
Sex
ΔDBPRed(mmHg)
yeast rice Other ingredients
Moncolin K
Control
Follow-up
ΔLDL-C
ΔTC
ΔApoB
age
(man %)(mg/day)(weeks)(mmol/L)(mmol/L)(g/L)-6.8-2.4 (mg/day)–
58Not mentioned
38.9
200
2
dietstrains
program
-0.96
-0.92
-0.18
Not mentioned
Lactoplantibacillus
plantarum(CECT7527,8CECT7528, and CECT7529)
51.9
64.1
not mentioned
10
Placebo
12
-0.40
-0.47
not mentioned
Not mentioned
Not mentioned
Phytosterols 800 mg, niacin 27 mg, policosanols 10 mg
51.5
44.7
not mentioned Guggulipid
5 extract 11 0mg, Placebo
8 μg
-0.84
-0.85
-0.15
Not mentioned
Not mentioned
chromium picolinate 50
35.5
50
750
7.5extract 110 mg, Placebo
8 μg
-0.57
-0.81
not mentioned
Not mentioned
Not mentioned
Guggulipid
chromium picolinate 50
44.7
Not mentioned
34.7
Not mentioned
750
Phytosterols
7.5 1.5 g, hydroxytyrosol
Placebo5 mg, vitamin E4 12 mg
-0.70
-0.72
not mentioned-5.2-4.9 not mentioned Coenzyme10Q10 30 mg
61.8
32.5
Placebo
12 (3 months)
-0.77
-0.85
-0.16
-1.9
-1.2 not mentioned Policosanol
500
mg, astaxanthin 80.5
folic acid 0.2 mg,
coenzyme Q10 2 mg -1.07
57.4
51
10 10 mg, berberine
dietprogram(2 mg,
months)-0.93
not mentioned
Not mentioned
Octacosanol
20 mg, chromium picolinate
50 μg, piperine-0.78
2.99 mg
44Not mentioned
67
200
3 12 mg, resveratrol
Placebo12-0.85
not mentioned
Not mentioned
Not mentioned
Sterol esters
425program
mg, curcumin 454mg,
mg
51.5
62.9
333
10 720 mg, stanolsdiet(30 olivedays)polyphenols 25
-0.95
-1.09
not mentioned
Not mentioned
Not mentioned
Berberine5200mg, chitosan 10mg,coenzyme Q10 10mg
53.3
50
166
Placebo
12 (3 months)
-0.86
-0.92
not mentioned-1.7-0.9 not mentioned Artichoke3extract 500 mg, banaba
extract 75 mg, coenzyme
Q10 50 mg, vitaminmg,
B-12 0.83 μg,-0.15
folic acid 110 μg
52.2
46Placebo12-0.83 B-3 9 mg, B-6 1.4not
mentioned-12.6 not mentioned-7.3 200
Phytosterols
2.5mg
52.2
10 400mg, L-tyrosol
Placebo
6
-0.78
-0.88
not mentioned
Not mentioned
Not mentioned
Q10 2 mg, hydroxytyrosol
5 mg / berberine 500
mg, policosanol 10 -0.99
mg, folic acid 0.2 mg,
50.2
60
not mentioned Berberine5500 mg, coenzyme
Placebo8-0.98
not coenzyme
mentionedQ10
0.5 mg Placebo
52
37.7
not mentioned / 2.0200mg, astaxanthin
10 / 34-1.01 and -0.70-1.19 and -0.77
not mentioned
Not mentioned
Not mentioned
Coenzyme3 Q10 20 mg, astaxanthin
57.3
37.3
200
Placebo0.5 mg, folic acid
12 200 μg
-0.72
-0.80
not mentioned
-10.4
-7.6
Hydroxytyrosol
9.32
mg
51.8
40
not mentioned
10.8
Placebo
8
-1.08
-1.12
-0.19
Not mentioned
Not mentioned
56.7
25.9
2400 and 1200 –24 and 12
Placebo12-1.29 and -1.26-1.33 and -1.30-0.30 and -0.25
Not mentioned
Not mentioned
Sugar cane
E 38.6 mg, B47.9
not mentioned
500
2 extract 11.1mg, artichoke
Placebo leaf dry extract
16 600 mg, garlic dry extract-0.7230 mg, pine bark extract-0.91 60 mg, vitamins
not mentioned
2 4.8 mg, B-3 8.8 mg, dicalcium phosphate 597 mg, microcrystalline cellulose 262 mg, calcium citrate 262 mg, tricalcium phosphate
47.2
30
500
2
Placebo
16
-0.36
-0.52
-0.13
102 mg, magnesium stearate 66 mg
51.1
31.1
1000 and 500
4 and 2
Placebo
4-0.67 and -0.83-0.67 and -0.80
not mentioned
Not mentioned
Not mentioned
Policosanol, artichoke leaf extract
59
48.9
1200
4.8
Placebo
8
-0.78
-1.19
not mentioned
Not mentioned
Not mentioned
Policosanol, artichoke leaf extract
51.5
46.9
370
4.8
Placebo
12
-0.70
-1.00
not mentioned
Not mentioned
Not mentioned
Niacin 25 mg, phytosterol esters 1300 mg, L-carnitine 300 mg, vitamin C 1000 mg, coenzyme Q10 50 mg
51.7
40
900
2
Placebo
12
-0.53
-0.43
not mentioned-4-5.3
Fresh bitter gourd 40 g, chlorella 1.5 g, soybean 1.1 g, licorice 2.2 g
55Not mentioned
52
200
3
Placebo
6
-1.06
-1.14
not mentioned
Not mentioned
Garlic
59.3
79.4
1200
11.6
Placebo
235
-0.56
-0.58
not mentioned
Not mentioned
Not mentioned
Berberine 500 mg, policosanol 10 mg
61-5.536
6.1
Placebo
24
-0.91
-0.94
not mentioned-4.3 3600
–
58.9
82
1200
11.6
Placebo
235
-0.68
-0.70
not mentioned
Not mentioned
Not mentioned
–
54.7
64
1200
13.5
Placebo
6
-1.03
-1.11
not mentioned
Not mentioned
Not mentioned
–
46.4
57
1200
11.4
Placebo
8
-1.37
-1.50
-0.39
Not mentioned
Not mentioned
–
58.7
58
1200
10
Placebo
6
-0.94
-1.01
not mentioned
Not mentioned
Not mentioned
–
58.1
66
1200
10
routine therapy
6
-1.14
-1.10
-0.34
Not mentioned
Not mentioned
–
42.5
75
2400
4.8
Placebo
8
-0.83
-0.80
not mentioned
Not mentioned
Not mentioned
–
61.5
55.4
2400
7.2
Placebo
12
-0.98
-1.04
not mentioned
Not mentioned
Not mentioned
Not mentioned
Not mentioned
Not mentioned–

LDL-C: LDL cholesterol; TG: triglyceride; TC: total cholesterol; HDL-C: HDL cholesterol; MetS: metabolic syndrome; MI: myocardial infarction; HT: hypertension; AP: angina pectoris; Δ: absolute change; ApoB:
apolipoprotein
B; SBP: systolicblood pressure;bloodpressure.
LDL-C: LDL cholesterol;
TG: triglyceride;
TC:DBP:
total diastoliccholesterol;
HDL-C:
HDL cholesterol; MetS: metabolic syndrome; MI: myocardial infarction; HT: hypertension; AP: angina pectoris; Δ: absolute change; ApoB:
apolipoprotein B; SBP: systolic blood pressure; DBP: diastolic blood pressure.

432

T Minamizuka, M Koshizaka, M Shoji, M Yamaga, A Hayashi, K Ide et al

Table 7. Correlation of red yeast rice, monacolin K and lipids, blood pressure

Content of red yeast rice (mg/day)Content of monacolin K (mg/day)

ΔTC(mmol/L)
-0.21
-0.45

ΔLDL-C(mmol/L)
-0.30
-0.46

ΔApoB
(g/L)
-0.61
-0.62

ΔSBP
(mmHg)
-0.39
-0.03

ΔDBP
(mmHg)-0.57-0.26

ApoB: apolipoprotein B; Δ: absolute change; TC: total cholesterol; LDL-C: LDL cholesterol; SBP: systolic blood pressure; DBP: diastolicblood pressure.
The correlation coefficient of the content of red yeast rice, monacolin K, and absolute change of LDL cholesterol, TC, ApoB, systolic bloodpressure, and diastolic pressure of randomized clinical trials are indicated.

fit of red yeast rice consumption. Lovastatin and monacolin K have a blood pressure-lowering effect. Moreover,
red yeast rice contains GABA,60 a neurotransmitter in thesympathetic nervous system that controls cardiovascularfunction. GABA has been reported to decrease blood pressure in animals and humans.61,62 Its presence may explain
the observed reduction in blood pressure in this study.
Monacolin K and GABA contained in red yeast rice could
contribute to ameliorate atherosclerosis.
Our results indicate that red yeast rice has a pleiotropic
effect on the cardiovascular system. Therefore, red yeast
rice can comprehensively treat patients with multiple cardiovascular risk factors, even as a supplement. We expected that baPWV would also reduce due to red yeast riceconsumption. Our finding that baPWV tended to decrease
after treatment was also consistent with previous studies.63,64 Previous studies also reported that statins could reduce PWV.65 The presence of monacolin K and GABA in
red yeast rice may explain the observed reduction in
baPWV in this study.
There is a famous Japanese menu called Tofuyo, in
which red yeast rice has been traditionally used in Okinawa
Prefecture, Japan. Tofuyo, a food made by fermenting bean
curd with red yeast rice and sake, was introduced to Okinawa from China in the 1800s and reportedly containedmuch monacolin K. Although the exact monacolin K content was not reported. According to a Tofuyo recipe, theingredients for 5 people contain 2 teaspoons (10 g) of red
yeast rice. In Okinawa, red yeast rice has also been traditionally used as red yeast rice vinegar and a colorant forcelebration foods, such as cooked red rice, red boiled eggs,
red fishcake, red cuttlefish meat, and so on since the1800s.66 The life expectancy in Okinawa was longer thanin other areas in Japan.
Despite these encouraging findings, we emphasize thatstatin drugs remain the best option for reducing LDL cholesterol in high-risk cardiovascular patients. In Japan, drug
therapy for hyper-LDL cholesterolemia should be considered early if the improvement of lifestyle habits cannot be
expected at a high risk of primary prevention.67 This study
was targeted at patients under the medium risk of primaryprevention and between periods of improvement of lifestyle habits and drug therapy. Red yeast rice supplementation can be recommended for patients with only moderately high LDL cholesterol. If such patients cannot achieve
appropriate results with diet and exercise therapy alone,they should not hesitate to take statins. However, red yeast
rice may be a solution for patients who refuse to use statinsbecause of nocebo effects and negative media coverage.
This study had a few noteworthy limitations. First, thestudy design was not double-blinded, and the lack of aplacebo may have affected the patients’ behavior. Second,
the number of patients was small. According to the exclusion criteria, five patients with cancer were excluded. The
sample size might have limited the opportunity to detect
adverse side effects, the most usual concern with red yeast
rice. It may also have been insufficient to evaluate thechange of baPWV, a secondary endpoint. Furthermore,large and long-term studies are needed. However, thisstudy showed the simultaneous reduction of LDL cholesterol and blood pressure in the low daily dose red yeast ricegroup. This was the first randomized controlled study toevaluate the effects of low daily dose red yeast rice for lipid
profile and blood pressure control in Japanese patients withmild dyslipidemia.
In conclusion, this study showed the usefulness of low
daily dose red yeast rice as a supplement to the diet therapy
administered to Japanese patients with mild dyslipidemia
in a clinical setting. Our findings that patients in the red
yeast rice group exhibited significantly greater reductionsin LDL cholesterol and blood pressure relative to the controls suggest that red yeast rice could reduce cardiovascular risks in this population. Low daily dose red yeast rice issuitable for patients who are reluctant to take statins because of nocebo effects, concerns regarding the chemical
nature of drugs, or negative media coverage.
ACKNOWLEDGEMENTS
The authors would like to thank the staff who contributed to thestudy and the participating patients.
AUTHOR DISCLOSURESThe authors declare no potential conflict of interest associatedwith this research. Red yeast rice was provided by Asahi Group
Holdings, Ltd. The funding source had no role in the design ofthis study and its execution, analyses, interpretation of the data,
and the decision to submit results.
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