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European Journal of Endocrinology (2005) 153 679–686 Efficacy and safety of Monascus purpureus Went rice in subjectswith hyperlipidemia Cheng-Chieh Lin, Tsai-Chung Li1 and Ming-May Lai Department of Family Medicine, China Medical University Hospital, Taichung 40447, Taiwan and 1Department of Institute of Chinese Medicine & PublicHealth, China Medical University, Taichung 40402, Taiwan (Correspondence should be addressed to Ming-May Lai; Email: [email protected]) Objective: The purpose of this study was to assess the lipid-lowering effect of Monascus purpureus Wentrice on serum lipids in patients with hyperlipidemia, and to assess its safety by reporting adverseevents and clinical laboratory measurements.
Design and methods: This was a randomized, double-blind, placebo-controlled study. In all, 79 patients(aged 23 – 65 years) with a mean baseline low-density lipoprotein cholesterol (LDL-C) level of5.28 mmol/l (203.9 mg/dl) received a twice daily dose of placebo or Monascus purpureus Went rice(600 mg) for 8 weeks.
Results: At week 8, Monascus purpureus Went rice therapy reduced LDL-C by 27.7%, total cholesterolby 21.5%, triglycerides by 15.8% and apolipoprotein B by 26.0%. High-density lipoprotein cholesteroland apolipoprotein A-I levels were increased by 0.9 and 3.4% respectively (not significant). No patientin the Monascus purpureus Went rice treatment group had an alanine aminotransferase (ALT), aspar-tate aminotransferase (AST) or creatine phosphokinase (CPK) measurement that was $ 3 times theupper limit of normal at week 4 and week 8.
Conclusion: Monascus purpureus Went rice significantly reduced LDL-C, total cholesterol, triglyceridesand apolipoprotein B levels, and was well tolerated in patients with hyperlipidemia. However, thisstudy only provides data from an 8-week trial and long-term safety and efficacy data are needed.
European Journal of Endocrinology 153 679–686 completing laboratory tests at regular intervals in sub-jects with hyperlipidemia.
called red yeast rice, is described as the fermented pro-duct of rice on which red yeast (Monascus purpureus) has been grown. This product has been used for centu- ries in China to make rice wine and to flavor foods. Tra-ditional red yeast rice continues to be a dietary staple in The study’s clinical phase began in December 2001 many Asian countries, including China and Japan, and was completed in January 2003. Subjects with with consumption ranging from 14 to 55 g/person hyperlipidemia in this study were recruited from the per day (1). Recent studies have shown that Monascus outpatient clinic at the China Medical University Hospi- purpureus rice contained 3-hydroxy-3-methylglutaryl- tal, Taichung, Taiwan or by advertising. Study partici- coenzyme A reductase inhibitors (statins), large quan- pants were men and women aged 18 – 65 years with a tities of unsaturated fatty acids (. 125 mg/g Monascus body mass index of , 30 kg/m2. Participants had to have purpureus rice preparation), beta-sitosterol, campesterol a total cholesterol level $ 6.22 mmol/l (240 mg/dl), an and stigmasterol (2 – 4). These components are effective LDL-C level $ 4.14 mmol/l (160 mg/dl) and a triglycer- in reducing serum lipid (5). The lipid-lowering effects of ides level # 4.52 mmol/l (400 mg/dL) at two qualifying Monascus purpureus rice have been shown in several visits 4 weeks apart. Women who were pregnant or animal models of hyperlipidemia to inhibit and prevent breastfeeding were excluded from the study, as were increases in total cholesterol, low-density lipoprotein patients who met any of the following conditions: cholesterol (LDL-C) and triglycerides (6). In this study, hypothyroidism, nephrotic syndrome or renal dysfunc- the efficacy and safety of Monascus purpureus Went tion (serum creatinine . 132.6 mmol/l (1.5 mg/dl)); rice were evaluated by measuring percentage changes diabetes mellitus; chronic gout; active liver disease of lipid profiles, observing any adverse effects and or hepatic dysfunction (aspartate aminotransferase q 2005 Society of the European Journal of Endocrinology EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 153 (AST) or alanine aminotransferase (ALT) . 2 times the the efficacy as well as the safety of Monascus purpureus upper limit of normal (ULN)); creatine phosphokinase (CPK) . 3 times the ULN; uncontrolled hypertension The sample size for this study was based on the pri- (systolic blood pressure . 160 mmHg or diastolic mary efficacy outcome, the change from baseline to 8 blood pressure . 100 mmHg); cerebrovascular disease, weeks in mean LDL-C was compared between the two cardiovascular surgery, myocardial infarction, coron- groups. The standard deviation (S.D.) of the mean LDL- ary angioplasty, coronary artery bypass graft, severe C level was 1 mmol/l (the S.D. of the mean for the treat- or unstable angina, or major operations within 6 ment group and that of the placebo group were similar).
months prior to the study period; current or recent his- We set the two-sided alpha (type I error) at 0.05 and the tory of alcohol abuse; significant abnormalities that the beta (type II error) at 0.10 (power of 90%). According to investigator believed could compromise the patient’s these assumptions, a sample size of approximately 17 safety in participating in the study; participation in subjects in each group was needed to detect a difference another clinical trial within the 30-day period before consideration for entry into this study; known hyper-sensitivity to lipid-modifying agents; and use of anydrugs known to affect lipid levels, immunosuppressive agents, drugs associated with rhabdomyolysis in combi- After a minimum of 4 weeks on an American Heart nation with statins (e.g. cyclosporine and erythromy- Association Step I diet, 79 patients were instructed to cin), or mibefradil dihydrochloride. Patients taking a continue the diet and were randomly assigned to 8 lipid-lowering drug could be considered for screening weeks of treatment with rice powder placebo or Monas- after a 4-week washout period, with the exception of cus purpureus Went rice (Fig. 1). All patients received probucol – which had to have been discontinued for dietary instruction from a registered dietitian at every at least 6 months. The study complied with the research visit and were contacted by telephone every Declaration of Helsinki. The institutional ethics review week during the study. The study was double-blind.
boards approved the protocol, and all participants We reviewed participants every 4 weeks and blood samples were obtained after 12-h overnight fasts. Thelaboratory staff responsible for analyses were blindedto treatment and received samples labeled with namecodes and dates. The study protocol was approved by the Institutional Review Board of China Medical Uni- versity Hospital and by the Department of Health,Taiwan.
A permuted-block randomization was employed to gen-erate the random assignment of subjects by order ofentry into two different treatment groups. Each group of subjects received either Monascus purpureus Wentrice or placebo. In this study, a sample size of 79 For the treatment group, Monascus purpureus Went rice patients was used for characterizing and comparing was pulverized and 600 mg of this milled preparation Figure 1 Flow of patients through the trial.
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 153 Efficacy and safety of Monascus purpureus Went rice Table 1 Composition of Monascus purpureus Went rice.
analyses were performed by Beckman & Coutler, Tokyoautoanalyzer. The intra-assay coefficients of variation (CV%) were 3.1, 2.3, 3.5 and 3.6% for LDL-C, total Serum apolipoprotein A-I and apolipoprotein B were measured by nephelometry (8) (intra-assay coefficient of variation, 2.2 and 1.9 respectively).
The primary analysis of efficacy endpoints was based on the intent-to-treat population and completing partici- pants. Baseline was defined as the measurements taken at randomization. The primary measure of effi- cacy was the percentage change in LDL-C level from baseline to week 8. Secondary measures of efficacy were percentage changes (from baseline to week 8) in total cholesterol, HDL-C, triglycerides, apolipoprotein Safety was evaluated in all randomized patients who had taken at least one dose of study medication and provided any follow-up information. All adverse effects that occurred during the clinical trial were recorded.
Their relation to the study drug (definitely, probably, possibly, unlikely, definitely not) and their intensity(mild, moderate, severe) were assessed by the investi- Data are based on unpublished analyses on file with Y & B Pharmaceuti- gator. Because statins are present in Monascus purpur- cals Co., Ltd, Taipei, Taiwan. HMG-CoA, 3-hydroxy-3-methylglutaryl coen-zyme A. Percentage concentrations are percentage by weight.
eus Went rice, ALT, AST and CPK were measured. In addition, physical examinations and clinical laboratorydeterminations were performed at screening, randomiz- encapsulated in each capsule under Good Manufactur- ation, week 4 and study termination.
ing Practices conditions (Y & B Pharmaceuticals Co.,Ltd, Taipei, Taiwan). The composition of Monascus pur- pureus Went rice is shown in Table 1. The placebo wasmade of grounded rice with food color mimicking the Descriptive statistics such as a number of observations, color and appearance of the active drug. Both Monascus means, standard deviations and percentages were used purpureus Went rice and placebo capsules were dis- to summarize the baseline variables. All available tests pensed by the hospital pharmacy in identical contain- were two sided and were evaluated at the 0.05 level of significance. For subjects’ demographic information, Participants were asked to take one capsule (600 mg the comparability between two groups was examined Monascus purpureus Went rice or placebo) twice daily, using an unpaired t-test for continuous variables, and 30 min after breakfast and dinner, for the 56 days of Fisher’s exact test and Mantel – Haenszel test for categ- the study, and to return the containers for capsule orical variables. Blood lipids, safety parameters, vital signs and laboratory examinations were analyzedbased on change from baseline; they were analyzedby unpaired t-test for between-group variation, andby paired t-test for within-group variation. Fisher’s exact test was used to compare the number of subjects All samples from a given individual were labeled by with adverse effects between groups.
code. Total cholesterol and triglycerides were deter-mined by the enzymatic method using commercial kits (Beckman & Coulter, Fullerton, CA, USA). High-density lipoprotein cholesterol (HDL-C) and LDL-C The sponsors of the study had no role in study design, were measured by the direct method (7) using commer- data collection, data analysis, data interpretation, or cial kits (Beckman & Coulter, LX 20 Pro, Japan). All the EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 153 Table 2 Patient characteristics at baseline by treatment group.
by 27.7% but placebo caused only a 1.5% decreaseat week 8. At baseline, the two groups showed com- parable total cholesterol, triglycerides and apolipopro- tein B levels (P . 0.05). The 8-week treatment with Monascus purpureus Went rice significantly reduced total cholesterol levels by 21.5%, triglycerides by 15.8% and apolipoprotein B by 26%. Worthy of special mention is that Monascus purpureus Went rice resulted in reductions in LDL-C level by 30.6%, total choles- terol level by 23.7%, triglycerides level by 13.4% and apolipoprotein B level by 28.9% that were observed as early as 4 weeks after its administration (Table 3).
In contrast, the placebo treatment resulted in almost Data are means^S.D.or number with percentage in brackets. BMI, body no reduction of total cholesterol (2 0.4%) and trigly- cerides (þ 1%) at week 4 and week 8. A 3.9% reduction of apolipoprotein B levels was observed after the placebo treatment at week 8. The capacityof Monascus purpureus Went rice to change HDL-Cand apolipoprotein A-I levels was limited. The differ- ence in the percentage change of HDL-C and apolipo-protein A-I was comparable between the two groups The characteristics of subjects who entered the studyare summarized in Table 2. The demographics and baseline characteristics of subjects in the two groupswere similar. The percentage of males and females A safety evaluation was performed based on the ‘safety was about equal in both groups. The age of subjects population’, which included a total of 75 subjects in both groups was about 46 years with a range of (n ¼ 37 in the Monascus purpureus Went rice group 23 – 65 years. Over 80% of subjects in both groups and n ¼ 38 in the placebo group) who were randomized had never smoked. A high percentage of subjects in and had taken at least one dose of the study medication, both groups had never had alcohol. Both groups had with follow-up information after randomization. We recorded any complaints mentioned, however trivial.
At baseline, there were no significant differences Therefore, up to 65% of the total safety population between groups for the efficacy parameters (LDL-C, (n ¼ 49) reported one or more adverse events and 8% total cholesterol, HDL-C, triglycerides, apolipoprotein of the total safety population (n ¼ 6) had one or more A-I and apolipoprotein B). All these data affirmed that drug-related adverse events. Nevertheless, the incidence the distribution of subjects between the two groups of ‘one or more adverse events’, ‘drug-related adverse events’ and ‘serious adverse events’ between the twogroups were comparable (P . 0.05) (Table 4). Monascuspurpureus Went rice treatment produced a slight increase in ALT (2.3 U/l) and AST (0.8 U/l), but nopatient had an ALT or AST measurement $ 3 times Of the 79 patients randomized to treatment, 39 the ULN at week 4. At week 8, Monascus purpureus received Monascus purpureus Went rice and 40 placebo.
Went rice had the same safety profile. Baseline serum Four participants who were randomized did not start CPK was similar in both groups and was not signifi- the study (Monascus purpureus Went rice, 2 patients cantly different after 8 weeks of the treatment. In the (5.1%); placebo, 2 patients (5.0%)). Compliance with Monascus purpureus Went rice group, mean serum study therapy (defined as $ 80% of pills taken) was CPK at baseline was 116.4 U/l (S.D. ¼ 66.0) and mean 81.6% for placebo and 89.2% for Monascus purpureus serum CPK at week 8 was 129.6 U/l (S.D. ¼ 42.3). In addition, there was no patient with myopathy (definedas a CPK level $ 10 times the ULN with muscle symp-toms) or CPK values $ 3 times the ULN at weeks 4 and 8. In particular, no cases of rhabdomyolysis or ana- Efficacy evaluation was carried out on completing par- phylaxis were observed. In addition, Monascus purpureus ticipants, in which 75 subjects were included. LDL-C Went rice did not alter other safety parameters levels, the primary efficacy endpoint, were comparable including vital signs, results of physical examination, between the two groups at baseline (Table 3). The hematology, serum chemistry, urine analysis and Monascus purpureus Went rice reduced LDL-C levels EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 153 Efficacy and safety of Monascus purpureus Went rice Table 3 Change from baseline in serum lipid variables, by week and treatment group (completer population).
Data are means^S.D.TC, total cholestrol; TG, triglycerides; Apo A-I, apolipoprotein A-I; Apo B, apolipoprotein B.
a To convert total cholesterol, HDL-C and LDL-C to mg/dL, divide values by 0.0259.
b To convert triglyceridess to mg/dL, divide values by 0.0113.
c To convert Apo A-I and Apo B to mg/dL, divide values by 0.01.
* Significantly different from baseline, P , 0.001.
† Significantly different from baseline, P , 0.05.
‡ Significantly different from control group at the same week, P , 0.001.
§ Significantly different from control group at the same week, P , 0.05.
Table 4 Number and percentage of patients with adverse events(AEs).
between the treatment groups, as was observed whenthese participants were not included in the analysis (Table 5). Furthermore, the mean reduction in LDL-C level across treatments was still significant at 26.3% (13.4%) (P , 0.001) for the Monascus purpureus Went rice-treated group when it was assumed that the four additional participants showed no change in response Coronary artery disease (CAD) is a leading cause of death in the developed world today. It is well estab- lished that increased total cholesterol, LDL-C and tri- glycerides concentrations, as well as decreased HDL-C Breast cancer: unrelated to the study drug.
concentrations, are strong independent predictors ofCAD (9). The statins have repeatedly been shown to During the trial, one serious adverse event (breast reduce mean serum LDL-C concentrations by 28 – carcinoma) occurred in the Monascus purpureus Went 35% in long-term trials (10 – 12), with corresponding rice-treated group. The 63-year-old female was diag- reductions in cardiovascular death of 23 – 32% in nosed with breast cancer after a 4-week administration both primary and secondary prevention trials (11, of Monascus purpureus Went rice. However, the incident 12). A previous study showed that red yeast rice was not related to Monascus purpureus Went rice.
(1.00 mmol/l), total cholesterol (1.09 mmol/l) and tri-glycerides (0.17 mmol/l) levels (2). In this study, Mon- ascus purpureus Went rice resulted in significant This study was also analyzed on the basis of intention reductions in LDL-C (1.59 mmol/l (30.6%)), total to treat, including the four individuals with baseline cholesterol (1.73 mmol/l (23.7%)) and triglycerides values who dropped out or were withdrawn. The differ- (0.21 mmol/l (13.4%)) levels from baseline to week ences in blood lipid levels were significantly different 4. These reductions were maintained at 8 weeks.
EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 153 Table 5 Change from baseline in serum lipid variables, by week and treatment group (intent-to-treat population).
Data are means^S.D. Abbreviations and symbols are as in Table 3.
The results of this study again confirm that Monascus purpureus Went rice also contains phytosterols, mainly purpureus Went rice has positive effects on plasma beta-sitosterol with campesterol and stigmasterol.
Plant sterols have been shown to decrease total choles- It is noteworthy that Monascus purpureus Went rice terol and LDL-C concentrations in several population reduced apolipoprotein B levels by 26.0% in this study. Each of the atherogenic particles – namely, In this study, all patients received dietary consul- very low density lipoprotein, intermediate-density lipo- tation but there was no record of diets of the partici- protein, LDL and lipoprotein(a) – contain one molecule pants. We compared BMI in the two treatment groups of apolipoprotein B. Thus, the serum concentration of at baseline, at 4 weeks and at 8 weeks. There were apolipoprotein B reflects the total number of these par- no significant differences in BMI within or between ticles. A systematic review showed the apolipoprotein B study groups. Therefore, we infer that neither dietary concentration to be a better estimate of the risk of vas- fat intake or exercise had an impact on lipid profile in cular events than the LDL-C level (13). This is sup- ported by the fact that apolipoprotein B has been Asymptomatic elevations of transaminases (. 3 accepted as an alternative to the cholesterol indices in times the ULN) have been observed with all the statins, the new Canadian Lipid Working Group on hypercho- are relatively common (0.1 – 2.0%) and are dose related lesterolemia and other dyslipidemias (14) and in the (22). It is interesting to note that no patient in the Mon- new Canadian Diabetes Association Guidelines (15).
ascus purpureus Went rice treatment group had an ALT A specialist commented that Monascus purpureus or AST measurement $ 3 times the ULN at week 4 or Went rice contains statins and yields similar hypolipi- week 8. Statin therapy is also known to cause increases demic effects to statins (16), therefore the other active in CPK activity, mostly during the initial stages of treat- components may only play a minor role in the action ment and upward dose titration. Nevertheless, no trials of Monascus purpureus Went rice. One study (17) have examined the effect of red yeast rice on CPK so far.
reported mean LDL-C reductions to be 20, 26, 19 and In this study, no cases of CPK measurement $ 3 times 24% for fluvastatin (80 mg), lovastatin (80 mg), pra- the ULN or rhabdomyolysis were reported. Possible vastatin (40 mg) and simvastatin (20 mg) respectively; Monascus purpureus Went rice-related adverse events mean apolipoprotein B levels were reduced by 16, 19, were one abnormal liver function test (ALT, 57 U/l; 16 and 20% respectively. In this study, 1200 mg of Monascus purpureus Went rice contains a total of 140 U/l), and one lactate dehydrogenase increase 13.9 mg statins (contains 11.4 mg lovastatin) but (208 U/l; ULN, 192 U/l). All these events were mild in reduced LDL-C by 27.7% and apolipoprotein B by severity and required no treatment. On the other 26.0%. Hence, we infer that the hypolipidemic effect hand, mild leukopenia (n ¼ 1), diarrhea (n ¼ 1) and of Monascus purpureus Went rice is unlikely to be due nausea (n ¼ 1) were found to be possibly drug-related solely to statins, but rather to result from other sub- adverse events in the placebo treated group. In general, stances in the Monascus purpureus Went rice. Monascus Monascus purpureus Went rice was well tolerated and no EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 153 Efficacy and safety of Monascus purpureus Went rice one discontinued the study due to adverse effects lowering effects of a monascus purpureus (red yeast) rice prep- caused by the study drug. Extensive animal studies of aration from traditional Chinese medicine. Current TherapeuticResearch 1997 58 964 – 978.
red yeast rice extracts have been conducted. In an 5 Goldstein MR. Effects of dietary phytosterols on cholesterol acute toxicity study in mice, there were no toxic effects metabolism and atherosclerosis. American Journal of Medicine noted when a single dose of the extract was adminis- tered at 533 times the typical human dose (23).
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