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Traditional Chinese lipid-lowering agent red yeast rice results in significant LDL reduction but safety is uncertain – A systematic review and meta-analysis

Open AccessPublished:April 11, 2015DOI:https://doi.org/10.1016/j.atherosclerosis.2015.04.004

      Highlights

      • We systematically reviewed and meta-analyzed the effectiveness and safety of red yeast rice extract for cardiovascular risk reduction.
      • We analyzed 20 randomized trials on 6663 patients.
      • The placebo-subtracted reduction of LDL was 0.68 till 1.44 mmol/l with a pooled estimate of −1.02 mmol/L (95% CI −1.20; −0.83).
      • The incidence of kidney injury and liver abnormalities was <5% in both RYR and control groups. The rate of myopathy did not differ between RYR and control groups.
      • The design and reporting of adverse events were in most studies insufficient to make a firm judgement on the safety of red yeast rice extract.

      Abstract

      Objective

      To verify the safety and effectiveness of traditional Chinese red yeast rice-extract (RYR) for reduction of LDL cholesterol.

      Methods

      Systematic literature review and meta-analysis. Medline and EMBASE were searched until November 2014. We selected randomized studies in which RYR with a known content of the active substance monacolin K was tested against placebo or an active control group. Outcome measures were the effect of RYR on LDL cholesterol and incidence of adverse reactions with emphasis on liver and kidney injury and muscle symptoms.

      Results

      Twenty studies were analyzed. Quality of safety assessment was low in the majority of studies. RYR lowered LDL cholesterol with 1.02 mmol/L [−1.20; −0.83] compared to placebo. Effect of RYR on LDL was not different from statin therapy (0.03 mmol/L [−0.36; 0.41]). The incidence of liver and kidney injury was 0–5% and the risk was not different between treatment and control groups (risk difference −0.01 [−0.01; 0.0] and 0.0 [−0.01; 0.02]).

      Conclusions

      RYR exerts a clinically and statistically significant reduction of 1.02 mmol/L LDL cholesterol. Only when the mild profile of adverse reactions can be affirmed in studies with adequate methodology for safety assessment, RYR might be a safe and effective treatment option for dyslipidemia and cardiovascular risk reduction in statin intolerant patients.

      Keywords

      1. Introduction

      Statins are the most effective agents for improving lipid spectrum in order to reduce the risk of atherosclerotic disease [
      • Sever P.S.
      • Dahlöf B.
      • Poulter N.R.
      • et al.
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac outcomes Trial–Lipid lowering arm (ASCOT-LLA): a multicentre randomis.
      ,
      • Collins R.
      • Armitage J.
      • Parish S.
      • Sleigh P.
      • Peto R.
      MRC/BHF heart Protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      ]. While statins are generally well tolerated, a minority of patients suffers from side effects which diminishes therapy adherence and limits the full potential of risk reduction [
      • Bates T.R.
      • Connaughton V.M.
      • Watts G.F.
      Non-adherence to statin therapy: a major challenge for preventive cardiology.
      ]. Several patients with a proven or perceived intolerance to statins and other established lipid lowering agents use alternative products to influence their lipid levels. Also other persons – even without dyslipidemia or increased cardiovascular risk – use alternative products to lower their cholesterol [
      • Yeh G.Y.
      • Davis R.B.
      • Phillips R.S.
      Use of complementary therapies in patients with cardiovascular disease.
      ]. It is a common belief that these ‘natural’ agents do not have side effects. Of these agents, the traditional Chinese red yeast rice extract (RYR), has been studied in more detail. In this article we systematically review the evidence on the potential benefits and risks of RYR in order to determine its suitability in clinical practice.
      Muscle symptoms are the major reason for statin intolerance. However, also non-specific symptoms such as fatigue, headache or gastrointestinal symptoms do contribute. The prevalence of statin intolerance may be up to 10% in clinical practice. Risk factors for statin intolerance include older age, female sex, renal disease, history of muscle symptoms and high statin dose [
      • Bruckert E.
      • Hayem G.
      • Dejager S.
      • Yau C.
      • Bégaud B.
      Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study.
      ]. As these risk factors tend to be exclusion criteria for clinical trials, prevalence of statin intolerance in trials is lower compared to clinical practice [
      • Stroes E.S.
      • Thompson P.D.
      • Corsini A.
      • et al.
      Clinical update statin-associated muscle symptoms: impact on statin therapy — European atherosclerosis society consensus panel statement on assessment, Aetiology and management.
      ].
      RYR is well-known in traditional Chinese medicine for its beneficial effects in cardiovascular disease [
      • Kalaivani M.
      • Sabitha R.
      • Kalaiselvan V.
      • Rajasekaran A.
      Health benefits and clinical impact of major nutrient, red yeast Rice: a review.
      ]. RYR consists of powdered Monascus purpureus fermented rice. Its cholesterol lowering effect is supported by empirical evidence and a plausible mechanism. Depending on the fermentation conditions of the rice and the Monascus strains used, HMG-CoA reductase inhibiting monacolins may be produced as metabolites. Several Monacolin subtypes were found in RYR products but the most profound subtype is monacolin K (MonK) which is identical to lovastatin [
      • Gordon R.Y.
      • Cooperman T.
      • Obermeyer W.
      • Becker D.J.
      Marked variability of monacolin levels in commercial red yeast rice products: buyer beware!.
      ]. In clinical trials, RYR doses varying from 200 mg to 4800 mg daily have been studied but monacolin content is not always reported. Also, commercially available supplements often lack a declaration of monacolin content [
      • Lachenmeier D.W.
      • Monakhova Y.B.
      • Kuballa T.
      • et al.
      NMR evaluation of total statin content and HMG-CoA reductase inhibition in red yeast rice (Monascus spp.) food supplements.
      ]. Another concern is the Monascus purpureus metabolite citritin (CTN), which is a mycotoxin that is known to cause nephrotoxicity [
      • Pascual-Ahuir A.
      • Vanacloig-Pedros E.
      • Proft M.
      Toxicity mechanisms of the food contaminant citrinin: application of a quantitative yeast model.
      ].
      Although RYR is claimed to be a safer alternative to regular statins, structural similarity with lovastatin implies that similar adverse reactions can be expected. Indeed anaphylaxis, toxic hepatitis and rhabdomyolysis have been associated with the use of RYR [
      • Grieco A.
      • Miele L.
      • Pompili M.
      • et al.
      Acute hepatitis caused by a natural lipid-lowering product: when “alternative” medicine is no “alternative” at all.
      ,
      • Wigger-Alberti W.
      • Bauer A.
      • Hipler U.C.
      • Elsner P.
      Anaphylaxis due to Monascus purpureus-fermented rice (red yeast rice).
      ,
      • Prasad G.V.R.
      • Wong T.
      • Meliton G.
      • Bhaloo S.
      Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient.
      ].
      In our study we determined to what extend RYR is an effective and safe agent for improving lipid profile. We systematically reviewed and meta-analyzed improvement of lipid profile, as measured by reduction of low density lipoprotein (LDL)-cholesterol and safety by assessing the incidence of adverse reactions.
      Tabled 1
      Added value to previous meta-analysis on red yeast rice extract
      The efficacy of RYR to reduce LDL cholesterol in patients with hyperlipidemia has been subject to meta-analysis before
      • Liu J.
      • Zhang J.
      • Shi Y.
      • Grimsgaard S.
      • Alraek T.
      • Fønnebø V.
      Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials.
      ,
      • Li Y.
      • Jiang L.
      • Jia Z.
      • et al.
      A meta-analysis of red yeast rice: an effective and relatively safe alternative approach for dyslipidemia.
      . Our study extends the knowledge by a systematic and extensive review of evidence on the safety of RYR.

      2. Methods

      We applied methods as recommended by the Cochrane collaboration and the report is written in accordance with PRISMA guidelines [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group T.P.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ,
      • Higgins J.
      • Deeks J.
      Obtaining standard deviations from standard errors and confidence intervals for group means.
      ]. The protocol was published online (http://www.crd.york.ac.uk/prospero, CRD42012003397).

      2.1 Search strategy and selection criteria

      We conducted a systematic literature search for randomized studies in which RYR with a known content of MonK was tested against placebo or an active control group for at least 4 weeks (Fig. S8). We searched EMBASE and Medline until November 2014. We did not apply language restrictions.

      2.2 Data extraction and assessment of risk of bias

      We selected eligible studies subsequently by title, abstract and full text (MG, CK). Any disagreement was solved by discussion or if required by the third reviewer. The authors extracted data on study design, lipid values and adverse reactions by a standardized data extraction form (MG, RT and HY for Chinese papers, MG and CK for English papers). Risk of bias was evaluated for all outcome domains. If lipid values were reported at more than 1 time point during follow-up, we included the 1st time point from 4 weeks in our analysis. Adverse reactions of special interest were kidney disease, liver abnormalities and myopathies. Other adverse reactions were arranged by organ system. Muscle symptoms were classified by symptoms and creatine kinase (CK) level [
      • Stroes E.S.
      • Thompson P.D.
      • Corsini A.
      • et al.
      Clinical update statin-associated muscle symptoms: impact on statin therapy — European atherosclerosis society consensus panel statement on assessment, Aetiology and management.
      ].

      2.3 Statistical analysis

      A meta-analysis was planned on the change in LDL cholesterol, and on the risk of adverse reactions. Authors were contacted to complete missing data. When data on lipid values persisted to be unavailable we used imputation [
      • Higgins J.
      • Deeks J.
      Obtaining standard deviations from standard errors and confidence intervals for group means.
      ]. Influence of imputations was assessed through sensitivity analyses. We separately analyzed cholesterol lowering efficacy for studies comparing RYR with placebo or active controls. Statistical heterogeneity was assessed with the I2-statistic. In case of heterogeneity we investigated potential causes by performing sensitivity analyses. If heterogeneity could not be reduced, we applied a random effects model. Excel 2010 and Review Manager were used for analysis. Results are presented as mean difference [95% confidence interval] unless otherwise specified.

      3. Results

      Our search yielded 286 unique publications. After exclusion of studies not fulfilling selection criteria, we analyzed 36 publications on 20 studies (Fig. 1) [
      • Becker D.J.
      • Gordon R.Y.
      • Halbert S.C.
      • French B.
      • Morris P.B.
      • Rader D.J.
      Red yeast Rice for dyslipidemia in statin-intolerant patients.
      ,
      • Becker D.J.
      • Gordon R.Y.
      • Halbert S.C.
      • Rader D.J.
      A novel approach to lipid-lowering in patients with statin-associated myalgias: a randomized, placebo-controlled, double-blind trial.
      ,
      • Bogsrud M.P.
      • Ose L.
      • Langslet G.
      • et al.
      HypoCol (red yeast rice) lowers plasma cholesterol - a randomized placebo controlled study.
      ,
      • Du B.
      • Lu Z.
      • Chen Z.
      • Wu Y.
      The beneficial effects of lipid-lowering therapy with xuezhikang on cardiac events and total mortality in coronary heart disease patients with or without hypertension: a random, double-blinded, placebo controlled clinical trial.
      ,
      • Du B.
      • Lu Z.
      • Chen Z.
      • Wu Y.
      • Zhao W.
      • Huang T.
      China coronary secondary prevention study: analysis of patients with different myocardial infarction history.
      ,
      • Fan X.
      • Deng Y.
      • Ye L.
      • et al.
      Effect of Xuezhikang capsule on serum tumor necrosis factor-alpha and interleukin-6 in patients with nonalcoholic fatty liver disease and hyperlipidemia.
      ,
      • Gong C.
      • Huang S.
      • Huang J.
      • et al.
      Effects of combined therapy of Xuezhikang capsule and Valsartan on hypertensive left ventricular hypertrophy and heart rate turbulence.
      ,
      • Halbert S.C.
      • French B.
      • Gordon R.Y.
      • et al.
      Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance.
      ,
      • Heber D.
      • Yip I.
      • Ashley J.M.
      • Elashoff D.A.
      • Elashoff R.M.
      • Go V.L.
      Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement.
      ,
      • Hu C.-L.
      • Li Y.-B.
      • Tang Y.-H.
      • et al.
      Effects of withdrawal of xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with coronary artery disease.
      ,
      • Huang C.-F.
      • Li T.-C.
      • Lin C.-C.
      • Liu C.-S.
      • Shih H.-C.
      • Lai M.-M.
      Efficacy of Monascus purpureus Went rice on lowering lipid ratios in hypercholesterolemic patients.
      ,
      • Huang Y.-S.
      • Wang S.-R.
      • Zhi Y.-F.
      • et al.
      Effects of xuezhikang capsules on vascular endothelial function and redox status in patients with coronary heart disease.
      ,
      • Jian J.
      • Hao X.
      • Deng C.
      • Zhou H.
      • Lin J.
      The effects of Xuezhikang on serum lipid profile, thromboxane A2 and prostacyclin in patients with hyperlipidemia.
      ,
      • Keithley J.K.
      • Swanson B.
      • Sha B.E.
      • Zeller J.M.
      • Kessler H.A.
      • Smith K.Y.
      A pilot study of the safety and efficacy of cholestin in treating HIV-related dyslipidemia.
      ,
      • Kou W.
      • Lu Z.
      • Guo J.
      Effect of xuezhikang on the treatment of primary hyperlipidemia.
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Impact of long-term Xuezhikang therapy on cardiovascular events in high-risk patients with nonspecific, preexisting abnormal liver tests: a post-hoc analysis from Chinese Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.
      • Kou W.-R.
      • et al.
      Impact of xuezhikang on coronary events in hypertensive patients with previous myocardial infarction (CCSPS study).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Beneficial impact of Xuezhikang on cardiovascular events and mortality in elderly hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Long-term effects of Xuezhikang on blood pressure in hypertensive patients with previous myocardial infarction: data from the Chinese Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Impact of Xuezhikang on coronary events in hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).
      ,
      • Lin C.-C.
      • Li T.-C.
      • Lai M.-M.
      Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia.
      ,
      • Liu L.
      • Wu M.
      • Wang H.-X.
      Clinical study on the treatment of abnormal blood lipids complicated with carotid atherosclerosis with lipid-reducing red rice minute powder: a randomized controlled trial.
      ,
      • Lu Z.-L.
      • Du B.
      • Chen Z.
      • Wu Y.
      • Yu X.
      • Zhao Y.-C.
      China coronary secondary prevention study (CCSPS): outcomes from analysis of coronary heart disease patients with diabetes.
      ,
      • Lu Z.-L.
      • Kou W.-R.
      • Du B.
      • et al.
      Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction.
      ,
      • Moriarty P.M.
      • Roth E.M.
      • Karns A.
      • et al.
      Effects of Xuezhikang in patients with dyslipidemia: a multicenter, randomized, placebo-controlled study.
      ,
      • Roth E.M.
      • Moriarty P.
      • Li S.
      • et al.
      Red yeast rice extract shows equivalency to statins.
      ,
      • Wang J.
      • Lu Z.
      • Chi J.
      • et al.
      Multicenter clinical trial of the serum lipid-lowering effects of a Monascus purpureus (red yeast) rice preparation from traditional Chinese medicine.
      ,
      • Wang W.-H.
      • Zhang H.
      • Yu Y.-L.
      • Ge Z.
      • Xue C.
      • Zhang P.
      Intervention of xuezhikang on patients of acute coronary syndrome with different levels of blood lipids.
      ,
      • Wu C.
      • Ye P.
      The beneficial effects of xuezhikang on top of extended-released nifedipine in hypertensive patients without severe hyperlipidemia.
      ,
      • Yang N.-C.
      • Chou C.-W.
      • Chen C.-Y.
      • Hwang K.-L.
      • Yang Y.-C.
      Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia.
      ,
      • Ye P.
      • Lu Z.-L.
      • Du B.
      • et al.
      Effect of xuezhikang on cardiovascular events and mortality in elderly patients with a history of myocardial infarction: a subgroup analysis of elderly subjects from the China Coronary Secondary Prevention Study.
      ,
      • Ye P.
      • Wu C.
      • Li H.
      • Zhi G.
      The effect of Xuezhikang on ventricular diastolic function in hypertension.
      ,
      • Ye P.
      • Wu C.
      • Sheng L.
      • Li H.
      Potential protective effect of long-term therapy with Xuezhikang on left ventricular diastolic function in patients with essential hypertension.
      ,
      • Zhao S.-P.
      • Liu L.
      • Cheng Y.-C.
      • Li Y.-L.
      Effect of xuezhikang, a cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease.
      ,
      • Zhao S.-P.
      • Liu L.
      • Cheng Y.-C.
      • et al.
      Xuezhikang, an extract of cholestin, protects endothelial function through antiinflammatory and lipid-lowering mechanisms in patients with coronary heart disease.
      ,
      • Zhao S.-P.
      • Lu Z.
      • Du B.
      • et al.
      Xuezhikang, an extract of cholestin, reduces cardiovascular events in type 2 diabetes patients with coronary heart disease: subgroup analysis of patients with type 2 diabetes from China coronary secondary prevention study (CCSPS).
      ]. Twenty-six papers were written in English and others were Chinese. The studies contained 6663 subjects in total, of which a large proportion was included in the Chinese Coronary Secondary Prevention Study (CCSPS) [
      • Du B.
      • Lu Z.
      • Chen Z.
      • Wu Y.
      The beneficial effects of lipid-lowering therapy with xuezhikang on cardiac events and total mortality in coronary heart disease patients with or without hypertension: a random, double-blinded, placebo controlled clinical trial.
      ,
      • Du B.
      • Lu Z.
      • Chen Z.
      • Wu Y.
      • Zhao W.
      • Huang T.
      China coronary secondary prevention study: analysis of patients with different myocardial infarction history.
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Impact of long-term Xuezhikang therapy on cardiovascular events in high-risk patients with nonspecific, preexisting abnormal liver tests: a post-hoc analysis from Chinese Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.
      • Kou W.-R.
      • et al.
      Impact of xuezhikang on coronary events in hypertensive patients with previous myocardial infarction (CCSPS study).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Beneficial impact of Xuezhikang on cardiovascular events and mortality in elderly hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Long-term effects of Xuezhikang on blood pressure in hypertensive patients with previous myocardial infarction: data from the Chinese Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Impact of Xuezhikang on coronary events in hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).
      ,
      • Lu Z.-L.
      • Du B.
      • Chen Z.
      • Wu Y.
      • Yu X.
      • Zhao Y.-C.
      China coronary secondary prevention study (CCSPS): outcomes from analysis of coronary heart disease patients with diabetes.
      ,
      • Lu Z.-L.
      • Kou W.-R.
      • Du B.
      • et al.
      Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction.
      ,
      • Ye P.
      • Lu Z.-L.
      • Du B.
      • et al.
      Effect of xuezhikang on cardiovascular events and mortality in elderly patients with a history of myocardial infarction: a subgroup analysis of elderly subjects from the China Coronary Secondary Prevention Study.
      ,
      • Zhao S.-P.
      • Lu Z.
      • Du B.
      • et al.
      Xuezhikang, an extract of cholestin, reduces cardiovascular events in type 2 diabetes patients with coronary heart disease: subgroup analysis of patients with type 2 diabetes from China coronary secondary prevention study (CCSPS).
      ]. The CCSPS aimed to demonstrate a reduction in cardiovascular events and had a follow-up duration of 3.5 years. All other studies, which had surrogate parameters as primary outcome had a shorter follow-up (2–24 months). Five studies were conducted in Europe and North America and 14 studies were conducted in China. One study included patients in North America as well as China [
      • Moriarty P.M.
      • Roth E.M.
      • Karns A.
      • et al.
      Effects of Xuezhikang in patients with dyslipidemia: a multicenter, randomized, placebo-controlled study.
      ,
      • Roth E.M.
      • Moriarty P.
      • Li S.
      • et al.
      Red yeast rice extract shows equivalency to statins.
      ]. Three studies compared RYR to statin therapy, 13 studies compared RYR to inactive treatment and in 4 studies RYR was compared to a non-statin active control group (Table 1).
      Figure thumbnail gr1
      Fig. 1Study selection. Flow chart of systematic literature search.
      Table 1Characteristics of included studies.
      Study + ReferenceCountryParticipantsInterventionsFollow-up (weeks)
      Number between brackets indicates the timepoint which was included in lipid analysis.
      MaskingPrimary outcomeFunding
      Main eligibility criteriaAge – mean (SD)Sex – % male
      Becker 2009
      • Becker D.J.
      • Gordon R.Y.
      • Halbert S.C.
      • French B.
      • Morris P.B.
      • Rader D.J.
      Red yeast Rice for dyslipidemia in statin-intolerant patients.
      ,
      • Becker D.J.
      • Gordon R.Y.
      • Halbert S.C.
      • Rader D.J.
      A novel approach to lipid-lowering in patients with statin-associated myalgias: a randomized, placebo-controlled, double-blind trial.
      USDL, statin intolerance (n = 62)61 (8.5)36RYR 3600 mg (6.1 mg MonK) vs. placebo24 (12)Double-blindLipid profile and RYR tolerabilityCommonwealth of Pennsylvania (unrestricted)
      Bogsrud 2010
      • Bogsrud M.P.
      • Ose L.
      • Langslet G.
      • et al.
      HypoCol (red yeast rice) lowers plasma cholesterol - a randomized placebo controlled study.
      NorwayDL, DM2 (n = 42)2400 mg RYR (4.8 mg MonK) vs. placebo16 (6)Double-blindLipid profilePharmalogica AS (Scandinavian distributor of RYR)
      CCSPS 2008
      • Du B.
      • Lu Z.
      • Chen Z.
      • Wu Y.
      The beneficial effects of lipid-lowering therapy with xuezhikang on cardiac events and total mortality in coronary heart disease patients with or without hypertension: a random, double-blinded, placebo controlled clinical trial.
      ,
      • Du B.
      • Lu Z.
      • Chen Z.
      • Wu Y.
      • Zhao W.
      • Huang T.
      China coronary secondary prevention study: analysis of patients with different myocardial infarction history.
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Impact of long-term Xuezhikang therapy on cardiovascular events in high-risk patients with nonspecific, preexisting abnormal liver tests: a post-hoc analysis from Chinese Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.
      • Kou W.-R.
      • et al.
      Impact of xuezhikang on coronary events in hypertensive patients with previous myocardial infarction (CCSPS study).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Beneficial impact of Xuezhikang on cardiovascular events and mortality in elderly hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Long-term effects of Xuezhikang on blood pressure in hypertensive patients with previous myocardial infarction: data from the Chinese Coronary Secondary Prevention Study (CCSPS).
      ,
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Impact of Xuezhikang on coronary events in hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).
      ,
      • Lu Z.-L.
      • Du B.
      • Chen Z.
      • Wu Y.
      • Yu X.
      • Zhao Y.-C.
      China coronary secondary prevention study (CCSPS): outcomes from analysis of coronary heart disease patients with diabetes.
      ,
      • Lu Z.-L.
      • Kou W.-R.
      • Du B.
      • et al.
      Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction.
      ,
      • Ye P.
      • Lu Z.-L.
      • Du B.
      • et al.
      Effect of xuezhikang on cardiovascular events and mortality in elderly patients with a history of myocardial infarction: a subgroup analysis of elderly subjects from the China Coronary Secondary Prevention Study.
      ,
      • Zhao S.-P.
      • Lu Z.
      • Du B.
      • et al.
      Xuezhikang, an extract of cholestin, reduces cardiovascular events in type 2 diabetes patients with coronary heart disease: subgroup analysis of patients with type 2 diabetes from China coronary secondary prevention study (CCSPS).
      ChinaCHD (n = 4870)58.9 (10)82RYR 1200 mg (11.6 mg MonK) vs. placebo168Double-blindReduction of cardiovascular eventsChinese National Scientific and Technological Projects, WPU
      Fan 2010
      • Fan X.
      • Deng Y.
      • Ye L.
      • et al.
      Effect of Xuezhikang capsule on serum tumor necrosis factor-alpha and interleukin-6 in patients with nonalcoholic fatty liver disease and hyperlipidemia.
      ChinaNon-alcoholic steatosis, DL (n = 84)54.5 (10)49RYR 1200 mg (10 mg MonK) vs. polyenylphosphatidylcholine 1.4 g24 (12)No maskingInflammatory factors (TNF-α, IL-6)Unknown
      Gong 2010
      • Gong C.
      • Huang S.
      • Huang J.
      • et al.
      Effects of combined therapy of Xuezhikang capsule and Valsartan on hypertensive left ventricular hypertrophy and heart rate turbulence.
      ChinaHypertension, LVH (n = 60)57.7 (7.9)50RYR 1200 mg (10 mg MonK) + valsartan vs. valsartan only
      3rd intervention group in these studies was not included in this systematic review. WPU = WBL Peking University Biotech, Ltd, China.
      104No maskingLeft ventricular mass & heart rate turbulenceUnknown
      Halbert 2010
      • Halbert S.C.
      • French B.
      • Gordon R.Y.
      • et al.
      Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance.
      USDL, statin intolerance (n = 43)62.6 (8)26RYR 4800 mg (MonK 9.96 mg) vs. pravastatin 40 mg24Double-blindMyalgiaCommonwealth of Pennsylvania (unrestricted), Center for CAM, National Institute on Aging
      Heber 1999
      • Heber D.
      • Yip I.
      • Ashley J.M.
      • Elashoff D.A.
      • Elashoff R.M.
      • Go V.L.
      Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement.
      USDL (n = 88)61.5 (9)562400 mg RYR (4.8 mg MonK) vs. placebo12 (6)Double-blindLipid profilePharmanex
      Pharmanex is a manufacturer of RYR. CAM = complementary and alternative medicine.
      (unrestricted). Heber is cochair of Pharmanex medical advisory board.
      Hu 2006
      • Hu C.-L.
      • Li Y.-B.
      • Tang Y.-H.
      • et al.
      Effects of withdrawal of xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with coronary artery disease.
      ChinaCHD (n = 50)54.7 (4.25)621200 mg RYR (13.5 mg total monacolins) vs. placebo
      3rd intervention group in these studies was not included in this systematic review. WPU = WBL Peking University Biotech, Ltd, China.
      6Double-blindLipid profile and CRPUnknown
      Huang 2006
      • Huang Y.-S.
      • Wang S.-R.
      • Zhi Y.-F.
      • et al.
      Effects of xuezhikang capsules on vascular endothelial function and redox status in patients with coronary heart disease.
      ChinaCHD (n = 112)61.2 (16.7)52RYR 1200 mg (10 mg MonK) vs. probucol 1000 mg8No maskingVascular endothelial function and redox state of vascular endotheliumSichuan Science and Technology Department
      Jian 1999
      • Jian J.
      • Hao X.
      • Deng C.
      • Zhou H.
      • Lin J.
      The effects of Xuezhikang on serum lipid profile, thromboxane A2 and prostacyclin in patients with hyperlipidemia.
      ChinaDL (n = 91)57.3 (10.8)631200 mg RYR (MonK 10 mg) vs. gemfibrozil 1200 mg8No maskingLipid profile, thromboxane A-2 and prostacyclinUnknown
      Keithley 2002
      • Keithley J.K.
      • Swanson B.
      • Sha B.E.
      • Zeller J.M.
      • Kessler H.A.
      • Smith K.Y.
      A pilot study of the safety and efficacy of cholestin in treating HIV-related dyslipidemia.
      USHIV, DL (n = 14)42.5 (7.8)75RYR 2400 mg (MonK 4.8 mg) vs. placebo8Double-blindLipid profile, safety (plasma HIV RNA, CD4+ cells, liver function tests)Pharmanex
      Pharmanex is a manufacturer of RYR. CAM = complementary and alternative medicine.
      provided study medication
      Kou 1997
      • Kou W.
      • Lu Z.
      • Guo J.
      Effect of xuezhikang on the treatment of primary hyperlipidemia.
      ChinaDL (n = 108)55.862RYR 1200 mg (10 mg MonK) vs. simvastatin 10 mg vs. placebo8 (4)No maskingChange of lipid profileUnknown
      Lin 2005
      • Huang C.-F.
      • Li T.-C.
      • Lin C.-C.
      • Liu C.-S.
      • Shih H.-C.
      • Lai M.-M.
      Efficacy of Monascus purpureus Went rice on lowering lipid ratios in hypercholesterolemic patients.
      ,
      • Lin C.-C.
      • Li T.-C.
      • Lai M.-M.
      Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia.
      TaiwanDL (n = 79)46.4 (10)57RYR 1200 mg (MonK 11.4 mg) vs. placebo8 (4)Double-blindLipid profile and safetyY&B pharmaceuticals (unrestricted).
      Liu 2011
      • Liu L.
      • Wu M.
      • Wang H.-X.
      Clinical study on the treatment of abnormal blood lipids complicated with carotid atherosclerosis with lipid-reducing red rice minute powder: a randomized controlled trial.
      ChinaDL, carotid atherosclerosis (n = 40)58.2 (5.7)60RYR 1200 mg (10 mg MonK) vs. lovastatin 20 mg
      3rd intervention group in these studies was not included in this systematic review. WPU = WBL Peking University Biotech, Ltd, China.
      24No maskingLipid profile and carotid intima-media thickness.department of TCM Administration
      Roth 2013
      • Moriarty P.M.
      • Roth E.M.
      • Karns A.
      • et al.
      Effects of Xuezhikang in patients with dyslipidemia: a multicenter, randomized, placebo-controlled study.
      ,
      • Roth E.M.
      • Moriarty P.
      • Li S.
      • et al.
      Red yeast rice extract shows equivalency to statins.
      US & ChinaDL (n = 116)56.7 (10.8)26RYR 2400 mg (24 mg MonK) vs. RYR 1200 mg (12 mg MonK) vs. placebo12Double-blindLipid profileWPU and Luye Pharma Group, China. 6/20 authors are employees of Luye Pharma group
      Wang 1997
      • Wang J.
      • Lu Z.
      • Chi J.
      • et al.
      Multicenter clinical trial of the serum lipid-lowering effects of a Monascus purpureus (red yeast) rice preparation from traditional Chinese medicine.
      ChinaDL (n = 502)56.1 (0.6)591200 mg (2.4 mg MonK) vs. jiaogulan (TCM)8 (4)Patients blindedLipid profile2/11 authors are employees of Pharmanex and 2/11 authors are employees of WPU.
      Wang 2004
      • Wang W.-H.
      • Zhang H.
      • Yu Y.-L.
      • Ge Z.
      • Xue C.
      • Zhang P.
      Intervention of xuezhikang on patients of acute coronary syndrome with different levels of blood lipids.
      ChinaCHD (n = 105)59.9 (8.8)65RYR 1200 mg (10 mg MonK) vs. none
      3rd intervention group in these studies was not included in this systematic review. WPU = WBL Peking University Biotech, Ltd, China.
      12No maskingEndothelial function and inflammation (hs-CRP)Unknown
      Wu 2006
      • Wu C.
      • Ye P.
      The beneficial effects of xuezhikang on top of extended-released nifedipine in hypertensive patients without severe hyperlipidemia.
      ChinaHypertension, DL (n = 100)56.7 (10.3)50RYR 1200 mg (MonK 10 mg) vs. placebo24Patients blindedLipid profile, myocardial fibrosis, left ventricular function, inflammationUnknown
      Yang 2009
      • Yang N.-C.
      • Chou C.-W.
      • Chen C.-Y.
      • Hwang K.-L.
      • Yang Y.-C.
      Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia.
      TaiwanDL (n = 47)53 (9.5)53RYR 1200 mg (16.4 mg MonK) + nattokinase 50 mg vs. nattokinase only
      3rd intervention group in these studies was not included in this systematic review. WPU = WBL Peking University Biotech, Ltd, China.
      24 (4)Double-blindLipid profile (change)Industry-Academy Cooperation Project of the Ministry of Education, Taiwan
      Zhao 2003
      • Zhao S.-P.
      • Liu L.
      • Cheng Y.-C.
      • Li Y.-L.
      Effect of xuezhikang, a cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease.
      ,
      • Zhao S.-P.
      • Liu L.
      • Cheng Y.-C.
      • et al.
      Xuezhikang, an extract of cholestin, protects endothelial function through antiinflammatory and lipid-lowering mechanisms in patients with coronary heart disease.
      ChinaCHD (n = 50)58.3 (5.7)661200 mg RYR (MonK 10 mg) vs. placebo6Double-blindEndothelial function and inflammation (hs-CRP)WPU Biotech Co, Ltd, China.
      Abbreviations: DL = dyslipidemia. CHD = coronary heart disease. DM2 = type 2 diabetes. RYR = Red yeast rice extract. MonK = Monacolin K. TCM = traditional Chinese medicine.
      a Number between brackets indicates the timepoint which was included in lipid analysis.
      b 3rd intervention group in these studies was not included in this systematic review. WPU = WBL Peking University Biotech, Ltd, China.
      c Pharmanex is a manufacturer of RYR. CAM = complementary and alternative medicine.
      Dose of RYR varied from 1200 mg to 4800 mg per day, containing 4.8 mg–24 mg MonK. Four studies reported the constituents of RYR including different monacolin subtypes and possible toxins. In these studies, the MonK subtype was 57–75% of the total monacolin content. Six studies reported the MonK content without further specification and other studies referred to the RYR manufacturer. Citrinin concentration was determined in 3 studies and varied from <0.05 mg to <18 mg per daily dose.

      3.1 Quality of evidence

      The majority of study reports did not contain sufficient information to judge all potential sources of bias. Risk of bias was evident in the assessment of adverse reactions which could have led to an underestimation of the incidence of adverse reactions in the RYR group (Fig. S1).

      3.1.1 Quality of safety assessment in included studies

      Liver abnormalities and kidney injury were assessed in 14 and 8 studies respectively. Seven studies reported the incidence of intervention-associated increased liver transaminases whereas 5 studies reported average levels of transaminases. Three studies did not report numerical outcomes although liver transaminases were assessed. Three studies reported incident cases of kidney injury and 2 studies reported average creatinine before and after treatment. Four studies reported no numerical outcomes for kidney injury although it was assessed. All but 1 study did not report cut-off values for laboratory parameters of kidney or liver injury [
      • Lin C.-C.
      • Li T.-C.
      • Lai M.-M.
      Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia.
      ].
      Muscle symptoms were assessed in 10 studies through CK and 2 studies also included anticipated symptom assessment through a validated questionnaire. Nine studies reported incident cases of muscle symptoms and 2 studies reported average CK before and after treatment.
      Seventeen studies assessed other adverse reactions. Three studies roughly described the way symptoms were assessed and this was not described in all other studies. Four studies reported all adverse reactions and three studies only reported adverse reactions that led to discontinuation of study treatment. Two studies did not present numerical data and in 8 studies criteria for reporting events were not specified. An overview on the methodology and reporting of safety outcomes is given in Table 2.
      Table 2Method and reporting of safety assessment in included studies. Method of evaluation and way of reporting for the 3 safety outcomes of interest and other adverse reactions and patient reported symptoms. All evaluations were done at baseline and end of study unless reported otherwise.
      StudyKidney diseaseLiver diseaseMuscle symptomsPatient reported symptoms
      BeckerMethodNot reported/not assessedAST and ALTCK, muscle symptoms (Brief Pain Inventory, validated) and muscle weakness (dynamometry, validated).Not reported
      ReportingNoneMeans (BL, 12 wk, EOS).Means (BL, 12 wk, EOS). Incident cases of intolerable persistent myalgia.Incident cases
      BogsrudMethodCreatinine and BUN (BL, 6 wk, EOS)AST, ALT, GGT (BL, 6 wk, EOS)CK (BL, 6 wk, EOS). No anticipated symptom assessment.Not reported
      ReportingNo numerical dataNo numerical dataNo numerical data/1incident caseIncident cases, specified by group and type.
      CCSPSMethodBUN and Creatinine every 6 monthsALT and AST every 6 monthsCK every 6 months. No anticipated symptom assessment.Assessed, not specified. “Symptoms were registered.”
      ReportingIncident cases (subgroup, n = 2704
      • Li J.-J.
      • Lu Z.-L.
      • Kou W.-R.
      • et al.
      Impact of Xuezhikang on coronary events in hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).
      )
      See column 'kidney disease'See column 'kidney disease'See column 'kidney disease'
      FanMethodNot reported/not assessedAST, ALT, GGT, cholinesterase.CK. No anticipated symptom assessment.Assessed, not specified.
      ReportingNoneMeans (BL, 12 wk, EOS).Means in treatment group (BL, 12 wk, EOS).1 incident case (no other obvious AEs were found)
      GongMethodRenal function every 3 monthsLiver function every 3 monthsNot reported/not assessedAssessed every 6 months, not specified.
      ReportingNo numerical dataNo numerical dataNoneIncident cases (few)
      HalbertMethodNot reported/not assessedAssessment of liver-associated enzymesCK, muscle symptoms (Brief Pain Inventory, validated) and muscle weakness (dynamometry, validated).Not reported
      ReportingNoneOutcome were assessed in t-test but numerical result is not reportedIncidence of different grades of myalgia. Means of muscle strength.Incidence of adverse reactions categorized by type, per treatment group.
      HeberMethodBUNALT, AST, GGT, LDHNot reported/not assessedNot reported
      ReportingMeans and incident casesMeans and incident casesNoneIncident cases
      HuMethodNot reported/not assessedNot reported/not assessedCK, no anticipated symptom assessment.Not reported
      ReportingNoneNoneIncident casesNone
      HuangMethodNot reported/not assessedNot reportedNot reported/not assessedNot reported
      ReportingNoneIncident casesNoneIncident cases
      JianMethodNot reported/not assessedNot reported/not assessedNot reported/not assessedNot reported/not assessed
      ReportingNoneNoneNoneNone
      KeithleyMethodNot reported/not assessedAlbumin, total and direct bilirubin, ALP, AST, ALT (BL, 2 wk, EOS).Not reported/not assessedActive questioning on any symptoms (2 wk, EOS).
      ReportingNoneChange in means from baseline to EOS.NoneNo numerical data
      KouMethodCreatinine and BUN (BL, 4 wk, EOS).Liver palpation, ALTCK (BL, 4 wk, EOS). No anticipated symptom assessment.Not reported
      ReportingIncident casesIncident casesIncident casesIncident cases
      LinMethodNot reported/not assessedAST, ALTCK (BL, 4 wk, EOS). No anticipated symptom assessment.Assessment of severity and relation to study agent of any AE
      ReportingNoneIncident casesIncident casesIncident cases
      Liu 2011MethodCreatinine and BUNALTNot reported/not assessedNot reported/not assessed
      ReportingNo numerical dataIncident case (1)NoneIncident cases
      RothMethodNot reported/not assessedALT (BL, 4 and 8 wk, EOS)CK (BL, 4 and 8 wk, EOS). No anticipated symptom assessment.Open-ended questioning on any AE (4 and 8 wk, EOS).
      ReportingNoneIncident casesIncident casesIncident cases
      Wang 1997MethodCreatinine and BUNALTCKAssessed (4 wk, EOS), not specified.
      ReportingNot reportedIncident casesIncident casesIncident cases
      Wang 2004MethodNot reported/not assessedNot reported/not assessedNot reportedNot reported/not assessed
      ReportingNoneNoneIncident casesIncident cases
      WuMethodNot reported/not assessedNot reported/not assessedNot reported/not assessedNot reported/not assessed
      ReportingNoneNoneNoneIncident cases
      YangMethodCreatinine and BUNAST, ALTNot reported/not assessedAssessed, not specified.
      ReportingMeans (BL, 4 and 12 wk, EOS).Means (BL, 4 and 12 wk, EOS).NoneNo numerical data
      ZhaoMethodNot reported/not assessedNot reported/not assessedNot reported/not assessedNot reported/not assessed
      ReportingNoneNoneNoneNone
      Abbreviations: BL = baseline. wk = weeks. EOS = end of study. AE = adverse event. ALP = alkaline phosphatase. ALT = alanine transaminase. AST = aspartate transaminase. BUN = blood urea nitrogen. CK = creatine kinase. GGT = gamma glutamyl transpeptidase. LDH = lactate dehydrogenase.

      3.2 Efficacy of RYR for improvement of lipid profile

      The effect of RYR on lipid profile was moderate to considerable heterogeneous. We performed sensitivity analyses on studies with different doses of RYR and MonK, different durations of follow-up and different ethnic study populations. Heterogeneity remained and we performed all meta-analyses on lipid profile by random-effect analysis.

      3.2.1 RYR versus inactive control treatment

      RYR was more effective for reduction of LDL cholesterol compared to placebo (Fig. 2). LDL decrease in the population treated with RYR varied from 0.5 to 1.59 mmol/L with a pooled estimate of −1.02 mmol/L [−1.20; −0.83] compared to placebo. Regarding changes in other lipid parameters, RYR resulted in a stronger reduction of total cholesterol compared with placebo (−1.0 mmol/L [−1.23; −0.77]). There was a small increase in high density lipoprotein (HDL) cholesterol of 0.07 mmol/L [0.03; 0.11] and a 0.26 mmol/L [−0.35; −0.17] decrease in triglycerides (Figs. S2–S4).
      Figure thumbnail gr2
      Fig. 2Effect of red yeast rice (RYR) extract compared to inactive control treatment, statin therapy and non-statin active control treatment on change in LDL cholesterol from baseline.

      3.2.2 RYR versus regular statin therapy

      Three studies comparing RYR with MonK 10 mg daily to regular statin therapy (pravastatin 40 mg, simvastatin 10 mg, lovastatin 20 mg) did not show a significant difference between the interventions. The mean difference of change scores were 0.03 mmol/L [−0.36; 0.41] for LDL (Fig. 2) and −0.05 mmol/L [−0.28; 0.18] for total cholesterol (Fig. S2).

      3.2.3 RYR versus non-statin active control treatment

      LDL reduction in RYR groups was 0.52 mmol/L [−0.9; −0.14] higher than the control group (Fig. 2). One study compared RYR to gemfibrozil and 3 other studies treated the control group with herbal agents. In the study comparing treatment with RYR to gemfibrozil, the gemfibrozil group had a greater improvement of triglycerides and RYR was beneficial on all other lipid parameters (Fig. S4).

      3.3 Safety of red yeast rice extract

      3.3.1 Kidney injury and elevation of liver transaminases

      The incidence of cases of liver abnormalities and kidney injury was between 0 and 5% in both RYR and control groups. We did not observe a significant effect of RYR on the risk of liver abnormalities or kidney injury (Figs. S5–S6). Average level of liver transaminases in the RYR group decreased in all 5 studies in which it was reported.

      3.3.2 Muscle symptoms

      The reported incidence of developing muscle symptoms was 0–23.8% for the population treated with RYR, versus 0–36% in the control groups. Rhabdomyolysis or myopathy with increased CK > 10 times upper limit of normal was not observed in any of the studies. The risk difference between RYR and control groups for myalgia was 0.00 [−0.01, 0.01] (Fig. S7).
      One study compared myopathies between subjects treated with RYR versus pravastatin in a population selected for its increased risk on developing adverse reactions [
      • Halbert S.C.
      • French B.
      • Gordon R.Y.
      • et al.
      Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance.
      ]. In this study the risk for developing muscle symptoms in the RYR group was 0.13 [−0.40; 0.15) lower compared to patients in the pravastatin group.

      3.3.3 Patient reported symptoms

      Other adverse reactions and patient reported symptoms were classified by organ system (Table 3). The overview is limited by the fact that in most studies the methods for evaluating, defining and reporting adverse reactions were unclear and the risk of bias was often high. Four studies that reported all adverse reactions found an incidence of 30–76% of mild adverse reactions. In the other studies for which the criterion was unclear only 0–9% of subjects experienced an adverse reaction. Patients mainly complained of gastro-intestinal and musculoskeletal symptoms. Besides, patients on RYR and controls reported nonspecific complaints (22/199 vs. 33/199).
      Table 3Adverse reactions and patient reported symptoms. Absolute incidence of categorized adverse reactions in RYR/control group.*hypertensive subgroup (n = 2704, results were not reported on full population).
      RYR/control

      SumBeckerBogsrudCCSPS*FanGongHalbertHeberHuangKouLinLiuRothWang 1997Wang 2004Wu
      Gastro-intestinalDiarrhea7/11/02/00/01/00/02/00/00/00/00/10/00/00/01/00/0
      GI discomfort42/190/01/110/30/03/13/00/00/22/10/11/015/105/02/00/0
      Other GI2/00/01/00/00/00/00/00/00/00/00/00/00/00/00/01/0
      Subtotal51/201/04/110/31/03/15/00/00/22/10/21/015/105/03/01/0
      Musculo-skeletalArthralgia14/70/00/00/00/00/01/10/00/00/00/00/00/00/00/00/0
      Weakness1/20/00/00/00/00/01/20/00/00/00/00/00/00/00/00/0
      Subtotal15/90/01/00/00/00/07/91/00/00/00/00/00/06/00/00/0
      LaboratoryLDH1/00/00/00/00/00/00/00/00/00/01/00/00/00/00/00/0
      Leukocytosis2/00/00/00/00/00/00/00/00/00/00/00/02/00/00/00/0
      Leukopenia0/10/00/00/00/00/00/00/00/00/00/10/00/00/00/00/0
      Hyperglycemia0/10/00/00/00/00/00/00/00/00/00/00/00/00/00/00/1
      Subtotal3/20/00/00/00/00/00/00/00/00/01/10/02/00/00/00/1
      InfectiousInfluenza1/00/01/00/00/00/00/00/00/00/00/00/00/00/00/00/0
      Urinary tract9/40/00/00/00/00/00/00/00/00/00/00/09/40/00/00/0
      Pneumonia0/10/00/00/00/00/00/00/10/00/00/00/00/00/00/00/0
      Subtotal10/50/01/00/00/00/00/00/10/00/00/00/09/40/00/00/0
      ImmunologicRash0/20/00/00/00/00/10/00/10/00/00/00/00/00/00/00/0
      Alopecia2/00/00/00/00/00/02/00/00/00/00/00/00/00/00/00/0
      Allergic5/20/00/03/20/00/00/00/00/00/00/00/00/00/00/02/0
      Subtotal7/40/00/03/20/00/12/00/10/00/00/00/00/00/00/02/0
      GeneralDizziness2/21/00/00/00/00/00/20/00/00/00/00/00/01/00/00/0
      Malaise1/00/01/00/00/00/00/00/00/00/00/00/00/00/00/00/0
      Fatigue3/40/00/00/00/00/00/30/00/03/10/00/00/00/00/00/0
      Subtotal6/61/01/00/00/00/00/50/00/03/10/00/00/01/00/00/0
      CNSHeadache5/50/00/00/00/00/02/20/10/00/00/00/03/20/00/00/0
      CardiovascularQT prolongation0/10/00/00/00/00/00/00/00/10/00/00/00/00/00/00/0
      Uncontrolled hypertension0/20/00/00/00/00/00/00/00/00/00/00/00/00/00/00/2
      Edema2/00/00/02/00/00/00/00/00/00/00/00/00/00/00/00/0
      Erectile dysfunction0/30/00/00/30/00/00/00/00/00/00/00/00/00/00/00/0
      Subtotal2/60/00/02/30/00/00/00/00/10/00/00/00/00/00/00/2
      MiscellaneousBreast cancer1/00/00/00/00/00/00/00/00/00/01/00/00/00/00/00/0
      Unspecified22/290/00/03/30/00/00/00/00/00/017/250/02/10/00/00/0
      Subtotal23/290/00/03/30/00/00/00/00/00/018/250/02/10/00/00/0
      The values in bold denote the total amount of cases for each adverse event (as opposed to the results in the individual studies).

      4. Discussion

      Our study shows that RYR reduces LDL cholesterol and suggests that the rate and type of adverse reactions are mild. Patients with an increased risk of adverse reactions on statins sometimes do tolerate RYR. However, the majority of studies did not contain enough data on safety.
      The LDL lowering effect of 1.02 mmol/L compared to placebo is relevant since in a recent meta-analysis, a corresponding cardiovascular risk reduction of 15–20 % was described [
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ]. Especially for statin-intolerant patients, where alternatives for regular statin therapy to achieve LDL reduction are scarce, RYR can contribute to significant reduction in cardiovascular events.
      In our analysis the average dose of MonK was 10.8 mg per day. Based on studies in which all monacolin subtypes were analyzed, the total monacolin content is expected to be 6.1–8.1 mg higher. It is likely that some of these other monacolin subtypes contribute to HMG-CoA reductase inhibition and reduction of LDL cholesterol, although unknown to which extent. Other studies evaluating the efficacy of 10–20 mg of lovastatin resulted in an equivalent LDL reduction of 1.01–1.8 mmol/L [
      • Jones P.
      • Kafonek S.
      • Laurora I.
      • Hunninghake D.
      Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study).
      ].
      Sometimes it is said that other non-statin components such as unsaturated fatty acids might explain the LDL lowering effect of RYR [
      • Ma J.
      • Li Y.
      • Ye Q.
      • et al.
      Constituents of red yeast rice, a traditional Chinese food and medicine.
      ]. However, when taking into account the total monacolin content – which is probably underestimated when looking at MonK only – RYR produces the same magnitude of LDL reduction compared to regular statin therapy. RYR consists of carbohydrates (75%), monacolins (10–15%), fatty acids (1.5%), pigments (including citrinin) and trace elements [
      • Ma J.
      • Li Y.
      • Ye Q.
      • et al.
      Constituents of red yeast rice, a traditional Chinese food and medicine.
      ]. In our conviction, it is unlikely that non-statin RYR components in the quantity present, exert a significant effect on LDL cholesterol or cardiovascular health via other pathways.
      The low incidence of adverse reactions that we observed is probably an underestimation of the true incidence, due to a poor methodology of safety evaluation in the majority of studies. Furthermore, most studies were not endowed to make a judgment on the occurrence of adverse reactions in the general population: by excluding elderly people and various comorbidities, patients vulnerable for adverse reactions were systematically excluded. However, incidence of liver and kidney injury was assessed in 7 and 3 studies respectively and was similar to control groups. Two studies defined and assessed muscle symptoms clearly and found an acceptable rate of adverse reactions in statin intolerant patients [
      • Becker D.J.
      • Gordon R.Y.
      • Halbert S.C.
      • French B.
      • Morris P.B.
      • Rader D.J.
      Red yeast Rice for dyslipidemia in statin-intolerant patients.
      ,
      • Halbert S.C.
      • French B.
      • Gordon R.Y.
      • et al.
      Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance.
      ]. Tolerance of RYR in these patients might be explained through a lower statin content of RYR. One study compared RYR containing 9.96 mg lovastatin to pravastatin 40 mg daily. While the correlation between statin dose and LDL reduction is generally low, adverse effects are more prevalent at higher statin doses [
      • Stroes E.S.
      • Thompson P.D.
      • Corsini A.
      • et al.
      Clinical update statin-associated muscle symptoms: impact on statin therapy — European atherosclerosis society consensus panel statement on assessment, Aetiology and management.
      ].
      Our results do not suggest that RYR results in different adverse reactions than the usual statin-associated adverse reactions. This conclusion is supported by case reports on RYR related adverse reactions, which describe mainly cases of usual statin-related adverse reactions. We investigated potential harm through the mycotoxin citrinin but we did not find an increased risk of kidney or liver injury. However, since RYR is sold as a dietary supplement, a registration study with thorough analysis of all possible adverse reactions has never been performed. For conventional statin therapy, incidence of muscle symptoms, liver and kidney damage has been analyzed over 45,000–290,000 person years [
      • Bangalore S.
      • Fayyad R.
      • Hovingh G.K.
      • et al.
      Statin and the risk of renal-related serious adverse events: analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and other placebo-controlled trials.
      ,
      • Nichols G.A.
      • Koro C.E.
      Does statin therapy initiation increase the risk for myopathy? an observational study of 32,225 diabetic and nondiabetic patients.
      ,
      • Pfeffer M.A.
      • Keech A.
      • Sacks F.M.
      • et al.
      Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project.
      ].
      Besides efficacy and safety, suitability of RYR in clinical practice is limited by financial and legal issues. RYR containing 10 mg MonK daily, is 3–12 times more expensive compared to regular brand HMG-CoA reductase inhibitors [
      • CVZ (Health Care insurance board) Medicijnkosten
      ]. Since RYR is a food supplement, there are no uniform standards for its production and monacolin content. The US Food and Drug Administration prohibits RYR containing MonK but as RYR supplements are not registered this prohibition is not maintained adequately [
      • Childress L.
      • Gay A.
      • Zargar A.
      • Ito M.K.
      Review of red yeast rice content and current food and drug administration oversight.
      ]. European regulation is limited to restrictions on health benefits that may be claimed through using food supplements. Within this framework, the European Food Safety Authority investigated and confirmed a beneficial effect of MonK on lipid spectrum [
      • Agostoni C.
      • Bresson J.-L.
      • Fairweather-Tait S.
      • et al.
      Scientific opinion on the substantiation of health claims related to monacolin K from red yeast rice and maintenance of normal blood LDL-cholesterol concentrations (ID 1648, 1700) pursuant to article 13(1).
      ]. However, since the monacolin concentration in over-the-counter available RYR is often uncertain, this claim may not be extrapolated to all RYR products.
      A strength of our study is the detailed analysis of adverse reactions that could be attributed to RYR. RYR has been subject to meta-analysis before and these analyses resulted in comparable effects on lipid profile but none of the studies thoroughly assessed the safety of RYR [
      • Liu J.
      • Zhang J.
      • Shi Y.
      • Grimsgaard S.
      • Alraek T.
      • Fønnebø V.
      Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials.
      ,
      • Li Y.
      • Jiang L.
      • Jia Z.
      • et al.
      A meta-analysis of red yeast rice: an effective and relatively safe alternative approach for dyslipidemia.
      ]. A weakness of this meta-analysis were the differences in design and primary outcomes of the studies analyzed. The differences in the objectives of included studies led to differences in their designs, and probably resulted in the high level of heterogeneity for our primary outcome.

      5. Conclusion

      In conclusion, RYR exerts a 1.02 mmol/L reduction of low density lipoprotein cholesterol. The beneficial effect was achieved with 10.4 mg (±4.5) MonK daily. Although safety analysis of RYR was not a priority of the majority of studies analyzed, the incidence of kidney injury (evaluated in 2895 subjects), liver injury (evaluated in 2895 patients) and muscle symptoms (evaluated thoroughly in 105 patients) was found to be an acceptable rate.
      To determine the suitability of RYR in clinical practice, monitoring of adverse reactions should become a priority of future trials which need to include patients at risk for statin intolerance. Only when the mild profile of adverse reactions can be affirmed, RYR might be a safe and effective treatment option for dyslipidemia and cardiovascular risk reduction.

      Contributors

      • -
        M.C. Gerards wrote the research protocol and was advised by V.E.A. Gerdes.
      • -
        M.C. Gerards and C.H.W. Koks selected and reviewed the studies in English.
      • -
        M.C. Gerards, Huixin Yu and Ruben Terlou reviewed the studies in Chinese.
      • -
        V.E.A. Gerdes was third reviewer in cases of disagreements.
      • -
        M.C. Gerards performed the analyses and wrote the manuscript, and was advised in this process by C.H.W. Koks and V.E.A. Gerdes.

      Competing interests

      None.

      Funding

      We did not request for, or receive funding for this research.

      Acknowledgments

      We thank Dr. M.P. Bogsrud for his efforts to supply missing data. We thank the statistics helpdesk of the Amsterdam Medical Centre for their advice.

      Appendix A. Supplementary data

      The following is the supplementary data related to this article:

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