Systematic review of red yeast rice compared with simvastatin in dyslipidaemia

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1 Journal of Clinical Pharmacy and Therapeutics, 2016 doi: /jcpt Review Article Systematic review of red yeast rice compared with simvastatin in dyslipidaemia Yi Chin Ong BPharm and Zoriah Aziz PhD Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia Received 26 January 2016, Accepted 10 February 2016 Keywords: dyslipidaemia, red yeast rice, simvastatin, Systematic Review, xuezhikang, zhibutuo SUMMARY What is known and objective: Red yeast rice is believed to be a useful alternative in the management of dyslipidaemia. However, the comparative effectiveness of red yeast rice and simvastatin for the management of dyslipidaemia is unknown. This review assesses the efficacy and safety of red yeast rice versus simvastatin in dyslipidaemia. Methods: Electronic databases were searched up to May 2015 without publication date and language restriction. The Cochrane Risk of Bias Assessment Tool was used to assess the quality of included trials. Changes in total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides were examined. Results and discussion: Ten randomized controlled trials involving 905 Chinese subjects with dyslipidaemia were systematically reviewed. Overall, red yeast rice and simvastatin did not show any statistically significant difference in any of the outcomes examined. What is new and conclusion: A number of small trials show that red yeast rice and simvastatin produce similar lipid-lowering effects. Larger trials with increased methodological rigour and trials with clinical outcomes are necessary for more robust inferences. WHAT IS KNOWN AND OBJECTIVE Worldwide, cardiovascular diseases are the leading causes of death and disability. Dyslipidaemia is one of the risk factors for cardiovascular diseases. 1 For the prevention of cardiovascular diseases and management of dyslipidaemia, international guidelines recommend 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibitors (statins) as first-line pharmacotherapy. 2,3 Statins were found to reduce all-cause mortality by 16%, and combined fatal and non-fatal cardiovascular endpoints by 30%. 4 However, statins have been associated with musclerelated adverse events such as myositis, myopathy, myalgia and rhabdomyolysis. 5 Between years , there was an estimated annual incidence of approximately 689 per million per year for statin-induced myalgia or myopathy. 6 Myopathy, a more common adverse event reported in real-life settings than in clinical trials, may result in poor adherence to or Correspondence: Z. Aziz, Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia. Tel.: ; fax: ; zoriah@um.edu.my Both authors contributed equally to this work. discontinuation of statin therapy. 7 Good medication adherence is important in the prevention of cardiovascular disease. Patients who were compliant had significantly fewer hospitalizations and lower total direct medical costs, excluding the cost of statin therapy. 8 In addition, good statin adherence was associated with a reduced incidence of major coronary events in those with and without prior coronary heart disease. 9 Recently, red yeast rice, or also known as xuezhikang 10,11 or zhibutuo 11 in Chinese, has been in use as an option in managing dyslipidaemia. Red yeast rice is rice fermented with Monascus purpureus (red yeast). Through this fermentation, monacolin compounds are formed. 12 In a reversible pathway, monacolin compounds inhibit the enzyme HMG-CoA reductase, which catalyses the conversion of HMG-CoA to mevalonate, an early precursor of cholesterol. 12 Among the monacolin compounds, monacolin K is found to be most abundant and structurally identical to lovastatin. 12 Several trials have shown that red yeast rice is effective in lowering lipids, including low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). 10,13 17 Clinical trials have reported no significant serious adverse events, but minor events include heartburn 10, flatulence 10,16, dizziness 10,13, myalgia 13 and loose stools. 13 Although previous reviews 11,18 23 have reported beneficial effects of red yeast rice on lipid modification, none has focused on comparing the effects of red yeast rice with simvastatin, which is one of the most prescribed statins. 24 Our review aimed to examine the efficacy and safety of red yeast rice relative to simvastatin. METHODS Search strategy The Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE â ), Excerpta Medica database (EMBASE â ), PubMed â, ScienceDirectAllied â, Complementary Medicine Database (AMED), Cumulative Index to Nursing and Allied Health Literature (CINAHL), BIOSIS â and Food Science and Technology Abstracts were searched from their earliest publication dates until May Potential trials were identified using search terms (randomi?ed AND control* AND trial*) OR (control* AND clinical AND trial) OR (random?ed) OR (randomly) OR (trial) OR (groups) OR (case*) OR (cohort*) AND (Monascus OR monascus purpureus OR (M. purpureus) OR red yeast rice OR xuezhikang OR zhibutuo OR cholestin OR red rice koji? OR red fermented rice OR red koji? rice OR anka? OR koji?) AND (hypercholester?emia* OR 2016 John Wiley & Sons Ltd 1

2 hypercholesterol?emia* OR hyperlipid?emia* OR hyperlipoprotein?emia* OR dylipid?emia OR cholesterol OR triglycerides OR lipid* OR lipoprotein* OR TC OR LDL OR HDL OR TG). Only randomized controlled trials and trials involving single preparation of red yeast rice were included. Participant demographics were restricted to adults. Other resources such as the ClinicalTrials.gov and Current Controlled Trials were also searched to identify additional trials. The reference lists of relevant trials and reviews were screened for suitable trials. Criteria for considering trials for this review Selection of trials. We included only randomized controlled trials comparing the use of all forms of single-preparation red yeast rice with simvastatin in subjects with primary hyperlipidaemia. Subjects were treated for at least 2 weeks. Trials published in any language were eligible for inclusion. Included trials have subjects who were as follows: (a) adult males or females (18 years and older) with (b) total cholesterol (TC) 52 mmol/l or (c) LDL- C 26 mmol/l or (d) TG 23 mmol/l or (e) high-density lipoprotein cholesterol (HDL-C) 10 mmol/l. Any co-intervention to the experimental or control arm(s) was allowed if all arms of the randomized allocation received the same co-intervention. Trials that included lifestyle changes during the course of the trial were included because a combination of lifestyle changes and pharmacotherapy have been recommended for the prevention of cardiovascular diseases. 2,3 We excluded trials with crossover designs and trials that involved subjects taking other medication(s) for hyperlipidaemia during the course of the trial. Data extraction and assessment of risk of bias. Two reviewers independently screened the title or abstract resulted from the searches. Full-text articles were obtained if they appeared to satisfy, or to potentially satisfy, the inclusion criteria. The reviewers independently extracted data and assessed the risk of bias of included trials as recommended in the Cochrane Handbook for Systematic Reviews of Interventions 25. We extracted data on changes in TC, LDL-C, HDL-C and TG compared with simvastatin to determine the efficacy of red yeast rice. Data on adverse events were also collected. Authors of trials were contacted for missing data. Any disagreements at the stages from selecting trials to data extraction and risk of bias assessment were resolved through discussions between the two reviewers. Data analysis. Data were pooled using Review Manager (version 53). Statistical significance was set at P < 005 for all outcomes. The presence of statistical heterogeneity was assessed by using the chi-squared test, and the amount of heterogeneity was estimated using I 2 statistic (which indicates the percentage of variation between trials that is due to heterogeneity rather than chance). A fixed-effect model was used if pooling seemed appropriate in view of clinical and methodological similarities between trials. RESULTS Description of trials Of 5369 articles identified during the initial search, after screening the titles and abstracts and removing the duplicates, 18 full articles Fig. 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses) flow-chart of trial selection. 2

3 Table 1. Characteristics of included trials and summary of outcomes reported Trial Total participants [intervention/ control(s)] Intervention (route, frequency, total dose/day) Control(s) [route, frequency, total dose/day] Chen and Liu 2002 Deng et al [34/31] Xuezhikang [oral, 3 times a day, 36 g/day] 100 [45/55] Xuezhikang [oral, 12 g/day] Ding and Zhou [40/40] Xuezhikang [oral, 12 g/day] Hua [70/66] Xuezhikang [oral, 2 times a day, 12 g/day] Li [40/40] Xuezhikang [oral, 10 g/day] Li et al [20/20/20] Xuezhikang [oral, 12 g/day] Pravastatin 20 mg/day] Lu and Huo [15/13] Xuezhikang [oral, daily, 12 g/day] [oral, 2 times a day, 20 mg/day Total trial duration (weeks) Inclusion criteria Exclusion criteria Adverse events 4 TC > 56 mmol/l Secondary hyperlipidaemia Upset stomach reported in both xuezhikang (29%) and simvastatin (32%) groups 8 TC 620 mmol/l and TG 170 mmol/l 4 TG > 52 mmol/l, LDL-C > 415 mmol/l 8 TC > 52 mmol/l, LDL-C > 312 mmol/l 8 TC 572 mmol/ L, LDL-C 364 mmol/l, 170 mmol/l TG 452 mmol/l 12 Without CHD risk factors, TC > 572 mmol/l, LDL > 364 mmol/l; with CHD risk factors, TC 572 mmol/l, LDL 312 mmol/l; with CHD, TC 468 mmol/ L, LDL 260 mmol/l 12 TC > 230 mg/dl or, TC > 230 mg/dl and TG > 200 mg/dl Secondary hyperlipidaemia, dysfunction of liver and kidney and dysfunction of blood coagulation Not specified Not reported Familial hyperlipidaemia, endocrine metabolic disorders and chronic liver, kidney disease, no lipid influential drug Hyperlipidaemia caused by liver and kidney disease and endocrine disorders (i) Having been diagnosed with acute myocardial infarction, cerebrovascular accident, major surgery within 3 months; (ii) severe liver and renal disease; (iii) uncontrolled diabetes; (iv) hypothyroidism; (v) secondary hyperlipidaemia caused by the combination of drugs, such as contraceptive preparations and steroid; (vi) pregnancy, lactation and allergic constitution Patients with liver, kidney and thyroid disease No adverse event observed in xuezhikang group, whereas ALT increased was reported in simvastatin (19%) group Nausea, mild abdominal distention and AST increased reported in both xuezhikang (57%) and simvastatin (60%) groups, whereas CPK increased was reported only in simvastatin (15%) group ALT increased and abdominal distention were reported in both xuezhikang (10%) and simvastatin (175%) groups, whereas dry mouth was reported only in simvastatin (5%) group No adverse event observed in xuezhikang group, whereas CPK increased was reported in simvastatin (5%) group and ALT increased was reported in pravastatin (5%) group Not reported (continued) 3

4 Table 1. (continued) Total trial duration (weeks) Inclusion criteria Exclusion criteria Adverse events Control(s) [route, frequency, total dose/day] Intervention (route, frequency, total dose/day) Total participants [intervention/ control(s)] Trial Gastrointestinal tract symptoms and ALT increased reported in both xuezhikang (161%) and simvastatin (188%) groups Serious cardiovascular disease, any secondary hyperlipidaemia and hyperlipidaemia caused by drug 8 TC > 62 mmol/l, TG > 22 mmol/l Qi et al [112/112] Xuezhikang [oral, 24 g/day] Mild symptoms of nausea and anorexia in both xuezhikang (36%) and simvastatin (65%) groups Familial hyperlipidaemia, endocrine and metabolic disorders, chronic liver and kidney disease, the use of drugs that can affect lipids 8 TC > 52 mmol/ L, LDL-C > 312 mmol/l 20 mg/day] Quan et al [56/46] Xuezhikang [oral, 12 g/day] Liver, renal and thyroid disease No adverse events observed in both xuezhikang and simvastatin groups 8 TC > 60 mmol/l or TC > 60 mmol/l and TG > 226 mmol/l 20 mg/day] 30 [16/14] Xuezhikang [oral, 12 g/day] Wang and Hu 2004 TC, total cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; CHD, coronary heart disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase. were retrieved (Fig 1). Only 10 trials were eligible and included in the review. Eight articles were excluded from this review. Five 26,27,29,30,32 trials did not meet the inclusion criteria, two trials 31,33 did not publish full articles, and one trial 28 had no endpoint data, and the author was not contactable to request for further details. The characteristics of each included trial are shown in Table 1. All trials were randomized controlled involving single preparations of red yeast rice with simvastatin as comparator except for one trial 42 whereby both simvastatin and pravastatin were comparators. The total daily dose of red yeast rice used in the trials ranged from 12 to36 g, whereas simvastatin total daily dose was either 10 mg or 20 mg. The ten trials included 905 Chinese subjects with sample sizes ranging from 28 to 224 subjects. Trial duration ranged from four to 12 weeks. All trials were conducted in one centre. All centres were located in China except for one trial 41 whereby the country was not specified. Risk of bias assessment The risk of bias for each included trial is tabulated and summarized in Fig 2 and Fig 3. All trials reported random allocation of trial participants, but no trials adequately described sequence generation and allocation concealment. The blinding procedures of the participants and outcome assessors could not be determined in all trials. The domain of incomplete outcome data was adequately addressed in seven trials 34,36,37, Two trials 38,39 had missing outcome data and no reasons were given, and there was inadequate information to judge the attrition bias for one trial 35. Three trials 34,40,41 were deemed to be free of selective reporting. None of the trials protocol was available. The baseline for all trials between the two groups was balanced. The effect of sponsorship on all trials was unclear. Overall, all of the trials had unclear risk of bias for random sequence generation, allocation concealment, blinding procedures of the participants and outcome assessors and receipt of financial support from pharmaceutical companies. Most trials had low risk of bias for addressing incomplete outcome data (70%) and high risk of bias for selective reporting (70%). Effects of intervention TC. All trials reported TC as an outcome measure. Fig 4 shows no significant difference between red yeast rice and simvastatin in TC [mean difference = 005 (95% CI: 017, 008) mmol/l; P = 044]. LDL-C. The meta-analysis of ten trials (Fig 5) shows that there is no significant difference between red yeast rice and simvastatin in improving LDL-C, even though two trials 35,42 showed a significant difference between the treatments favouring red yeast rice [mean difference = 097 (95% CI: 152, 042) mmol/l, P = 00005; mean difference = 052 (95% CI: 098, 006) mmol/l, P = 00005]. HDL-C. All trials except one 38 reported on HDL-C. The metaanalysis shows no significant difference in HDL-C between red yeast rice and simvastatin (Fig 6). However, two trials 35,36 showed a significant difference between the treatments favouring simvastatin [mean difference = 020 (95% CI: 010, 030) mmol/l, P < 00001; mean difference = 031 (95% CI: 011, 051) mmol/l, P = 0003]. 4

5 Fig. 2. Methodological quality summary: review authors judgments about each methodological quality item for each included trial. Fig. 3. Methodological quality graph: Judgments of review authors on each methodological quality item presented as percentages across all included trials. TG. Two trials 35,40 did not report on TG as an outcome measure. The meta-analysis of all other trials shows that there is no significant difference between red yeast rice and simvastatin in TG [mean difference = 003 (95% CI: 015, 008) mmol/l, P = 057] (Fig 7). Adverse events. Except for two trials 35,43, all other trials provided information on adverse events. There were no serious adverse events reported. Two trials 36,42 did not observe any adverse event in the red yeast rice group, whereas one trial 41 reported no adverse 5

6 Fig. 4. Forest plot of comparisons of xuezhikang versus simvastatin (outcome: TC). Fig. 5. Forest plot of comparisons of xuezhikang versus simvastatin (outcome: LDL-C). 6

7 Fig. 6. Forest plot of comparisons of xuezhikang versus simvastatin (outcome: HDL-C). Fig. 7. Forest plot of comparisons of xuezhikang versus simvastatin (outcome: TG). 7

8 event in both treatment groups. The same adverse events reported between the red yeast rice and simvastatin groups were upset stomach 34, nausea 37,40, abdominal distention 37,38, AST increased 37, ALT increased 38,39 and anorexia 40. One trial 39 reported gastrointestinal symptoms as an adverse event in both treatment groups with no further description of symptoms. Dry mouth 38 and CPK increased 37,42 were reported only in the simvastatin group. for most domains of the risk of bias. We found that several trials did not include important methodological information such as randomization method, allocation concealment and blinding. With inadequate allocation concealment, evidences have shown that assignment between experimental and control groups can be manipulated This may result in better treatment outcome within the experimental arm. 51 DISCUSSION This systematic review assessed the efficacy and safety of red yeast rice versus simvastatin in the management of dyslipidaemia. The evidence suggests that red yeast rice and simvastatin have similar effects in reducing TC, LDL and TG and increasing HDL. This is the first systematic review that specifically compared the usage of red yeast rice with simvastatin in dyslipidaemia. Of two earlier systematic reviews 11,20, one 20 did not specifically examine red yeast rice, but included other Chinese herbal medicines in the experimental arm. An earlier systematic review 11 focused on red yeast rice, but included trials with other comparators. Monacolin K in red yeast rice is structurally identical to lovastatin 12, and because lovastatin is structurally similar to simvastatin 44, we had expected red yeast rice to have similar efficacy to simvastatin. With similarities in chemical, pharmacokinetic and pharmacodynamic properties between lovastatin and simvastatin 44,45, we had also expected the effects of red yeast rice and simvastatin to be similar. As trials 46,47 have shown no significant difference in efficacy and tolerability for the treatment of dyslipidaemia between lovastatin and simvastatin, we had expected the same between red yeast rice and simvastatin. However, because the included trials in this review were of low quality, we are unable to conclusively suggest replacing simvastatin with red yeast rice for the management of dyslipidaemia particularly as red yeast rice is not standardized in active drug content. Furthermore, all trial subjects were recruited from Chinese populations. Hence, the results of this review may not be applicable to other populations. Therefore, the beneficial effects of red yeast rice over simvastatin need to be established using trials with larger sample size, diverse population, improved methodology and longer duration of treatment. Adverse events reported in the included trials were mild, but not all included trials reported on adverse events. Quality of the evidence The design, reporting and methodology of all included trials were of low quality. Overall, the included trials have unclear risk of bias Strengths and limitations This systematic review was conducted based on the recommendations of the Cochrane Collaboration for systematic reviews of interventions 25. We have minimized possible publication bias with intensive searching for publications, with no language restriction. We used a computerized search strategy. Authors of relevant trials were contacted for unpublished work and to provide missing information. However, few authors responded and there was still a possibility of missing out unpublished trials with unfavourable results. Results of this systematic review need to be interpreted with caution because of the small number of trials, small number of trial subjects. The lack of robustness means that the comparative effectiveness of red yeast rice and simvastatin is still inadequately well defined. WHAT IS NEW AND CONCLUSION Limited evidence suggests that red yeast rice and simvastatin have similar effects on elevated lipid levels. Therefore, the use of red yeast rice as an alternative to simvastatin is not supported on current evidence except perhaps for those intolerant to the statins. Trials included in this review had small sample sizes and lacked methodological rigour. Future trials should include larger sample sizes and improvement in reporting quality according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement 52. Trials using clinical outcomes are also needed. CONFLICTS OF INTEREST None. SOURCE OF FUNDING This review is funded by University of Malaya, Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia (PG A). REFERENCES 1. Mendis S, Puska P, Norrving B, eds. Global atlas on cardiovascular disease prevention and control. Geneva: World Health Organization, Reiner Z, Catapano AL, De Backer G et al. 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