Efficacy And Safety Of Red Yeast Rice In Regulating Lipids Profiles And Considerations For Developing Guidelines For Management Of Dyslipidemia

Objective:To summarize the current status of evidence of red yeast rice(RYR)single-herb preparations for dyslipidemia,to analyze the efficacy and safety of RYR and its modulation of other cardiovascular disease(CVD)risk factors;to analyze and compare the consistency between clinical practice,research,and guidelines on lipid management,and to discuss the considerations for RYR guidelines on lipid management,thus to provide a reference for optimizing lipid management protocols and RYR application and research.Methods:1 The body of evidence of RYR for dyslipidemiaTen databases[PubMed,Embase,Cochrane Library,Web of Science,China National Knowledge Infrastructure(CNKI),Wanfang Data,Chongqing VIP(CQVIP),China Biomedical Literature Database(SinoMed),Citation Information by National Institute of Informatics(CINII),Japan Science and Technology Agency(J-STAGE)and Technology Agency(J-STAGE)],three clinical research protocol registration platforms[ClinicalTrials.gov,Chinese Clinical Trial Registry(ChiCTR),Australia-New Zealand Clinical Trial Registry(ANZCTR)]and two registries for systematic review protocols[International Perspective Register of Systematic Reviews(PROSPERO)and the International Platform of Registered Systematic Review and Meta-analysis Protocols(INPLASY)]were searched for clinical studies on RYR.Furthermore,included studies were classified according to the evidence pyramid recommended by the State University of New York,USA.The quality of included systematic reviews(SRs)were assessed using the Risk of Bias in Systematic Reviews(ROBIS),A Measurement Tool to Assess Systematic Reviews-2(AMSTAR 2),and Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA).The quality of included randomized controlled trials(RCTs)and Non-RCTs were assessed using The Cochrane Risk of Bias Tool(ROB).The quality of included cohort studies was assessed using the Newcastle-Ottawa Scale(NOS).The quality of included case series studies were assessed using the Institute of Health Economics(IHE)Scale.After data cleaning of the keywords included in the studies,word cloud maps based on Python were drawn to summarize the themes of the studies.2 Bayesian Meta-analysis of RYR for dyslipidemiaThe RCTs included in the first part of the study were selected and data were extracted to analyze the efficacy and safety of different single-herb preparations of RYR for lipid modulation and the effect on other CVD risk factors,with outcomes including:major adverse cardiovascular events(MACE),low density lipoprotein cholesterol(LDL-C),lipoprotein(a)[Lp(a)],high-density lipoprotein cholesterol(HDL-C),total cholesterol(TC),triglyceride(TG),apolipoprotein A1(ApoA1),apolipoprotein B(ApoB),fasting blood glucose(FBG),2 hours postprandial blood glucose(2hPG),glycosylated hemoglobin Alc(HbA1c),systolic blood pressure(SBP),diastolic blood pressure(DBP),and adverse reactions,including muscular drug adverse reactions,liver dysfunctions,and gastrointestinal reactions.Bayesian Meta-analysis was performed using RStudio software based on Markov Chain Monte Carlo(MCMC)algorithm.Efficacy ranking was constructed and ranked by surface under cumulative ranking curve(SUCRA)values.The quality of evidence was assessed using the grading of recommendations assessment development and evaluation(GRADE).3 Analysis of outpatient prescriptions for dyslipidemiaThe data were obtained from the hospital information system(HIS)of a 3A Chinese medical hospital and a 3A general hospital in Beijing,and the outpatient hyperlipidemia prescriptions in 2019 were extracted from all departments of the Chinese hospital and the integrative medicine cardiology department of the general hospital.The clinicians’ prescribing behaviors for the treatment of hyperlipidemia were analyzed.The gender and age distribution of patients,the distribution of co-morbidities,the classification of prescriptions for lipid-lowering drugs and the ranking of dosing frequency(defined daily doses,DDDs),the proportion of prescriptions for Chinese and Western lipid-lowering drugs,and the proportion of prescriptions for RYR were observed.RStudio software was used to analyze the differences in prescriptions between the two hospitals,and stepwise logistic regression was used to analyze the factors influencing the prescription of intensive lipid-lowering therapy and RYR.4 Qualitative study of interviews with experts in the development of lipid management guidelinesBased on the principle of theoretical saturation,one-to-one interviews were conducted with 28 experts involved in developing dyslipidemia and related guidelines,using a semi-structured interview method.The NVivo12 software was used to analyze the data using the three-level coding method based on the Grounded theory.The following data was summarized:characteristics of dyslipidemia patients and prescribing habits in experts’ clinical practice,experts’ experience in using and developing guidelines on lipid management,experts’ views on the diagnosis and management experience of dyslipidemia in concurrent disease and guideline recommendations,views on lipid goals and ASCVD risk stratification,and considerations of Chinese medicine including RYR in guideline recommendations.The results were cross-checked with those of the previous studies to further summarize the gaps between clinical practice,research,and guideline recommendations for lipid management,to discuss the methodological considerations and rationale for the formulation of recommendations for Chinese medicine,including RYR,in the guidelines,and to analyze the factors considered in developing guidelines for lipid management.Results:1 The current status of evidence of RYR for dyslipidemiaA total of 29,262 studies were retrieved from 10 databases and 5 registration platforms,and 909 clinical studies were included after the screening.Of these,864 studies were published in Chinese and 45 in English,of which 18 were published by Chinese researchers,25 by foreign authors,and 2 by Chinese and foreign collaborators.Of these,31 SRs(620 included studies,89,880 cases);414 RCTs(43,100 cases),90 Non-RCTs(9,100 cases),32 cohort studies(3,542 cases)and 342 case series(21,820 cases)were included.The initial publication of the clinical studies was in 1996,with the largest number of studies(88)published in 2000.The RYR preparations include Xuezhikang(XZK),Zhibituo(ZBT),functional RYR,Cholestin,Ankascin,Hypocol,and Artechol.When cleaning the keyword data,it was found that the outcome citation was seriously missing,with 692 studies(76.1%)with missing outcome indicators,146 studies(16.1%)with missing disease citation,188 studies(20.7%)with missing or incorrect intervention citation,and 157 studies(17.3%)with missing control measure citation.The analysis of the subject terms revealed that:fatty liver,diabetes mellitus,obesity and myocardial infarction were the most common co-morbidities in the included population;XZK and ZBT were the main interventions;the outcome indicators were mostly glucolipid metabolism indicators such as LDL-C,HDL-C,TC,TG,and glucose,in addition to blood pressure,blood flow and other outcome indicators related to cardiovascular and cerebrovascular diseases.The results of the AMSTAR 2 assessment suggested that of the 31 SRs,23 were of very low overall quality,seven were of low quality and one was of moderate quality.The results of the ROBIS assessment suggested that the overall risk of bias for SRs was all high.The results of the PRISMA assessment suggested that reporting risk of bias,heterogeneity analysis and sensitivity analysis was incomplete for most SRs.As assessed by the ROB,405 RCTs were judged to be at unclear risk of bias due to lack of random allocation concealment,362 RCTs were judged to be at high risk of implementation bias due to lack of blinding,and 393 RCTs were judged to be as unclear risk of bias due to lack of funding information and conflicts of interest.Most Non-RCTs were judged to be at high risk of implementation bias due to lack of blinding,and funding and conflicts of interest were under-reported.A common problem in cohort studies,as assessed by the NOS,is under-reporting of follow-up,including underreporting of the shedding sample size and the impact on the study.The case series studies were assessed by the IHE Scale to be deficient in terms of whether patients were consecutively included,whether the conditions were consistent,whether the outcome evaluators were blinded,and the reporting of conflicts of interest.2 Bayesian Meta-analysis of RYR for dyslipidemiaA total of 43,100 cases were included in 414 RCTs.Mean age ranged from 25.6 to 85.1 years,with two RCTs(127 cases,0.29%)having subjects with a mean age ≥80 years and 22 RCTs(1,998 cases,4.64%)aged>60 years.The proportion of males was greater than that of females.Forty-seven trials included subjects with combined diabetes(3,968 cases,9.21%),56 trials included subjects with combined coronary heart disease(9,952 cases,23.09%)and ten trials included subjects with combined hypertension(786 cases,1.82%).RYR single-drug preparations involved XZK,ZBT,Hypocol,Cholestin,Ankascin 568plus,and RYR powder.Seven studies reported ASCVD risk stratification,but no interventions by stratification.Most networks were not fully connected and therefore analyzed as sub-networks;MCMC converged well;the overall model fit was adequate,most posterior distributions were symmetric or approximately symmetric,and the prior and posterior distributions were similar.XZK+CHD conventional therapy showed fewer MACE events than CHD conventional therapy(P<0.05,moderate-certainty evidence).Several RYR singledrug preparations showed effects in regulating lipids(LDL-C,HDL-C,TC,TG)and glucose metabolism indicators(FBG)compared with placebo(P<0.05,moderate-very low-certainty evidence).RYR showed lower adverse effects compared to statins(P<0.05,moderate-very low-certainty evidence),and RYR combined with statins reduced adverse effects(P<0.05,low-certainty evidence).XZK showed an effect on reducing Lp(a)levels(P<0.05,moderate-certainty evidence),ZBT shows a tendency to reduce Lp(a)levels compared to placebo.3 Analysis of outpatient prescriptions for dyslipidemiaThere were 123,779 patients with dyslipidemia in the hospital of Chinese medicine,32,136 patients with dyslipidemia in the cardiology department of the hospital of Chinese medicine,and 8,099 cases in the department of integrative medicine cardiology department of general hospital,respectively.The proportion of patients over 60 years old exceeded 50%,more than 10%over 80 years old,and the proportion of female patients after 52-60 years of age was higher than that of men.The proportion of comorbidities sequenced as hypertension,heart disease,and diabetes,from high to low.ASCVD risk stratification was missing from the medical records,therefore a comprehensive analysis of the ASCVD risk stratification distribution in patients was unavailable.The prescriptions for dyslipidemia in both hospitals were dominated by chemical lipid-lowering drugs,with atorvastatin and rosuvastatin DDDs in the top ranking and a small proportion of Chinese patent medicines used.The lipid-lowering Chinese patent medicines included:Xuezhitong Capsules,Jiangzhi Tongmai Capsules,XZK Capsules,Jinshuibao Tablets,Xinyuan Capsules,Zhikang Granules,Songling Xuemaikang,Yindan Xinnaotong Capsules,Zhibituo Tablets,and Hedan Capsules.The proportion of prescriptions for RYR was slightly higher in the general hospital(XZK,3.89%)than in the Chinese medicine hospital(XZK and ZBT,3.15%),and the proportion of prescriptions for RYR herbal medicine was higher in the Chinese medicine hospital(4.73%)than in the general hospital(2.16%).Factors influencing the prescription of RYR were similar in both hospitals,with male patients using RYR less than females,patients with combined hypertension or diabetes using RYR less than patients without combined hypertension or diabetes,and patients with medical insurance or publicly funded medical treatment using RYR more than self-funded patients(P<0.05).Other factors such as age,osteoporosis,abnormal liver function,tumors,and gastrointestinal disease showed different trends of influence in prescribing RYR in the two hospitals.The proportion of lipid-lowering drug combinations was not high in the two hospitals(P<0.0001),and the main modalities of lipid-lowering drug combinations in the general hospital and Chinese medicine hospital were:chemical lipid-lowering drugs combined with chemical lipid-lowering drugs and proprietary Chinese medicines combined with chemical lipid-lowering drugs,respectively.The same factors influencing the prescription of intensive lipid-lowering for ASCVD patients in both hospitals were:intensive lipid-lowering prescription for patients over 60 years old was lower than that for patients under 60 years old(P<0.05),intensive lipid-lowering prescription for patients over 80 years old was lower than that for patients aged 60-79 years old,intensive lipid-lowering prescription for male patients was higher than that for female patients(P<0.05),intensive lipid-lowering prescription for patients with hypertension was higher than that for patients without hypertension(P<0.05),patients with osteoporosis had higher prescriptions for intensive lipid-lowering than those without osteoporosis,and patients with medical insurance or publicly funded medical treatment had higher prescriptions for intensive lipid-lowering than those with self-payment(P<0.05).Other influencing factors such as diabetes,coronary heart disease and depression showed different trends in the prescription of intensive lipid-lowering in the two hospitals.4 Qualitative study of interviews with experts in the development of lipid management guidelinesThe 28 interviewed experts all worked in AAA hospitals,all with senior titles,and were involved in Chinese medicine,Integrative medicine,and Western medicine specializing in cardiovascular medicine,geriatrics,neurology,endocrinology,and nephrology,and belonged to the following regions:Beijing,Fujian,Guangdong,Hebei,Jilin,Jiangsu,Shanghai,Shanxi,Xinjiang,and Zhejiang.The cumulative interview length was 1450 min,with an average length of 51.8 min and 193 577 words of transcribed textual material.The core theory was formed using the three-level coding:considerations for developing lipid management guidelines.The development of lipid management guidelines requires a comprehensive consideration of clinical practice,research on lipid management,and various aspects of the guidelines.By considering the consistency between clinical research and clinical practice in lipid management,the recommendations for lipid management in patients with co-morbidities and elderly patients should be further improved,the efficacy and safety of statins in elderly patients should be further discussed,the recommendations for the management of adverse effects of statins should be further improved,and the recommendations for patients who refuse to use chemical lipid-lowering drugs should be further discussed from the perspective of improving compliance.The current recommendations on RYR in the guidelines are inaccurately positioned.RYR has multiple lipid-lowering components and has multiple advantages in its lipid-regulating effects,and the recommendations on RYR and other Chinese medicines in the guidelines on lipid management should be based on their advantages and comprehensive consideration of their modulating effects on ASCVD risk factors other than blood lipids.It is necessary to accept "using lipids-regulating Chinese medicines in Western medicine" in a scientific manner,promote the healthy development of western use of traditional Chinese medicines,and optimize and improve the descriptions of recommendations in the guidelines and the drug manuals;strengthen Western medicine doctors learning from Chinese medicine;developing guidelines on lipid-lowering Chinese patent medicines to provide reference for Western physicians.The three cores of clinical practice,guidelines and research in lipid management were interactive.The differences between clinical practice,research and existing guidelines provided the basis for analyzing the shortcomings of clinical guidelines;the queries identified in clinical practice and the recommendations of guidelines informed the direction of scientific research on lipid management;the recommendations of guidelines and the evidence of scientific findings improved clinical practice;the experience of clinical practice and the findings of research on lipid management inform the recommendations of guidelines.Conclusions:1 The lipid-modulating effects of RYR have received worldwide attention,and a large body of evidence has accumulated,but there is still room for improvement in the design and reporting quality of various types of studies.RYR SRs should strengthen the registration of implementation protocols,enhance the completeness of reporting,and to avoid research bias.RYR RCTs should strengthen the reporting of methods of concealment of random allocation,implementation of blinding,and conflict of interest statements.Follow-up design and reporting of cohort studies need to be strengthened and multi-center collaboration further enhanced.2 The different ranking of RYR as well as chemical lipid-lowering agents across comorbidities and across outcome indicators may be related to drug interactions,the pathophysiology of dyslipidemia comorbidities and the content of the lipid-lowering active ingredient of RYR.RYR reduces Lp(a)and reduces MACE and has the effect of regulating a variety of cardiovascular disease risk factors such as glucolipid metabolism,blood pressure,and inflammatory factors,which may account for the further reduction in MACE events with RYR compared to statins.The lipid-regulating components and combined effects of RYR need to be further studied.3 There are gaps between clinical practice,research and guidelines on patient characteristics and interventions for dyslipidemia.It is recommended that clinical trials on dyslipidemia should be closer to clinical practice in terms of sample selection and increase the proportion of female and elderly patients;strengthen intensive lipidlowering management in ASCVD and strengthen lipid management studies in specific groups of patients such as those with combined cerebrovascular disease,osteoporosis,and depression.The prescription of lipid management in both hospitals is basically in line with the recommendations of the guidelines.The application of lipid-lowering drugs is dominated by statins,intensive lipid-lowering is more commonly used in ASCVD patients with risk factors such as hypertension and diabetes mellitus,intensive lipid-lowering is used more cautiously in the elderly,and intensive lipid-lowering in patients with coronary heart disease is better implemented in the cardiovascular disease department.RYR has advantages in the elderly,osteoporosis,gastrointestinal disease,oncology and in patients with liver dysfunction,and may play a role as a complementary alternative to statins.There is less evidence for Chinese patent medicines and for the combination of Chinese patent medicines with chemical lipidlowering agents,and more research is needed.4 The expert interviews validated the findings of the previous sections of the study and constructed considerations for the development of lipid management guidelines,reflecting the complementary relationship between the three core areas of clinical practice,guidelines,and research in lipid management,which need to be considered together in the development of lipid management guidelines.