The Efficacy and Safety of Zanghongqu Herbal Slices in the Treatment of Hyperlipidemia: study protocol for a multicenter, randomized, double-blind, placebo controlled clinical trial

The Efficacy and Safety of Zanghongqu Herbal Slices in the Treatment of Hyperlipidemia: study protocol for a multicenter, randomized, double-blind, placebo controlled clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol The Efficacy and Safety of Zanghongqu Herbal Slices in the Treatment of Hyperlipidemia: study protocol for a multicenter, randomized, double-blind, placebo controlled clinical trial Yilin Zhang, Jingjing Wei, Aolong Wang, Bin Li, Rui Yu, Lijie Qiao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9524517/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Introduction Dyslipidemia, especially the elevation of low-density lipoprotein cholesterol (LDL-C), is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). Although statins are recommended as a first-line treatment, their long-term application may be limited by adverse reactions and poor adherence in some patients. ZangHongQu(ZHQ) herbal slice is a novel red yeast rice formulation formed by the fermentation of highland barley and red yeast rice bacteria, containing natural Monacolin K and various bioactive components, which has lipid-lowering and metabolic regulatory effects. However, currently, there is a lack of high-quality randomized controlled trials systematically evaluating its efficacy and safety. This study aims to assess the efficacy and safety of ZHQ in treating dyslipidemia. Methods This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. It plans to enroll 240 patients aged 18–75 years with dyslipidemia and LDL-C ≥ 3.4 mmol/L. Participants will be randomly assigned in a 1:1 ratio to either the intervention group receiving ZHQ or the control group receiving placebo. The primary outcome measure is the change in LDL-C levels. Secondary outcomes include other lipid parameters, blood glucose, insulin, uric acid, and homocysteine levels. Safety assessments encompass liver and kidney function, creatine kinase, vital signs, and adverse events monitoring. Assessments will be conducted at baseline, 4 weeks, and 12 weeks after intervention. Discussion This study aims to provide high-quality evidence-based medicine for the efficacy and safety of ZHQ in treating dyslipidemia, and to provide a scientific basis for its potential application in cardiovascular risk management. Clinical Trial Registration and Ethics http://itmctr.ccebtcm.org.cn/ , ITMCTR2025001724. Ethical Review Number: 2025HL-359-01. Hyperlipidemia Zanghongqu Red yeast rice Chinese medicine Protocol Figures Figure 1 Figure 2 Introduction Atherosclerotic cardiovascular disease (ASCVD) accounts for a significant portion of deaths worldwide, with related deaths accounting for approximately one-fifth of all deaths[ 1 ]. Hyperlipidemia is a major risk factor for ASCVD and also a major contributing factor to multiple chronic diseases such as atherosclerosis, hypertension, coronary heart disease, diabetes, and stroke[ 2 , 3 ]. In recent years, with the improvement of living standards and changes in dietary structure, the prevalence of hyperlipidemia has increased significantly and is affecting younger age groups. According to statistics, the prevalence of hyperlipidemia among Chinese residents aged 18 and above is 38.1%, while the awareness, treatment and control rates are only 11.7%, 10.1% and 4.8% respectively[ 4 ]. In some developed countries, the prevalence rate reaches as high as 55%[ 5 ]. Among children and adolescents, the prevalence of elevated triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) has shown a year-on-year upward trend, with the overall prevalence of dyslipidemia reaching 19%[ 6 ]. Notably, serum lipoprotein levels during childhood and adolescence usually persist into adulthood and are closely related to the occurrence of cardiovascular and cerebrovascular diseases later in life[ 7 ]. Consequently, the prevention and control of dyslipidemia present a significant challenge and has become one of the most important public health events in the world. Hyperlipidemia has been identified as one of the primary risk factors for cardiovascular disease, approximately doubling the associated risk[ 8 ]. In China, it is projected that between 2010 and 2030, elevated cholesterol levels will lead to approximately 9.2 million additional cardiovascular disease events, reflecting a continuously increasing burden of dyslipidemia-related diseases in the future[ 9 ]. LDL-C, in particular, is widely recognized as a core risk factor for ASCVD and plays a direct pathogenic role in the initiation and progression of atherosclerosis[ 10 ]. Studies have shown that CVD burden attributable to high LDL-C accounts for 25.1% of the total burden, with a particularly prominent contribution to the burden of coronary heart disease and stroke, attributable risks as high as 41.9% and 9.6%, respectively[ 11 ]. Evidence-based medicine suggests that in patients with hyperlipidemia, a 1 mmol/L reduction in LDL-C levels can reduce the 5-year incidence of coronary events, ischemic stroke, and heart failure by approximately 20%[ 12 , 13 ]. Therefore, early intervention and standardized treatment of hyperlipidemia, especially effective reduction of LDL-C levels, are crucial for improving the prognosis and reducing cardiovascular mortality. Statins serve as cornerstone medications in lipid-lowering therapy, but long-term, high-dose, or irrational use can exacerbate the burden on the liver. Adverse reactions such as myotoxicity and liver injury associated with statins therapy remain key clinical concerns[ 14 ]. Chinese medicine therapies offer the advantage of multi-target integrated efficacy, rich clinical experience, and plays an important role in the prevention and treatment of cardiovascular and cerebrovascular diseases. Existing research has demonstrated that Xuezhikang effectively blocks the activation of the NF-κB signaling pathway, reduces the secretion and synthesis of pro-inflammatory factors such as TNF-α and IL-6, and interferes with the adhesion between monocytes and vascular endothelial cells, thereby inhibiting excessive inflammatory responses within the body[ 15 ]. Jianpi Qutan formula combined with moxibustion therapy can effectively improve lipid levels and TCM syndrome scores[ 16 ]. Electroacupuncture at Zusanli can improve lipid disorders in hyperlipidemic mice, reduce the expression of IL-1β, NLRP3, and TLR4 in the intestinal mucosa of hyperlipidemic animals, alleviate the inflammatory response, and maintain the integrity of the intestinal barrier[ 17 ]. Natural statins, represented by red yeast rice(RYR), have certain advantages in terms of bioavailability and safety. Research indicates that Xuezhikang, with RYR as its main component, has multiple effects including lowering cholesterol, improving vascular and cardiac function, inhibiting the progression of atherosclerosis, and demonstrating high safety, and has been recommended by many global guidelines[ 18 , 19 ]. ZangHongQu(ZHQ) is made by fermenting barley, a unique resource of the Qinghai-Tibet Plateau, with RYR bacteria. Barley is a traditional Tibetan medicine that is rich in cellulose, protein, and various vitamins, while relatively low in fat and sugar, and thus possesses significant health benefits and nutritional value. Barley grains contain a variety of bioactive components such as β-glucan, ferulic acid, flavonoid compounds, anthocyanins, and dietary fiber, which can help regulate blood glucose and blood pressure levels[ 20 , 21 ], lower cholesterol[ 22 ], and modulate immune activity[ 23 ]. ZHQ combines the characteristics of both barley and RYR, and demonstrates excellent efficacy in lowering blood lipids. However, current evidence-based medical evidence remains relatively limited, lacking systematic evaluations from large-sample, multicenter, randomized controlled clinical trials and long-term follow-up data. Its efficacy and safety still need further verification. Therefore, this study, through conducting a multicenter, randomized controlled clinical trial on the treatment of hyperlipidemia with ZHQ, provides more robust high-level evidence-based medical evidence for the efficacy and safety of Chinese medicine in treating hyperlipidemia. This is of great significance for promoting the modernization and internationalization of Chinese medicine, as well as for advancing the integration of Chinese and Western medicine in the prevention and treatment of cardiovascular diseases. Methods Trial design This is a multicenter, randomized, double-blind, placebo-controlled clinical trial. This protocol was developed and drafted in strict adherence to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (Supplementary Material 1; Chan et al., 2013). Participants who meet the eligibility criteria will be randomly allocated in a 1:1 ratio to receive either ZHQ or placebo. The run-in period lasts 2 weeks, followed by a 12-week intervention period. Study visits will be conducted during the run-in period, at baseline, and at weeks 4 and 12. Each patient must attend hospital visits within 3 days before or after the specified time points. The flowchart of this trial is shown in Fig. 1 . The timeline for recruitment, intervention, and data evaluation is presented in Fig. 2 . Trial registration is available at International Traditional Medicine Clinical Trial Registry (ITMCTR2025001724). The protocol has been approved by Ethics Committee of The First Affiliated Hospital of Henan University of CM(2025HL-359-01). Recruitment of participants This study will be conducted at the First Affiliated Hospital of Henan University of Chinese Medicine, the Seventh People's Hospital of Zhengzhou, the Affiliated Hospital of Shanxi University of Chinese Medicine, Anyang Hospital of Chinese Medicine, Huixian Hospital of Chinese Medicinel, and Zhumadian Hospital of Chinese Medicine. Participants will be recruited through hospital outpatient departments or by posting recruitment posters, with a total of 240 participants enrolled. Participant screening and eligibility assessment will be conducted by qualified cardiovascular specialists. Patients who meet the criteria and voluntarily agree to participate in this study must sign a written informed consent form (Supplementary Material 2), confirming that they fully understand the study’s primary objectives, implementation procedures, and all potential safety risks. All personal privacy information of the participants and the research data will be kept confidential, with access restricted to authorized study personnel. Participants can obtain the relevant materials upon reasonable request. Diagnostic criteria According to the Chinese Lipid Management Guidelines (2023), hyperlipidemia can be diagnosed if any one of the following criteria is met: TC ≥ 5.2mmol/L; TG ≥ 1.7mmol/L; LDL-C ≥ 3.4mmol/L; HDL-C < 1.0mmo1/L。 Inclusion criteria To be eligible for this study, participants must meet all of the following inclusion criteria: (1) Meet the diagnostic criteria for hyperlipidemia with LDL-C ≥ 3.4 mmol/L; (2) Be aged 18 and 75 years, regardless of gender; (3) Understand the purpose of the clinical trial, provide voluntary consent, and sign an informed consent form. Exclusion criteria Participants meeting any of the following criteria will be excluded: (1) Secondary dyslipidemia caused by disease, medication, or other factors; (2) Currently using heparin, thyroid medications, or other drugs affecting lipid metabolism; (3) Patients with familial refractory hyperlipidemia; (4) Patients who have been taking statins or lipid-lowering Chinese herbal medicine/formulations for a long time and cannot discontinue the medication; (5) Patients with a history of cardiovascular or cerebrovascular diseases (angina pectoris, myocardial infarction, heart failure, stroke, transient ischemic attack, prior coronary artery revascularization or other arterial revascularization procedures); (6) Patients with peripheral artery disease or aortic aneurysm; (7) Patients with severe hypertension (SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg), severe arrhythmia (rapid atrial fibrillation, complete bundle branch block, etc.), type 1 diabetes, or type 2 diabetes; (8) Patients with abnormal liver function (ALT/AST > 1.5 times the upper limit of normal) or abnormal kidney function (Cr > the upper limit of normal); (9) Patients with malignant tumors, organ failure, post-transplant status, or other severe chronic diseases; (10) Pregnant or lactating women, or those planning pregnancy within 3 months; (11) Patients with chronic alcohol abuse, drug dependence, or mental illness; (12) Patients allergic to the drugs used in this study; (13) Patients with poor compliance, withdraw from the study, severe organ damage, acute critical illness, or infectious diseases; (14) Patients who have participated in or are currently participating in other drug clinical trials within the past 3 months; (15) Patients deemed unsuitable for participation in this clinical trial by the investigators. Withdrawal/termination criteria During the trial, participants will be terminated if any of the following occurs: (1) Serious adverse events occurs, rendering the participant unfit to continue the study; (2) Disease-related complications, comorbidity, or significant physiological change occurs, rendering continued trial participation inappropriate; (3) Poor compliance, including failure to use the study drug or attend scheduled visits as prescribed; (4) Voluntary withdrawal from the study at any time for any reason; (5) Unblinding or the need for emergency unblinding during the study period for any reason. In cases of treatment discontinuation or protocol deviation, the time of the last drug administration will be documented, and relevant assessment data will be collected. Randomization and allocation concealment The randomization sequence will be created using a centralized system at the Evidence-Based Medicine Center at the First Affiliated Hospital of Henan University of Chinese Medicine. Participants will be randomly assigned to either the intervention group or the control group in a 1:1 ratio. Patients in the intervention group (n = 120) will receive ZHQ, while participants in the control group (n = 120) will receive a placebo matched in appearance to the ZHQ. Researchers will obtain randomized patient and drug numbers through a central randomization system. All numbers are managed centrally by the Evidence-Based Medicine Center of the First Affiliated Hospital of Henan University of Chinese Medicine. Blinding The trial will be conducted under a double-blind design, with both participants and investigators blinded to treatment allocation for the duration of the study. A two-stage blinding method is implemented: first-stage blinding, where the investigational drug is blinded by packaging it identically to the placebo; and second-stage blinding, where the packaging number of the investigational drug is blinded. Clinical investigators obtained participant assignment codes through the hospital's EDC system and administered the corresponding intervention based on these codes. Unblinding is permitted in cases of serious adverse events or when urgent measures are necessary to ensure patient safety. Interventions XiZang HongQu Biotechnology Co., Ltd. (Lasa, People’s Republic of China) will provide ZHQ herbal slices and placebo. The placebo's packaging, shape, and color are identical to the ZHQ, ensuring no impact on the implementation of the blinding. The medication instructions, production batch number, manufacturer, and drug code are printed on the outer packaging. Researchers will administer the drug to participants for 28 days at baseline, followed by an additional 56 days during the fourth-week follow-up visit. During the study period, participants must not take any other Chinese or Western medicine for lowering blood lipids. Participants allocated to the intervention group will receive treatment with ZHQ, 3g twice daily, brewed with boiling water. The total daily intake should not be less than 800 ml, until it loses its flavor or the residue is chewed and swallowed; the treatment will last for 12 weeks. In addition, researchers will provide consultation on lipid management. Participants allocated to the group will receive a placebo, administered in the same manner as the intervention group for 12 weeks. Researchers will also provide counseling on lipid management. Primary outcome The primary efficacy endpoints are Mean percentage change in LDL-C from baseline to week 12. Secondary outcomes (1) Mean percentage change in LDL-C from baseline to week 4. (2) Proportion of patients whose LDL-C level decreased by ≥ 30% from baseline after 12 weeks of treatment; (3) Mean percentage change in TC, TG, HDL-C and non-HDL-C at baseline and at weeks 4 and 12 of treatment; (4) Changes in fasting blood glucose and fasting insulin at baseline and at weeks 4 and 12 of treatment; (5) Changes in uric acid and homocysteine at baseline and at weeks 4 and 12 of treatment. Safety indicators (1) Assess vital signs (temperature, blood pressure, heart rate, respiration, etc.) during the run-in period, baseline period, and at 4 and 12 weeks of medication; (2) Assess complete blood count, urinalysis, stool routine, liver function, kidney function, creatine kinase, and electrocardiogram during the run-in period and at 4 and 12 weeks of medication; (3) Perform urine pregnancy tests on women of childbearing age during the run-in period. Adverse events All adverse events, including those reported by participants and researchers, will be recorded in the Case Report Form (CRF). Depending on the nature and severity of the adverse event, different management approaches will be implemented, such as terminating the clinical trial, adjusting the drug dosage, providing symptomatic treatment, or observation, and it will be assessed whether they are related to the study drug. Appropriate measures will be taken to ensure participant safety in case of potential harm. Any serious adverse event will be reported to the principal investigator, the clinical trial office, and the ethics committee within 24 hours. Reporting starts from the first administration of the study drug and continues until the conclusion of the participant's final visit. Sample size calculation This study is a randomized, double-blind, placebo-controlled trial. The outcome measure is a quantitative variable, and participants are randomly assigned to the intervention and control groups in a 1:1 ratio. The sample size calculation formula is as follows: Based on literature review findings[ 25 ], the LDL-C change rate in the Xuezhikang treatment group decreased by 27%, while the LDL-C change rate in the placebo control group increased by 2.8%. Assuming that the LDL-C change rate decrease of 27% in the ZHQ treatment group and the LDL-C change rate increase of 2.8% in the placebo control group, the superiority margin is set at 10.8%. We set the significance level α = 0.05 and β = 0.10 for a one-tailed test. The sample size ratio between the intervention and control groups is 1:1. Based on the formula, the sample size in each group is 107 cases, and the total sample size is 214 cases. Accounting for a 10% loss to follow-up, the sample size in each group should be 119 cases, and the total sample size is 238 cases. Therefore, this study plans to enroll 120 subjects in each group, totaling 240 subjects. Data management and monitoring This study uses Electronic Data Capture (EDC) for clinical research data. Data in the Electronic Case Report Form (eCRF) comes from original documents such as source medical records and laboratory test reports, and remains consistent with these source documents. All paper original documents will be stored in a locked office. Researchers should complete, review, and submit the eCRF promptly, and respond to inquiries from data administrators and medical reviewers in a timely manner. Two independent investigators will double - checked all original documents and eCRF. The supervisor is responsible for verifying the proper completion of eCRFs and ensuring that it is consistent with the original data. After data cleaning, researchers will sign the completed eCRF for confirmation. The data management process will adhere to the regulatory requirements of the "Regulations on Quality Management of Clinical Trials" and the "Technical Guidelines for Clinical Trial Data Management" to ensure data authenticity, completeness, accuracy, and traceability. The findings of this study will be communicated through peer-reviewed publications, academic conferences, and doctoral theses to ensure broad dissemination. However, any personally identifiable information collected during the course of the study will be kept strictly confidential and used solely for the purposes of this research. Statistical analysis After treatment, R software will be used to analyze and evaluate efficacy and safety. Continuous variables will be presented as mean ± standard deviation or median (interquartile range) according to their distribution, whereas categorical variables will be summarized as frequencies and percentages. Chi-square test will be used for comparisons between groups for categorical data, and independent samples t-test or Mann-Whitney U test will be used for continuous data. All hypothesis tests will employ a two-tailed. Unless otherwise specified, P < 0.05 will be considered statistically significant. Missing data will be addressed using imputation methods, intention-to-treat analysis, and sensitivity analyses. Discussion Elevated LDL-C, as a major component of dyslipidemia, is widely recognized as a major contributor to the development and progression of ASCVD[ 26 , 27 ]. Although statins have proven efficacy in lowering LDL-C and reducing the risk of cardiovascular events, their documented adverse effects — including myopathy, new-onset diabetes, elevated hepatic enzyme levels, and hemorrhagic stroke — limit their long-term use[ 28 ]. Therefore, exploring safe, effective, and long-term alternative or complementary lipid-lowering therapies is of significant clinical importance. RYR preparations, as a natural lipid-lowering drug, have a main active ingredient, Monacolin K, which is chemically similar to lovastatin and can exist in both lactone and open-ring acid forms[ 29 ]. After absorption in vivo, monacolin K rapidly converts from the lactone form to its active hydroxy acid form, reducing cholesterol synthesis by inhibiting the activity of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase, thereby exerting its lipid-lowering effect[ 30 ]. In contrast, pure lovastatin exhibits low absolute oral bioavailability (< 5%) due to its extensive first-pass effect and limited solubility. Lovastatin derived from RYR, however, demonstrates significantly improved oral bioavailability owing to increased solubility and reduced crystallinity, resulting in superior absorption and utilization efficiency within the body[ 31 ]. As early as 1999, a randomized controlled trial by Herber[ 32 ] demonstrated that, compared with placebo, dietary supplements based on RYR has been associated with significant decreases in TC, LDL-C, and TG levels, providing early evidence for its lipid-lowering effect. The study by Sungthong[ 33 ] further showed that the use of RYR extract was significantly associated with a reduction in the risk of myocardial infarction, revascularization, and sudden cardiac death, suggesting its potential clinical value in the secondary prevention of cardiovascular diseases. Multiple studies in recent years have supplemented and reinforced these findings. A meta-analysis showed that[ 34 ] in patients with hyperlipidemia, administration of RYR extract resulted in a statistically significant decrease in TC and LDL-C levels, without an increased risk of life-threatening adverse reactions. Within the recommended dosage range, RYR preparations can be considered a lipid-lowering option that combines both efficacy and safety[ 35 ]. ZHQ is a novel RYR formulation produced by fermenting barley, a characteristic resource of the Qinghai-Tibet Plateau, with RYR bacteria. It has unique advantages in improving blood lipid levels and stabilizing plaques. Animal experiments have shown that ZHQ extract can improve serum TC, TG, HDL-C and LDL-C levels, and high-dose ZHQ demonstrates superior efficacy to lovastatin in lowering TC and LDL-C, reduces abdominal and epididymal fat deposition, and inhibits weight gain and fatty liver formation[ 36 ]. Clinical studies indicate that ZHQ is comparable to atorvastatin in reducing TC, TG, and LDL-C levels, preventing the increase of carotid intima-media thickness, and stabilizing plaques[ 37 ]. In terms of increasing HDL-C levels and reducing fasting blood glucose levels, it is superior to atorvastatin[ 38 ], and has a higher safety profile[ 39 ]. However, current studies often suffer from limitations such as small sample sizes, insufficiently rigorous study designs, and inadequate blinding. Furthermore, there is a lack of high-quality randomized controlled trials to provide reliable evidence-based support for its clinical application. This study employs a multicenter, randomized, double-blind, placebo-controlled design to systematically evaluate the efficacy and safety of ZHQ in treating hyperlipidemia. The aim is to provide high-quality evidence-based medicine for ZHQ in improving of dyslipidemia, laying the foundation for subsequent long-term follow-up studies, mechanism exploration, and cardiovascular endpoint studies. Regarding outcome indicators, this study used the change in LDL-C from baseline to 12 weeks as the primary outcome indicator, and set secondary outcome indicators such as early efficacy observation, LDL-C achievement rate, TC, TG, HDL-C and non-HDL-C, which helps to comprehensively evaluate the lipid-lowering effects of ZHQ and its dynamic trends. In addition, this study incorporated fasting blood glucose, fasting insulin, uric acid, and homocysteine as secondary outcome measures to evaluate the potential benefits of ZHQ from the perspective of overall cardiovascular metabolic risk, providing supplementary evidence for its possible role in metabolic syndrome management. Regarding safety assessment, this study systematically monitored liver and kidney function, creatine kinase, complete blood count, and the occurrence of adverse events to comprehensively evaluate the tolerability and safety of ZHQ. The randomized, double-blind, placebo-controlled study design helps minimize bias and objectively identify drug-related adverse reactions, providing a reliable basis for safety evaluation. Overall, the results of this study are expected to provide a potential alternative treatment option for patients with dyslipidemia, especially those who cannot tolerate or are unwilling to use statins long-term, and provide a basis for their rational application in clinical practice. Our study also has certain limitations. First, the intervention period is 12 weeks, aiming to assess the effects of ZHQ on lipid indicators, but it is difficult to directly reflect its long-term efficacy, cardiovascular endpoint effect, and sustained safety. These need to be further validated in future long-term follow-up or extended studies. Second, the study subjects are individuals with dyslipidemia without a clear history of cardiovascular disease, therefore, the applicability of the study results is mainly limited to the context of primary prevention. The efficacy and safety for patients with previous cardiovascular and cerebrovascular events, high-risk groups with diabetes, or other high-risk subgroups require further investigation. In conclusion, this study, conducted through a rigorously designed randomized, double-blind, placebo-controlled trial, is expected to address the current lack of evidence-based medical data for natural RYR preparations, and provide important support for future high-quality studies focusing on long-term clinical outcomes and mechanisms of action. Furthermore, it will contribute to the international dissemination of Chinese medicine in the prevention and management of cardiovascular diseases, providing a replicable research model for integrating Chinese medicine into the modern evidence-based medicine system. Declarations Acknowledgements We sincerely thank all the authors involved in the preparation of this paper for their diligent efforts and significant contributions, and we also express our heartfelt gratitude to the First Affiliated Hospital of Henan University of Chinese Medicine for providing comprehensive support and safeguards that ensured the successful conduct of this clinical trial. Authors’ contributions YLZ and JJW participated in the development of the study protocol and drafted this manuscript. ALW and BL were responsible for statistical design and study coordination; RY and LJQ contributed to the clinical design and feasibility assessment; and YFX was responsible for sample size estimation and data management. XLW, XYL and MJZ conceptualized the study, led the overall design, and provided critical revisions. All authors read and approved the final manuscript. Funding The author(s) declare that financial support was received for the research and/or publication of this article. This work was funded by the Special Research and Evaluation Project of China Association of Chinese Medicine (Grant No. CACMRE2025-A-05), the National Natural Science Foundation of China (Grant No. 82505477), The Youth Talent Support Project of the Chinese Association of Chinese Medicine(Grant No. CACM-2025-QNRC2-B01), Henan Province Key Research and Development Project (Grant No.231111310200), Henan Province Science and Technology Research Project (Grant No.252102311270). In addition, Xizang Hongqu Biotechnology Co., Ltd. (Lasa, People’s Republic of China) provided the investigate drugs. The company had no role in the study design, data collection, data analysis, data interpretation, or manuscript preparation. Data availability The data generated in this clinical trial will be accessible from the corresponding author upon reasonable request after the primary results have been published. Ethical approval and consent to participate Protocol version: V2.1 was finished on 31 August 2025. The study was conducted in accordance with the Declaration of Helsinki and was approved by The First Affiliated Hospital of Henan University of CM(2025HL-359-01) (Supplementary Material 3). Any substantial modifications to the study protocol, including changes to the design, eligibility criteria, or sample size, will require prior approval from the ethics committee. Written informed consent will be obtained from all participants before enrollment. Consent for publication All authors agreed to the publication of the article. Competing interest All co-authors declare that this clinical study involved no conflicts of interest. Xizang Hongqu Biotechnology Co., Ltd. provided support for this study by supplying the investigational drugs; it did not participate in any other aspects of the study's implementation, including the overall design of the research protocol, the collection and organization of clinical data, statistical data analysis, the interpretation of research findings, or the drafting of the manuscript. This collaborative arrangement has been acknowledged and approved by the company; furthermore, there exists no financial or other relationship between the company and any of the authors that would constitute a potential conflict of interest. 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Front Microbiol. 2016;7:129. https://doi.org/10.3389/fmicb.2016.00129 . Wang C, Hu N, Fan D, et al. Influence of highland barley rice on glucose fluctuation in patients with impaired fasting glucoseand its correlative factors analysis. Chin J Disaster Med. 2017;5:561–5. https://doi.org/10.13919/j.issn.2095-6274.2017.10.00 . Li Y, Li T, Liu RH. Bioactive compounds of highland barley and their health benefits. J Cereal Sci. 2022;103:103366. https://doi.org/10.1016/j.jcs.2021.103366 . Han L, Meng M, Guo M, et al. Immunomodulatory activity of a water-soluble polysaccharide obtained from highland barley on immunosuppressive mice models. Food Funct. 2019;10:304–14. https://doi.org/10.1039/c8fo01991f . Chan A-W, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. https://doi.org/10.1136/bmj.e7586 . Moriarty PM, Roth EM, Karns A, et al. Effects of Xuezhikang in patients with dyslipidemia: a multicenter, randomized, placebo-controlled study. J Clin Lipidol. 2014;8:568–75. https://doi.org/10.1016/j.jacl.2014.09.002 . Zadelaar S, Kleemann R, Verschuren L, et al. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol. 2007;27:1706–21. https://doi.org/10.1161/ATVBAHA.107.142570 . Williams KJ, Feig JE, Fisher EA. Rapid regression of atherosclerosis: insights from the clinical and experimental literature. Nat Clin Pract Cardiovasc Med. 2008;5:91–102. https://doi.org/10.1038/ncpcardio1086 . Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532–61. https://doi.org/10.1016/S0140-6736(16)31357-5 . Vitiello A, Izzo L, Castaldo L, et al. The Questionable Quality Profile of Food Supplements: The Case of Red Yeast Rice Marketed Products. Foods. 2023;12:2142. https://doi.org/10.3390/foods12112142 . Lin C-C, Li T-C, Lai M-M. Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia. Eur J Endocrinol. 2005;153:679–86. https://doi.org/10.1530/eje.1.02012 . Chen C-H, Yang J-C, Uang Y-S, et al. Improved dissolution rate and oral bioavailability of lovastatin in red yeast rice products. Int J Pharm. 2013;444:18–24. https://doi.org/10.1016/j.ijpharm.2013.01.028 . Heber D, Yip I, Ashley JM, et al. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr. 1999;69:231–6. https://doi.org/10.1093/ajcn/69.2.231 . Sungthong B, Yoothaekool C, Promphamorn S, et al. Efficacy of red yeast rice extract on myocardial infarction patients with borderline hypercholesterolemia: A meta-analysis of randomized controlled trials. Sci Rep. 2020;10:2769. https://doi.org/10.1038/s41598-020-59796-5 . Trogkanis E, Karalexi MA, Sergentanis TN, et al. Safety and Efficacy of the Consumption of the Nutraceutical Red Yeast Rice Extract for the Reduction of Hypercholesterolemia in Humans: A Systematic Review and Meta-Analysis. Nutrients. 2024;16:1453. https://doi.org/10.3390/nu16101453 . Fogacci F, Banach M, Mikhailidis DP, et al. Safety of red yeast rice supplementation: A systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2019;143:1–16. https://doi.org/10.1016/j.phrs.2019.02.028 . Zhao C. Research on the effect and mechanism of highlandbarley Monascus purpureus Went. melioratesnonalcoholic fatty liver disease. Master Jiangxi Univ Chin Med. 2022. https://doi.org/10.27180/d.cnki.gjxzc.2022.000353 . Luo H, Zhong Z, Zhang Z. Application of Tibetan Monascus in patients with intima media thickeningand its effects on blood lipid, carotid intima media thickness and plaque. China Mod Med. 2022;29:16–9. https://doi.org/10.3969/j.issn.1674-4721.2022.31.005 . Luo H, Zhong Z. The effect of Tibetan Monascus on blood lipid levels in patients with dyslipidemia. China‘s Naturop. 2020;28:57–9. https://doi.org/10.19621/j.cnki.11-3555/r.2020.1628 . Li J. Analysis of Application Effect of Zanghongqu Combined with Atorvastatin in Patients with Dyslipidemia. Chin Community Dr. 2024;40:74–6. https://doi.org/10.3969/j.issn.1007-614x.2024.05.026 . Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials1V1.0.doc SupplementaryMaterials2.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 09 May, 2026 Reviewers agreed at journal 09 May, 2026 Reviewers invited by journal 05 May, 2026 Submission checks completed at journal 05 May, 2026 First submitted to journal 05 May, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9524517","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":637305738,"identity":"8d846e6b-b8c5-4355-8eef-ba4f13217b33","order_by":0,"name":"Yilin Zhang","email":"","orcid":"","institution":"Department of Cardiovascular Disease, The first Affiliated Hospital of Henan University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yilin","middleName":"","lastName":"Zhang","suffix":""},{"id":637305739,"identity":"af0bfe8c-0c24-4a7d-829f-6b697f620ea2","order_by":1,"name":"Jingjing 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09:55:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9524517/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9524517/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109215009,"identity":"9f00a36e-5630-4cd7-a6a1-cbd20f70c2b5","added_by":"auto","created_at":"2026-05-13 17:50:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":222934,"visible":true,"origin":"","legend":"\u003cp\u003eStudy process: flowchart of the study procedure\u003c/p\u003e","description":"","filename":"OnlineFig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-9524517/v1/2842d9e030ad9e369b3377af.png"},{"id":109249565,"identity":"b9fd63ad-f5d7-4a66-a73e-404963ec19b8","added_by":"auto","created_at":"2026-05-14 08:56:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78410,"visible":true,"origin":"","legend":"\u003cp\u003eThe schedule of enrolment, interventions, and assessments\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9524517/v1/3cca38cffbc798e1a049b205.png"},{"id":109252169,"identity":"7ad53d34-1ec6-40e9-a1e7-e6be097ca33b","added_by":"auto","created_at":"2026-05-14 09:21:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":666164,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9524517/v1/05232a13-87a0-4b45-8097-c6e2accb30f2.pdf"},{"id":109249130,"identity":"3005edda-72ef-4843-b47c-3fe5f6ce2787","added_by":"auto","created_at":"2026-05-14 08:42:47","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":131366,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials1V1.0.doc","url":"https://assets-eu.researchsquare.com/files/rs-9524517/v1/de7c2bc8a1e45666651f4a1f.doc"},{"id":109215011,"identity":"895d1c15-7e18-41b7-b746-5c28cdde410d","added_by":"auto","created_at":"2026-05-13 17:50:26","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23173,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9524517/v1/27e4a9af4477d40259650276.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Efficacy and Safety of Zanghongqu Herbal Slices in the Treatment of Hyperlipidemia: study protocol for a multicenter, randomized, double-blind, placebo controlled clinical trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAtherosclerotic cardiovascular disease (ASCVD) accounts for a significant portion of deaths worldwide, with related deaths accounting for approximately one-fifth of all deaths[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hyperlipidemia is a major risk factor for ASCVD and also a major contributing factor to multiple chronic diseases such as atherosclerosis, hypertension, coronary heart disease, diabetes, and stroke[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In recent years, with the improvement of living standards and changes in dietary structure, the prevalence of hyperlipidemia has increased significantly and is affecting younger age groups. According to statistics, the prevalence of hyperlipidemia among Chinese residents aged 18 and above is 38.1%, while the awareness, treatment and control rates are only 11.7%, 10.1% and 4.8% respectively[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In some developed countries, the prevalence rate reaches as high as 55%[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Among children and adolescents, the prevalence of elevated triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) has shown a year-on-year upward trend, with the overall prevalence of dyslipidemia reaching 19%[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Notably, serum lipoprotein levels during childhood and adolescence usually persist into adulthood and are closely related to the occurrence of cardiovascular and cerebrovascular diseases later in life[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Consequently, the prevention and control of dyslipidemia present a significant challenge and has become one of the most important public health events in the world.\u003c/p\u003e \u003cp\u003eHyperlipidemia has been identified as one of the primary risk factors for cardiovascular disease, approximately doubling the associated risk[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In China, it is projected that between 2010 and 2030, elevated cholesterol levels will lead to approximately 9.2\u0026nbsp;million additional cardiovascular disease events, reflecting a continuously increasing burden of dyslipidemia-related diseases in the future[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. LDL-C, in particular, is widely recognized as a core risk factor for ASCVD and plays a direct pathogenic role in the initiation and progression of atherosclerosis[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Studies have shown that CVD burden attributable to high LDL-C accounts for 25.1% of the total burden, with a particularly prominent contribution to the burden of coronary heart disease and stroke, attributable risks as high as 41.9% and 9.6%, respectively[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Evidence-based medicine suggests that in patients with hyperlipidemia, a 1 mmol/L reduction in LDL-C levels can reduce the 5-year incidence of coronary events, ischemic stroke, and heart failure by approximately 20%[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, early intervention and standardized treatment of hyperlipidemia, especially effective reduction of LDL-C levels, are crucial for improving the prognosis and reducing cardiovascular mortality.\u003c/p\u003e \u003cp\u003eStatins serve as cornerstone medications in lipid-lowering therapy, but long-term, high-dose, or irrational use can exacerbate the burden on the liver. Adverse reactions such as myotoxicity and liver injury associated with statins therapy remain key clinical concerns[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Chinese medicine therapies offer the advantage of multi-target integrated efficacy, rich clinical experience, and plays an important role in the prevention and treatment of cardiovascular and cerebrovascular diseases. Existing research has demonstrated that Xuezhikang effectively blocks the activation of the NF-κB signaling pathway, reduces the secretion and synthesis of pro-inflammatory factors such as TNF-α and IL-6, and interferes with the adhesion between monocytes and vascular endothelial cells, thereby inhibiting excessive inflammatory responses within the body[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Jianpi Qutan formula combined with moxibustion therapy can effectively improve lipid levels and TCM syndrome scores[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Electroacupuncture at Zusanli can improve lipid disorders in hyperlipidemic mice, reduce the expression of IL-1β, NLRP3, and TLR4 in the intestinal mucosa of hyperlipidemic animals, alleviate the inflammatory response, and maintain the integrity of the intestinal barrier[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNatural statins, represented by red yeast rice(RYR), have certain advantages in terms of bioavailability and safety. Research indicates that Xuezhikang, with RYR as its main component, has multiple effects including lowering cholesterol, improving vascular and cardiac function, inhibiting the progression of atherosclerosis, and demonstrating high safety, and has been recommended by many global guidelines[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eZangHongQu(ZHQ) is made by fermenting barley, a unique resource of the Qinghai-Tibet Plateau, with RYR bacteria. Barley is a traditional Tibetan medicine that is rich in cellulose, protein, and various vitamins, while relatively low in fat and sugar, and thus possesses significant health benefits and nutritional value. Barley grains contain a variety of bioactive components such as β-glucan, ferulic acid, flavonoid compounds, anthocyanins, and dietary fiber, which can help regulate blood glucose and blood pressure levels[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], lower cholesterol[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and modulate immune activity[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. ZHQ combines the characteristics of both barley and RYR, and demonstrates excellent efficacy in lowering blood lipids. However, current evidence-based medical evidence remains relatively limited, lacking systematic evaluations from large-sample, multicenter, randomized controlled clinical trials and long-term follow-up data. Its efficacy and safety still need further verification. Therefore, this study, through conducting a multicenter, randomized controlled clinical trial on the treatment of hyperlipidemia with ZHQ, provides more robust high-level evidence-based medical evidence for the efficacy and safety of Chinese medicine in treating hyperlipidemia. This is of great significance for promoting the modernization and internationalization of Chinese medicine, as well as for advancing the integration of Chinese and Western medicine in the prevention and treatment of cardiovascular diseases.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTrial design\u003c/h2\u003e \u003cp\u003eThis is a multicenter, randomized, double-blind, placebo-controlled clinical trial. This protocol was developed and drafted in strict adherence to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (Supplementary Material 1; Chan et al., 2013). Participants who meet the eligibility criteria will be randomly allocated in a 1:1 ratio to receive either ZHQ or placebo. The run-in period lasts 2 weeks, followed by a 12-week intervention period. Study visits will be conducted during the run-in period, at baseline, and at weeks 4 and 12. Each patient must attend hospital visits within 3 days before or after the specified time points. The flowchart of this trial is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The timeline for recruitment, intervention, and data evaluation is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Trial registration is available at International Traditional Medicine Clinical Trial Registry (ITMCTR2025001724). The protocol has been approved by Ethics Committee of The First Affiliated Hospital of Henan University of CM(2025HL-359-01).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRecruitment of participants\u003c/h3\u003e\n\u003cp\u003eThis study will be conducted at the First Affiliated Hospital of Henan University of Chinese Medicine, the Seventh People's Hospital of Zhengzhou, the Affiliated Hospital of Shanxi University of Chinese Medicine, Anyang Hospital of Chinese Medicine, Huixian Hospital of Chinese Medicinel, and Zhumadian Hospital of Chinese Medicine. Participants will be recruited through hospital outpatient departments or by posting recruitment posters, with a total of 240 participants enrolled. Participant screening and eligibility assessment will be conducted by qualified cardiovascular specialists. Patients who meet the criteria and voluntarily agree to participate in this study must sign a written informed consent form (Supplementary Material 2), confirming that they fully understand the study\u0026rsquo;s primary objectives, implementation procedures, and all potential safety risks. All personal privacy information of the participants and the research data will be kept confidential, with access restricted to authorized study personnel. Participants can obtain the relevant materials upon reasonable request.\u003c/p\u003e\n\u003ch3\u003eDiagnostic criteria\u003c/h3\u003e\n\u003cp\u003e According to the Chinese Lipid Management Guidelines (2023), hyperlipidemia can be diagnosed if any one of the following criteria is met:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTC\u0026thinsp;\u0026ge;\u0026thinsp;5.2mmol/L;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTG\u0026thinsp;\u0026ge;\u0026thinsp;1.7mmol/L;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLDL-C\u0026thinsp;\u0026ge;\u0026thinsp;3.4mmol/L;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHDL-C\u0026thinsp;\u0026lt;\u0026thinsp;1.0mmo1/L。\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e\n\u003ch3\u003eInclusion criteria\u003c/h3\u003e\n\u003cp\u003eTo be eligible for this study, participants must meet all of the following inclusion criteria:\u003c/p\u003e \u003cp\u003e(1) Meet the diagnostic criteria for hyperlipidemia with LDL-C\u0026thinsp;\u0026ge;\u0026thinsp;3.4 mmol/L;\u003c/p\u003e \u003cp\u003e(2) Be aged 18 and 75 years, regardless of gender;\u003c/p\u003e \u003cp\u003e(3) Understand the purpose of the clinical trial, provide voluntary consent, and sign an informed consent form.\u003c/p\u003e\n\u003ch3\u003eExclusion criteria\u003c/h3\u003e\n\u003cp\u003eParticipants meeting any of the following criteria will be excluded:\u003c/p\u003e \u003cp\u003e(1) Secondary dyslipidemia caused by disease, medication, or other factors;\u003c/p\u003e \u003cp\u003e(2) Currently using heparin, thyroid medications, or other drugs affecting lipid metabolism;\u003c/p\u003e \u003cp\u003e(3) Patients with familial refractory hyperlipidemia;\u003c/p\u003e \u003cp\u003e(4) Patients who have been taking statins or lipid-lowering Chinese herbal medicine/formulations for a long time and cannot discontinue the medication;\u003c/p\u003e \u003cp\u003e(5) Patients with a history of cardiovascular or cerebrovascular diseases (angina pectoris, myocardial infarction, heart failure, stroke, transient ischemic attack, prior coronary artery revascularization or other arterial revascularization procedures);\u003c/p\u003e \u003cp\u003e(6) Patients with peripheral artery disease or aortic aneurysm;\u003c/p\u003e \u003cp\u003e(7) Patients with severe hypertension (SBP\u0026thinsp;\u0026ge;\u0026thinsp;180 mmHg and/or DBP\u0026thinsp;\u0026ge;\u0026thinsp;110 mmHg), severe arrhythmia (rapid atrial fibrillation, complete bundle branch block, etc.), type 1 diabetes, or type 2 diabetes;\u003c/p\u003e \u003cp\u003e(8) Patients with abnormal liver function (ALT/AST\u0026thinsp;\u0026gt;\u0026thinsp;1.5 times the upper limit of normal) or abnormal kidney function (Cr\u0026thinsp;\u0026gt;\u0026thinsp;the upper limit of normal);\u003c/p\u003e \u003cp\u003e(9) Patients with malignant tumors, organ failure, post-transplant status, or other severe chronic diseases;\u003c/p\u003e \u003cp\u003e(10) Pregnant or lactating women, or those planning pregnancy within 3 months;\u003c/p\u003e \u003cp\u003e(11) Patients with chronic alcohol abuse, drug dependence, or mental illness;\u003c/p\u003e \u003cp\u003e(12) Patients allergic to the drugs used in this study;\u003c/p\u003e \u003cp\u003e(13) Patients with poor compliance, withdraw from the study, severe organ damage, acute critical illness, or infectious diseases;\u003c/p\u003e \u003cp\u003e(14) Patients who have participated in or are currently participating in other drug clinical trials within the past 3 months;\u003c/p\u003e \u003cp\u003e(15) Patients deemed unsuitable for participation in this clinical trial by the investigators.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eWithdrawal/termination criteria\u003c/h2\u003e \u003cp\u003eDuring the trial, participants will be terminated if any of the following occurs:\u003c/p\u003e \u003cp\u003e(1) Serious adverse events occurs, rendering the participant unfit to continue the study;\u003c/p\u003e \u003cp\u003e(2) Disease-related complications, comorbidity, or significant physiological change occurs, rendering continued trial participation inappropriate;\u003c/p\u003e \u003cp\u003e(3) Poor compliance, including failure to use the study drug or attend scheduled visits as prescribed;\u003c/p\u003e \u003cp\u003e(4) Voluntary withdrawal from the study at any time for any reason;\u003c/p\u003e \u003cp\u003e(5) Unblinding or the need for emergency unblinding during the study period for any reason.\u003c/p\u003e \u003cp\u003eIn cases of treatment discontinuation or protocol deviation, the time of the last drug administration will be documented, and relevant assessment data will be collected.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRandomization and allocation concealment\u003c/h3\u003e\n\u003cp\u003eThe randomization sequence will be created using a centralized system at the Evidence-Based Medicine Center at the First Affiliated Hospital of Henan University of Chinese Medicine. Participants will be randomly assigned to either the intervention group or the control group in a 1:1 ratio. Patients in the intervention group (n\u0026thinsp;=\u0026thinsp;120) will receive ZHQ, while participants in the control group (n\u0026thinsp;=\u0026thinsp;120) will receive a placebo matched in appearance to the ZHQ. Researchers will obtain randomized patient and drug numbers through a central randomization system. All numbers are managed centrally by the Evidence-Based Medicine Center of the First Affiliated Hospital of Henan University of Chinese Medicine.\u003c/p\u003e\n\u003ch3\u003eBlinding\u003c/h3\u003e\n\u003cp\u003eThe trial will be conducted under a double-blind design, with both participants and investigators blinded to treatment allocation for the duration of the study. A two-stage blinding method is implemented: first-stage blinding, where the investigational drug is blinded by packaging it identically to the placebo; and second-stage blinding, where the packaging number of the investigational drug is blinded. Clinical investigators obtained participant assignment codes through the hospital's EDC system and administered the corresponding intervention based on these codes. Unblinding is permitted in cases of serious adverse events or when urgent measures are necessary to ensure patient safety.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eXiZang HongQu Biotechnology Co., Ltd. (Lasa, People\u0026rsquo;s Republic of China) will provide ZHQ herbal slices and placebo. The placebo's packaging, shape, and color are identical to the ZHQ, ensuring no impact on the implementation of the blinding. The medication instructions, production batch number, manufacturer, and drug code are printed on the outer packaging. Researchers will administer the drug to participants for 28 days at baseline, followed by an additional 56 days during the fourth-week follow-up visit. During the study period, participants must not take any other Chinese or Western medicine for lowering blood lipids.\u003c/p\u003e \u003cp\u003eParticipants allocated to the intervention group will receive treatment with ZHQ, 3g twice daily, brewed with boiling water. The total daily intake should not be less than 800 ml, until it loses its flavor or the residue is chewed and swallowed; the treatment will last for 12 weeks. In addition, researchers will provide consultation on lipid management.\u003c/p\u003e \u003cp\u003eParticipants allocated to the group will receive a placebo, administered in the same manner as the intervention group for 12 weeks. Researchers will also provide counseling on lipid management.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcome\u003c/h2\u003e \u003cp\u003eThe primary efficacy endpoints are Mean percentage change in LDL-C from baseline to week 12.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003e(1) Mean percentage change in LDL-C from baseline to week 4.\u003c/p\u003e \u003cp\u003e(2) Proportion of patients whose LDL-C level decreased by \u0026ge;\u0026thinsp;30% from baseline after 12 weeks of treatment;\u003c/p\u003e \u003cp\u003e(3) Mean percentage change in TC, TG, HDL-C and non-HDL-C at baseline and at weeks 4 and 12 of treatment;\u003c/p\u003e \u003cp\u003e(4) Changes in fasting blood glucose and fasting insulin at baseline and at weeks 4 and 12 of treatment;\u003c/p\u003e \u003cp\u003e(5) Changes in uric acid and homocysteine at baseline and at weeks 4 and 12 of treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSafety indicators\u003c/h2\u003e \u003cp\u003e(1) Assess vital signs (temperature, blood pressure, heart rate, respiration, etc.) during the run-in period, baseline period, and at 4 and 12 weeks of medication;\u003c/p\u003e \u003cp\u003e(2) Assess complete blood count, urinalysis, stool routine, liver function, kidney function, creatine kinase, and electrocardiogram during the run-in period and at 4 and 12 weeks of medication;\u003c/p\u003e \u003cp\u003e(3) Perform urine pregnancy tests on women of childbearing age during the run-in period.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eAll adverse events, including those reported by participants and researchers, will be recorded in the Case Report Form (CRF). Depending on the nature and severity of the adverse event, different management approaches will be implemented, such as terminating the clinical trial, adjusting the drug dosage, providing symptomatic treatment, or observation, and it will be assessed whether they are related to the study drug. Appropriate measures will be taken to ensure participant safety in case of potential harm. Any serious adverse event will be reported to the principal investigator, the clinical trial office, and the ethics committee within 24 hours. Reporting starts from the first administration of the study drug and continues until the conclusion of the participant's final visit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculation\u003c/h2\u003e \u003cp\u003eThis study is a randomized, double-blind, placebo-controlled trial. The outcome measure is a quantitative variable, and participants are randomly assigned to the intervention and control groups in a 1:1 ratio. The sample size calculation formula is as follows:\u003c/p\u003e \u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/127393_c7e80a1c9bb65875/127393_custom_files/img1778668492.png\"\u003e\u003c/p\u003e \u003cp\u003eBased on literature review findings[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], the LDL-C change rate in the Xuezhikang treatment group decreased by 27%, while the LDL-C change rate in the placebo control group increased by 2.8%. Assuming that the LDL-C change rate decrease of 27% in the ZHQ treatment group and the LDL-C change rate increase of 2.8% in the placebo control group, the superiority margin is set at 10.8%. We set the significance level α\u0026thinsp;=\u0026thinsp;0.05 and β\u0026thinsp;=\u0026thinsp;0.10 for a one-tailed test. The sample size ratio between the intervention and control groups is 1:1. Based on the formula, the sample size in each group is 107 cases, and the total sample size is 214 cases. Accounting for a 10% loss to follow-up, the sample size in each group should be 119 cases, and the total sample size is 238 cases. Therefore, this study plans to enroll 120 subjects in each group, totaling 240 subjects.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eData management and monitoring\u003c/h2\u003e \u003cp\u003eThis study uses Electronic Data Capture (EDC) for clinical research data. Data in the Electronic Case Report Form (eCRF) comes from original documents such as source medical records and laboratory test reports, and remains consistent with these source documents. All paper original documents will be stored in a locked office. Researchers should complete, review, and submit the eCRF promptly, and respond to inquiries from data administrators and medical reviewers in a timely manner. Two independent investigators will double - checked all original documents and eCRF. The supervisor is responsible for verifying the proper completion of eCRFs and ensuring that it is consistent with the original data. After data cleaning, researchers will sign the completed eCRF for confirmation. The data management process will adhere to the regulatory requirements of the \"Regulations on Quality Management of Clinical Trials\" and the \"Technical Guidelines for Clinical Trial Data Management\" to ensure data authenticity, completeness, accuracy, and traceability. The findings of this study will be communicated through peer-reviewed publications, academic conferences, and doctoral theses to ensure broad dissemination. However, any personally identifiable information collected during the course of the study will be kept strictly confidential and used solely for the purposes of this research.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAfter treatment, R software will be used to analyze and evaluate efficacy and safety. Continuous variables will be presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range) according to their distribution, whereas categorical variables will be summarized as frequencies and percentages. Chi-square test will be used for comparisons between groups for categorical data, and independent samples t-test or Mann-Whitney U test will be used for continuous data. All hypothesis tests will employ a two-tailed. Unless otherwise specified, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 will be considered statistically significant. Missing data will be addressed using imputation methods, intention-to-treat analysis, and sensitivity analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eElevated LDL-C, as a major component of dyslipidemia, is widely recognized as a major contributor to the development and progression of ASCVD[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Although statins have proven efficacy in lowering LDL-C and reducing the risk of cardiovascular events, their documented adverse effects \u0026mdash; including myopathy, new-onset diabetes, elevated hepatic enzyme levels, and hemorrhagic stroke \u0026mdash; limit their long-term use[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, exploring safe, effective, and long-term alternative or complementary lipid-lowering therapies is of significant clinical importance.\u003c/p\u003e \u003cp\u003eRYR preparations, as a natural lipid-lowering drug, have a main active ingredient, Monacolin K, which is chemically similar to lovastatin and can exist in both lactone and open-ring acid forms[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. After absorption in vivo, monacolin K rapidly converts from the lactone form to its active hydroxy acid form, reducing cholesterol synthesis by inhibiting the activity of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase, thereby exerting its lipid-lowering effect[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In contrast, pure lovastatin exhibits low absolute oral bioavailability (\u0026lt;\u0026thinsp;5%) due to its extensive first-pass effect and limited solubility. Lovastatin derived from RYR, however, demonstrates significantly improved oral bioavailability owing to increased solubility and reduced crystallinity, resulting in superior absorption and utilization efficiency within the body[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. As early as 1999, a randomized controlled trial by Herber[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] demonstrated that, compared with placebo, dietary supplements based on RYR has been associated with significant decreases in TC, LDL-C, and TG levels, providing early evidence for its lipid-lowering effect. The study by Sungthong[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] further showed that the use of RYR extract was significantly associated with a reduction in the risk of myocardial infarction, revascularization, and sudden cardiac death, suggesting its potential clinical value in the secondary prevention of cardiovascular diseases. Multiple studies in recent years have supplemented and reinforced these findings. A meta-analysis showed that[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] in patients with hyperlipidemia, administration of RYR extract resulted in a statistically significant decrease in TC and LDL-C levels, without an increased risk of life-threatening adverse reactions. Within the recommended dosage range, RYR preparations can be considered a lipid-lowering option that combines both efficacy and safety[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eZHQ is a novel RYR formulation produced by fermenting barley, a characteristic resource of the Qinghai-Tibet Plateau, with RYR bacteria. It has unique advantages in improving blood lipid levels and stabilizing plaques. Animal experiments have shown that ZHQ extract can improve serum TC, TG, HDL-C and LDL-C levels, and high-dose ZHQ demonstrates superior efficacy to lovastatin in lowering TC and LDL-C, reduces abdominal and epididymal fat deposition, and inhibits weight gain and fatty liver formation[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Clinical studies indicate that ZHQ is comparable to atorvastatin in reducing TC, TG, and LDL-C levels, preventing the increase of carotid intima-media thickness, and stabilizing plaques[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In terms of increasing HDL-C levels and reducing fasting blood glucose levels, it is superior to atorvastatin[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], and has a higher safety profile[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. However, current studies often suffer from limitations such as small sample sizes, insufficiently rigorous study designs, and inadequate blinding. Furthermore, there is a lack of high-quality randomized controlled trials to provide reliable evidence-based support for its clinical application.\u003c/p\u003e \u003cp\u003eThis study employs a multicenter, randomized, double-blind, placebo-controlled design to systematically evaluate the efficacy and safety of ZHQ in treating hyperlipidemia. The aim is to provide high-quality evidence-based medicine for ZHQ in improving of dyslipidemia, laying the foundation for subsequent long-term follow-up studies, mechanism exploration, and cardiovascular endpoint studies. Regarding outcome indicators, this study used the change in LDL-C from baseline to 12 weeks as the primary outcome indicator, and set secondary outcome indicators such as early efficacy observation, LDL-C achievement rate, TC, TG, HDL-C and non-HDL-C, which helps to comprehensively evaluate the lipid-lowering effects of ZHQ and its dynamic trends. In addition, this study incorporated fasting blood glucose, fasting insulin, uric acid, and homocysteine as secondary outcome measures to evaluate the potential benefits of ZHQ from the perspective of overall cardiovascular metabolic risk, providing supplementary evidence for its possible role in metabolic syndrome management. Regarding safety assessment, this study systematically monitored liver and kidney function, creatine kinase, complete blood count, and the occurrence of adverse events to comprehensively evaluate the tolerability and safety of ZHQ. The randomized, double-blind, placebo-controlled study design helps minimize bias and objectively identify drug-related adverse reactions, providing a reliable basis for safety evaluation. Overall, the results of this study are expected to provide a potential alternative treatment option for patients with dyslipidemia, especially those who cannot tolerate or are unwilling to use statins long-term, and provide a basis for their rational application in clinical practice.\u003c/p\u003e \u003cp\u003eOur study also has certain limitations. First, the intervention period is 12 weeks, aiming to assess the effects of ZHQ on lipid indicators, but it is difficult to directly reflect its long-term efficacy, cardiovascular endpoint effect, and sustained safety. These need to be further validated in future long-term follow-up or extended studies. Second, the study subjects are individuals with dyslipidemia without a clear history of cardiovascular disease, therefore, the applicability of the study results is mainly limited to the context of primary prevention. The efficacy and safety for patients with previous cardiovascular and cerebrovascular events, high-risk groups with diabetes, or other high-risk subgroups require further investigation.\u003c/p\u003e \u003cp\u003eIn conclusion, this study, conducted through a rigorously designed randomized, double-blind, placebo-controlled trial, is expected to address the current lack of evidence-based medical data for natural RYR preparations, and provide important support for future high-quality studies focusing on long-term clinical outcomes and mechanisms of action. Furthermore, it will contribute to the international dissemination of Chinese medicine in the prevention and management of cardiovascular diseases, providing a replicable research model for integrating Chinese medicine into the modern evidence-based medicine system.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank all the authors involved in the preparation of this paper for their diligent efforts and significant contributions, and we also express our heartfelt gratitude to the First Affiliated Hospital of Henan University of Chinese Medicine for providing comprehensive support and safeguards that ensured the successful conduct of this clinical trial. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYLZ and JJW participated in the development of the study protocol and drafted this manuscript. ALW and BL were responsible for statistical design and study coordination; RY and LJQ contributed to the clinical design and feasibility assessment; and YFX was responsible for sample size estimation and data management. XLW, XYL and MJZ conceptualized the study, led the overall design, and provided critical revisions. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declare that financial support was received for the research and/or publication of this article. This work was funded by the Special Research and Evaluation Project of China Association of Chinese Medicine (Grant No. CACMRE2025-A-05), \u0026nbsp;the National Natural Science Foundation of China (Grant No. 82505477), The Youth Talent Support Project of the Chinese Association of Chinese Medicine(Grant No. CACM-2025-QNRC2-B01), Henan Province Key Research and Development Project (Grant No.231111310200), Henan Province Science and Technology Research Project (Grant No.252102311270).\u003c/p\u003e\n\u003cp\u003eIn addition, Xizang Hongqu Biotechnology Co., Ltd. (Lasa, People\u0026rsquo;s Republic of China) provided the investigate drugs. The company had no role in the study design, data collection, data analysis, data interpretation, or manuscript preparation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data generated in this clinical trial will be accessible from the corresponding author upon reasonable request after the primary results have been published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProtocol version: V2.1 was finished on 31 August 2025. The study was conducted in accordance with the Declaration of Helsinki and was approved by The First Affiliated Hospital of Henan University of CM(2025HL-359-01) (Supplementary Material 3). Any substantial modifications to the study protocol, including changes to the design, eligibility criteria, or sample size, will require prior approval from the ethics committee. Written informed consent will be obtained from all participants before enrollment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors agreed to the publication of the article.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll co-authors declare that this clinical study involved no conflicts of interest. Xizang Hongqu Biotechnology Co., Ltd. provided support for this study by supplying the investigational drugs; it did not participate in any other aspects of the study\u0026apos;s implementation, including the overall design of the research protocol, the collection and organization of clinical data, statistical data analysis, the interpretation of research findings, or the drafting of the manuscript. This collaborative arrangement has been acknowledged and approved by the company; furthermore, there exists no financial or other relationship between the company and any of the authors that would constitute a potential conflict of interest.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eDepartment of Cardiovascular Disease, The first Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, 450000, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u0026nbsp;\u003c/sup\u003eHenan University of Chinese Medicine, Zhengzhou, Henan, 450000, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u0026nbsp;\u003c/sup\u003eHenan Evidence-based Medicine Center of Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, 450000, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMartin SS, Aday AW, Almarzooq ZI, et al. 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Chin Community Dr. 2024;40:74\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3969/j.issn.1007-614x.2024.05.026\u003c/span\u003e\u003cspan address=\"10.3969/j.issn.1007-614x.2024.05.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-complementary-medicine-and-therapies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcam","sideBox":"Learn more about [BMC Complementary Medicine and Therapies](https://bmccomplementmedtherapies.biomedcentral.com/)","snPcode":"","submissionUrl":"","title":"BMC Complementary Medicine and Therapies","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hyperlipidemia, Zanghongqu, Red yeast rice, Chinese medicine, Protocol","lastPublishedDoi":"10.21203/rs.3.rs-9524517/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9524517/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDyslipidemia, especially the elevation of low-density lipoprotein cholesterol (LDL-C), is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). Although statins are recommended as a first-line treatment, their long-term application may be limited by adverse reactions and poor adherence in some patients. ZangHongQu(ZHQ) herbal slice is a novel red yeast rice formulation formed by the fermentation of highland barley and red yeast rice bacteria, containing natural Monacolin K and various bioactive components, which has lipid-lowering and metabolic regulatory effects. However, currently, there is a lack of high-quality randomized controlled trials systematically evaluating its efficacy and safety. This study aims to assess the efficacy and safety of ZHQ in treating dyslipidemia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. It plans to enroll 240 patients aged 18–75 years with dyslipidemia and LDL-C ≥ 3.4 mmol/L. Participants will be randomly assigned in a 1:1 ratio to either the intervention group receiving ZHQ or the control group receiving placebo. The primary outcome measure is the change in LDL-C levels. Secondary outcomes include other lipid parameters, blood glucose, insulin, uric acid, and homocysteine levels. Safety assessments encompass liver and kidney function, creatine kinase, vital signs, and adverse events monitoring. Assessments will be conducted at baseline, 4 weeks, and 12 weeks after intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aims to provide high-quality evidence-based medicine for the efficacy and safety of ZHQ in treating dyslipidemia, and to provide a scientific basis for its potential application in cardiovascular risk management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration and Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ehttp://itmctr.ccebtcm.org.cn/ , ITMCTR2025001724. Ethical Review Number: 2025HL-359-01.\u003c/p\u003e","manuscriptTitle":"The Efficacy and Safety of Zanghongqu Herbal Slices in the Treatment of Hyperlipidemia: study protocol for a multicenter, randomized, double-blind, placebo controlled clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-13 17:50:21","doi":"10.21203/rs.3.rs-9524517/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-09T09:26:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247525628145183058732800654675305637547","date":"2026-05-09T09:22:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-05T20:31:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-05T18:34:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Complementary Medicine and Therapies","date":"2026-05-05T16:23:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-complementary-medicine-and-therapies","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcam","sideBox":"Learn more about [BMC Complementary Medicine and Therapies](https://bmccomplementmedtherapies.biomedcentral.com/)","snPcode":"","submissionUrl":"","title":"BMC Complementary Medicine and Therapies","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"736790de-e86c-4379-88dd-2dcee47a10c5","owner":[],"postedDate":"May 13th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-09T09:26:39+00:00","index":21,"fulltext":""},{"type":"reviewerAgreed","content":"247525628145183058732800654675305637547","date":"2026-05-09T09:22:04+00:00","index":20,"fulltext":""},{"type":"reviewersInvited","content":"10","date":"2026-05-05T20:31:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-05T18:34:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Complementary Medicine and Therapies","date":"2026-05-05T16:23:33+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T17:50:21+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-13 17:50:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9524517","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9524517","identity":"rs-9524517","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}