Comparing the effectiveness of Chinese patent medicines containing red yeast rice on hyperlipidaemia: A network meta‐analysis of randomized controlled trials

Abstract Introduction The purpose of this study was to evaluate the therapeutic effectiveness of Chinese patent medicines containing red yeast rice for the treatment of hyperlipidaemia. Methods Relevant literature published until 13 August 2021, was retrieved from six electronic databases. Randomized clinical trials of Chinese patent medicines containing red yeast rice in patients with hyperlipidaemia were included in the review. Network meta‐analysis was performed using Stata 13.1 software. Methodological quality was assessed using the Cochrane risk of bias tool. The surface under the cumulative ranking (SUCRA) curve probability values were used to rank the treatments. Results This study included 47 trials involving 4824 subjects. In terms of reduced total cholesterol levels, Xuezhikang (SUCRA: 84.5%) had the highest probability of being the most effective formulation, with Simvastatin (66.4%) and Zhibitai (65.4%) ranked second and third, respectively. Xuezhikang also had the highest probability of reducing low‐density lipoprotein cholesterol levels to the greatest extent (SUCRA: 82.6%) with Simvastatin (SUCRA: 74.9%) and Zhibituo (SUCRA: 52.8%) being the second and third choices, respectively. For reduced triglyceride levels, Zhibituo (SUCRA: 80.2%) exhibited the highest probability of being the most effective, with Xuezhikang (SUCRA: 63.4%) and Simvastatin (SUCRA: 57.6%) in second and third places, respectively. Finally, in terms of improving high‐density lipoprotein cholesterol levels, Zhibituo (SUCRA: 90.1%) had the highest probability of being the most effective, with Simvastatin (SUCRA: 82.1%) and Xuezhikang (SUCRA: 51.1%) ranked second and third, respectively. Conclusions Xuezhikang was found to have the highest probability of being the most effective formulation for reducing total cholesterol and low‐density lipoprotein cholesterol levels, while Zhibituo had the highest probability of being the most effective for controlling triglyceride and high‐density lipoprotein cholesterol levels. The studies included in the review exhibited certain limitations and, therefore, more rigorously designed studies should be performed. Trial registration: INPLASY registration number: INPLASY202130017.


| INTRODUC TI ON
Hyperlipidaemia is a common, global metabolic syndrome associated with lipid abnormalities, including increased levels of triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and decreased levels of high-density lipoprotein cholesterol (HDL-C). 1,2 Serum lipid levels in the Chinese population have gradually increased, and the prevalence of dyslipidaemia among Chinese adults has reached 40.4%. [3][4][5] Hyperlipidaemia is a major contributory factor to various diseases, including cardiovascular diseases, type 2 diabetes, Alzheimer's disease and Parkinson's disease. [6][7][8] Therefore, measures to effectively and treat dyslipidaemia are crucial for preventing cardiovascular and cerebrovascular diseases.
Statins are currently the drug of choice for the treatment of hypercholesterolemia. 9,10 However, the side effects caused by their use often limit their application. 11 Previous studies have suggested that extracts of red yeast rice (RYR) reduce blood lipid levels. 12,13 There are many varieties of oral Chinese patent medicines containing RYR for the treatment of hyperlipidaemia, such as Xuezhikang, Zhibituo and Zhibitai capsules, which are widely used in China for the treatment of hyperlipidaemia. 14 However, the efficacy of these Chinese patent medicines has not been directly compared for the treatment of hyperlipidaemia; therefore, it is not possible to select an optimal formulation for patients with hyperlipidaemia. Consequently, we conducted a network metaanalysis to compare the therapeutic effectiveness of Chinese patent medicines for treating hyperlipidaemia and identify which of them was consistently ranked as the most effective.

| MATERIAL S AND ME THODS
The protocol for this meta-analysis was registered using the INPLASY (No. INPLASY202130017), available on Inplasy.com (https://doi. org/10.37766/ inpla sy2021.3.0017). Ethics approval for this study was not required, as the meta-analysis did not involve identifiable patient data.

| Bibliographic search strategy
Two authors (XGQ and DXL) conducted the literature searches.

| Inclusion criteria
Trials were included in the present study following the PICOS framework (population, intervention, comparisons, outcomes and study type

| Exclusion criteria
Studies were excluded for the following reasons: (1) duplicate publications; (2) case reports, reviews, or studies with animals as research subjects; (3) patient comorbidities (eg diabetes, cardiovascular diseases and cerebrovascular diseases), (4) incorrect or missing data or (5) trials with <50 cases.

| Outcome measures
The main outcomes were serum lipid levels, including TC, TG, LDL-C and HDL-C levels. The secondary outcomes included ADRs.

| Data extraction
Two reviewers (XGQ and DXL) independently selected the studies.
Titles and abstracts were screened to identify potential articles, and then, the full texts of the screened articles were read to determine suitable studies based on the inclusion and exclusion criteria.
Discrepancies in selection were resolved through team discussion.
The selection procedures were based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart. 15 Trial registration: INPLASY registration number: INPLASY202130017.

K E Y W O R D S
Chinese patent medicine, evidence-based medicine, network meta-analysis 2.6 | Assessment of quality Two researchers (XGQ and DXL) independently assessed the risk of bias in the studies included in this review using the risk of bias tool from the Cochrane Handbook. Any disagreements were resolved using an arbiter. The following items were evaluated: selection bias (random sequence generation, allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of assessors), attrition bias and other types of bias. The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence. 16 According to the GRADE approach, evidence quality is classified into four levels: high, moderate, low and very low.
RCTs provide high-quality evidence; however, the evidence can be downgraded from high to low quality owing to five factors: study limitation (risk of bias), indirectness, inconsistency, imprecision and publication bias.

| Statistical analysis
A statistical software (Stata 13.1; Stata Corporation) was used for the present study. The results were reported as mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity assessment was performed using chi-squared (χ 2 ) tests; if I 2 was ≤50%, the heterogeneity was considered to be low, and network metaanalysis could be performed; if I 2 > 50%, heterogeneity was deemed to be high, and the study could be conducted when the source of heterogeneity could be found. For indirect comparisons, the treatment effects of all regimens were estimated using a two-stage network meta-analysis as follows: Initially, an inconsistency test was performed using a node-splitting model, and fitting consistency or inconsistency models were constructed and presented using the network command; if inconsistency was not statistically significant (p > .05), a consistency model was used; otherwise, an inconsistency model was employed. Pairwise comparisons were conducted using the 'interval plot' command. Ranking probabilities for each intervention were then estimated using the 'network rank' command.
Surface under the cumulative ranking (SUCRA) curve values were calculated to rank the efficacy of each intervention. Larger SUCRA values indicate a more effective intervention. Publication bias was evaluated using comparison-adjusted funnel plots.

| Baseline characteristics of included studies
A total of 47 RCTs involving 4824 participants diagnosed with hyperlipidaemia satisfied the study selection criteria and were included in the study. From these 47 RCTs, the effects on hyperlipidaemia resulting from the use of three Chinese patent medicines containing RYR were summarized. The characteristics of the included studies are summarized in Table 1. The included studies showed that all baseline values were comparable.

| Risk of bias in included studies
The risk-of-bias graphs for the 47 studies are shown in Figure 2.
All studies included randomization, five 21,22,28,37,46 described the generation of a random sequence using a random number table,

| Test of inconsistency and network plot
The evidence network is shown in Figure 3. The network metaanalysis included closed loops, and formal tests for inconsistency were performed. We found inconsistencies were not statistically significant (TC, p = .58; TG, p = .26; LDL-C, p = .64; and HDL-C, p = .32), and a network meta-analysis was performed using a consistency model.

| Publication bias
A comparison-adjusted funnel plot of all outcomes demonstrated, by its asymmetry, that some publication bias existed, for which that of TC is displayed in Figure 8. Bold values indicate statistically significant values p < 0.05.

| Quality of evidence
The GRADE approach was used to assess the quality of evidence.
The quality of evidence for the outcomes was low, and the results are presented in Table 6, and the reasons for downgrading included study limitations (risk of bias) and imprecision. Most of the included studies were classified as high risk; there was imprecision because the ranking probabilities based on SUCRA values were very close, and publication bias was observed.

| DISCUSS ION
The incidence of hyperlipidaemia has increased owing to heredity, nutrition, diet, medication and other factors. 64 Hyperlipidaemia is a major risk factor for cardiovascular diseases and atherosclerosis. 65 There is increasing evidence that traditional Chinese medicines that eliminate phlegm and blood stasis can successfully reverse the symptoms of hyperlipidemia. 66 RCTs were included in our study. In 2019, Fogacci et al. 71 performed a meta-analysis on the safety data surrounding RYR, whereas the purpose of our study was to evaluate the therapeutic effectiveness.
In 2020, Sungthong et al. 72 performed a meta-analysis to analyse the efficacy of RYR on cardiovascular outcomes in patients with myocardial infarction, while the participants of our study were diagnosed with hyperlipidaemia. RYR showed overall tolerability and safety for hyperlipidaemia, based on a previous meta-analysis. 71 The results of our meta-analysis provide evidence that Chinese patent medicines containing RYR are highly efficient for the treatment of hyperlipidaemia.
The present network meta-analysis is the first study to as- The RYR has been widely used in China for many years. 73 Previous studies have shown that it can reverse the symptoms of hyperlipidaemia, the mechanism of action of which is similar to that of statins. 74 Statins are the key lipid-lowering medications and are the current recommended initial therapy for blood lipid disorders. 75,76 The mechanism is that its efficacy component, monacolin

TA B L E 6
Results of GRADE evidence evaluation the specific methods of random sequence generation, three randomized, double-blind, placebo-controlled trials 36,52,53 and four randomized, placebo-controlled trials. 50,58,61,63 In addition, the quality of evidence for the outcomes was low. (4) The number of trials that compared some of the medicines was relatively small, causing the comparative results to not be incredibly persuasive, and those cases should be considered with caution. Thus, additional, well-designed, double-blinded, multicentre RCTs are required to establish the efficacy of Chinese patent medicines for the treatment of hyperlipidaemia.

| CON CLUS IONS
To reduce the levels of TC and LDL-C, Xuezhikang displayed the highest probability of being the most effective option. To reduce TG levels, Zhibituo exhibited the highest probability of being the most effective, and Zhibituo may have the highest probability of ameliorating levels of HDL-C, whereas there was no significant difference between Zhibituo and Xuezhikang. Owing to the limitations of this study, the validity of our results requires confirmation using largesample, high-quality, multicentre, prospective RCTs.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflicts of interest regarding this study.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.