Chinese red yeast rice (<it>Monascus purpureus</it>) for primary hyperlipidemia: a meta-analysis of randomized controlled trials

1749-8546-1-4 1749-8546 Review Chinese red yeast rice (<it>Monascus purpureus</it>) for primary hyperlipidemia: a meta-analysis of randomized controlled trials Liu Jianping Jianping.liu@fagmed.uit.no Zhang Jing n@fagmed.uit.no Shi Yi a@fagmed.uit.no Grimsgaard Sameline b@fagmed.uit.no Alraek Terje c@fagmed.uit.no Fønnebø Vinjar Vinjar.Fonnebo@fagmed.uit.no

National Research Centre in Complementary and Alternative Medicine (NAFKAM), University of Tromso, Tromso N-9037, Norway

Evidence-Based Medicine Centre in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Cai Lun Lu 1200, Pudong, Shanghai 201203, China

The Institute of Traditional Chinese Medicine Literature, Shanghai University of Traditional Chinese Medicine, Cai Lun Lu 1200, Pudong, Shanghai 201203, China

Evidence-Based Chinese Medicine Research Centre, Beijing University of Chinese Medicine, Beijing 100029, China

Chinese Medicine 1749-8546 2006 1 1 4 http://www.cmjournal.org/content/1/1/4 17302963 10.1186/1749-8546-1-4 28 2 2006 23 11 2006 23 11 2006 2006 Liu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Extracts of Chinese red yeast rice (RYR, a traditional dietary seasoning of Monascus purpureus) contains several active ingredients including lovastatin, and several trials of its possible lipid-lowering effects have been conducted. This meta-analysis assesses the effectiveness and safety of RYR preparations on lipid modification in primary hyperlipidemia. We included randomized controlled trials testing RYR preparation, compared with placebo, no treatment, statins, or other active lipid-lowering agents in people with hyperlipidemia through searching PubMed, CBMdisk, TCMLARS, the Cochrane Library, and AMED up to December 2004. Ninety-three randomized trials (9625 participants) were included and three RYR preparations (Cholestin, Xuezhikang and Zhibituo) were tested. The methodological quality of trial reports was generally low in terms of generation of the allocation sequence, allocation concealment, blinding, and intention-to-treat. The combined results showed significant reduction of serum total cholesterol levels (weighted mean difference -0.91 mmol/L, 95% confidence interval -1.12 to -0.71), triglycerides levels (-0.41 mmol/L, -0.6 to -0.22), and LDL-cholesterol levels (-0.73 mmol/L, -1.02 to -0.043), and increase of HDL-cholesterol levels (0.15 mmol/L, 0.09 to 0.22) by RYR treatment compared with placebo. The lipid modification effects appeared to be similar to pravastatin, simvastatin, lovastatin, atorvastatin, or fluvastatin. Compared with non-statin lipid lowering agents, RYR preparations appeared superior to nicotinate and fish oils, but equal to or less effective than fenofibrate and gemfibrozil. No significant difference in lipid profile was found between Xuezhikang and Zhibituo. RYR preparations were associated with non-serious adverse effects such as dizziness and gastrointestinal discomfort. Current evidence shows short-term beneficial effects of RYR preparations on lipid modification. More rigorous trials are needed, and long-term effects and safety should be investigated if RYR preparations are to be recommended as one of the alternative treatments for primary hyperlipidemia.

Background

Red yeast rice (RYR) is a traditional Chinese cuisine and medicinal agent prepared by using Monascus purpureus fermented with rice, which has been recorded in ancient Chinese pharmacopoeia Ben Cao Gang Mu-Dan Shi Bu Yi during the Ming Dynasty (1368–1644)1. The extracts from RYR contain starch, sterols, isoflavones, and monounsaturated fatty acids, and other compounds 23; depending on Monascus strains used and fermentation conditions, it may contain polyketides called monacolins 4. Monacolin K is lovastatin, which is a commonly prescribed lipid-lowering drug. Several randomized clinical trials have indicated beneficial effects of the RYR preparations including Xuezhikang and Zhibituo in the treatment of hyperlipidemia 56789. Xuezhikang has been in clinical use as a Chinese proprietary medicine in China and has recently been marketed in several European countries including Norway and Italy. As these preparations contain different compositions and concentration of lovastatin, evaluation of their effectiveness and safety from clinical trials is warranted.

People with hyperlipidemia have responded well to the lipid-lowering agents including HMG-CoA reductase inhibitors (statins), fibrates, nicotinic acids, and n-3 fatty acids 10. However, long-term safety and potential drug interaction between statins and other hypolipidemic agents may become problematic 111213. Nowadays, many people would like to use naturaceuticals instead of chemical drugs. A previous systematic review identified four randomized trials of the lipid-lowering effects of RYR and concluded a lack of sufficient clinical research to support their efficacy 14. The objective of this review is to assess the beneficial effects of lipid modification and safety of RYR preparations for their use in people with primary hyperlipidemia.

Methods

Search strategy

To identify relevant studies, we searched the following databases up to December 2004: The Cochrane Library, PubMed, Chinese Biomedical Database (CBMdisk), Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), and the Allied and Complementary Medicine Database (AMED). We used the search terms 'red yeast rice, Monascus purpureus, Xuezhikang, Cholestin, Hypochol, Hypocol, Lipascor', combined with 'hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertriglyceridemia, hyperlipoproteinemia', and limited our search to clinical trials. Depending on the database, various combinations of both MeSH terms and the free text terms were used, but no limitation with regard to language and report type. We also screened the reference lists of identified papers and review articles, and contacted pharmaceutical companies.

Inclusion criteria

We included randomized clinical trials comparing RYR vs. placebo, no intervention, or established lipid-lowering agents in individuals with primary hyperlipidemia on outcomes of lipid profile and adverse effects. Eligible trials had to include adult participants meeting the National Cholesterol Education Programme diagnostic criteria of hyperlipidemia 15 and excluded secondary causes such as hypothyroidism, familial hypercholesterolemia, diabetes mellitus, liver or kidney diseases. Trials comparing different RYR preparations were included, but trials comparing different dosage of RYR preparations or comparing RYR with other herbal medicines were excluded.

Validity assessment

The methodological quality of trials was assessed using the generation of the allocation sequence, the allocation concealment, double blinding, and withdrawals/dropouts 16171819.

Data abstraction

One author (JL) extracted data and another author (JZ) cross-checked the data, and any disagreement was resolved by consensus. The following study characteristics were abstracted from the trials: design, participants and diagnosis, intervention regimen, and outcome measures.

Data synthesis

We used the statistical package (RevMan 4.2) provided by the Cochrane Collaboration for data analyses. Dichotomous data were presented as relative risk (RR) and continuous outcomes as weighted mean difference (WMD), both with 95% confidence interval (CI). We assessed data by both random effects and fixed effect analyses, but reported the random effect analysis if the heterogeneity was significant, which was assessed by the I²statistic and used P < 0.10 as significance limit 20.

Results

Included trials

We identified 647 records on RYR preparations from electronic and manual searches. By reading titles and abstracts, we excluded 275 citations that were clearly duplicates, review articles, or non-clinical studies. A total of 372 articles published in Chinese or English were retrieved for further assessment. Of these, 279 articles were excluded because they were non-controlled clinical studies or randomized trials with different research objectives. Two of these were ongoing placebo-controlled trials testing 'Hypocol' in Norway and 'Lipolysar' in Italy 21, but data were not available while writing this report. In total, 93 randomized clinical trials 678222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111 were identified and they reported to allocate participants with primary hyperlipidemia (n = 9625) randomly to RYR preparation or no treatment (2 trials), placebo (8 trials), statins (37 trials), other lipid-lowering agents (42 trials), or to a different RYR preparation (7 trials), in which three trials had more than two arms. The 93 trials were parallel group trials, and 91 were published in Chinese and two published in English 749. Three RYR preparations were tested in the included trials: The RYR dietary supplement (Cholestin), and the Chinese proprietary medicines Xuezhikang and Zhibituo. Their constituents, dosages, and treatment regimens are listed in Table 1. All trials reported lipid profile outcome and 77 trials also reported adverse effects.

Table 1

Composition and treatment regimens of red yeast rice preparations

Preparation

Composition

Dosage

Administration

Red yeast rice dietary supplement (Cholestin) capsules

Extracts of fermented Monascus purpureus rice

2.4 g/day (containing 5 mg lovastatin)

0.6 g/cap 2 caps, twice daily

Xuezhikang capsule

Extracts from fermented Monascus purpureus rice, Fructus Crataegi, Radix Salviae miltiorrhizae, Rhizoma Curcumae longae, Radix Rhizoma rhei, etc.

1.2 g/day (containing 10 mg lovastatin)

0.3 g/cap 2 caps, twice daily

Zhibituo tablet

Extracts from fermented Monascus purpureus rice, Fructus Crataegi, Rhizoma Atractylodis macrocephalae, Rhizoma Alismatis orientalis, etc.

3.15 g/day (containing lovastatin 9 mg)

0.35 g/tab 3 tabs, thrice daily

Methodological quality of included trials

Of the 93 trials, only three trials reported the methods to generate the allocation sequence (random number table or permuted blocks) 73270, and two trials were assessed as having adequate concealment 729. Five trials applied double-blinding 725262730, and three trials blinded the outcome assessors 2951106. One trial reported prior sample size estimation and information on withdrawal/dropout 7, but no trial mentioned intention-to-treat analysis. Accordingly, the included trials had generally low methodological quality. All trials provided baseline data for the comparability among groups. The average sample size of the randomized trials was 103, ranging from 28 to 450 participants per trial.

Total cholesterol (TC) levels (Tables 2 and 3)

Table 2

Net benefit of RYR preparations in lipid profile in placebo-controlled trials

No. of subjects

Baseline

Post-treatment

Difference

P value

Mean (SD)

Mean (95% CI)

% Change

TC levels (mmol/L)

Cholestin

6.47 (0.78)

5.43 (0.80)

-1.04 (-1.38 to -0.70)

-16%

< 0.00001

Placebo

6.59 (0.75)

6.47 (0.93)

-0.12 (-0.49 to 0.25)

-2%

0.52

6.68 (0.98)

5.31 (0.84)

-1.37 (-1.83 to -0.91)

-21%

5.81 (0.63)

4.26 (0.63)

-1.55 (-1.85 to -1.25)

-27%

Xuezhikang

101

7.30 (1.40)

5.90 (1.40)

-1.40 (-1.79 to -1.01)

-19%

5.65 (1.31)

3.16 (1.31)

-2.49 (-3.15 to -1.83)

-44%

Subtotal: 194

-1.63 (-2.00 to -1.26)

< 0.00001

6.72 (0.97)

6.43 (0.93)

-0.29 (-0.79 to 0.21)

-4%

5.84 (0.67)

4.94 (0.67)

-0.90 (-1.24 to -0.56)

-15%

Placebo

6.80 (1.40)

6.70 (1.40)

-0.10 (-0.64 to 0.44)

-1%

5.55 (1.02)

4.95 (1.02)

-0.60 (-1.23 to 0.03)

-11%

Subtotal: 129

-0.50 (-0.90 to -0.11)

0.01

5.90 (0.95)

4.94 (0.65)

-0.96 (-1.71 to -0.21)

-16%

Zhibituo

6.70 (1.10)

5.80 (0.90)

-0.90 (-1.41 to -0.39)

-13%

104

7.10 (1.70)

5.60 (1.30)

-1.50 (-1.91 to -1.09)

-21%

Subtotal: 143

-1.17 (-1.59 to -0.74)

< 0.00001

5.83 (0.57)

5.56 (0.53)

-0.27 (-0.78 to 0.24)

-5%

Placebo

6.70 (1.50)

6.40 (1.30)

-0.30 (-1.01 to 0.41)

-4%

101

6.00 (1.80)

6.50 (0.70)

0.50 (0.12 to 0.88)

Subtotal: 140

0.02 (-0.56 to 0.60)

0.95

TG levels (mmol/L)

Cholestin

1.50 (0.54)

1.40 (0.50)

-0.10 (-0.32 to 0.12)

-7%

0.38

Placebo

1.61 (0.52)

1.65 (0.53)

0.04 (-0.19 to 0.27)

2.84 (0.57)

2.38 (0.62)

-0.46 (-0.76 to -0.16)

-16%

2.10 (0.92)

1.82 (0.92)

-0.28 (-0.72 to 0.16)

-13%

Xuezhikang

101

3.60 (2.40)

2.30 (1.60)

-1.30 (-1.86 to -0.74)

-36%

2.62 (0.58)

1.47 (0.58)

-1.15 (-1.44 to -0.86)

-44%

Subtotal: 194

-0.78 (-1.26 to -0.31)

0.001

2.74 (0.73)

2.57 (0.69)

-0.17 (-0.54 to 0.20)

-6%

Placebo

2.14 (0.94)

1.91 (0.94) 3.00 (1.60)

-0.23 (-0.71 to 0.25) -0.30 (-0.92 to 0.32)

-11%

3.30 (1.60)

3.00 (1.60)

-0.30 (-0.92 to 0.32)

-9%

2.50 (0.50)

2.11 (0.50)

-0.39 (-0.70 to -0.08)

-16%

Subtotal: 129

-0.29 (-0.49 to -0.09)

0.005

2.46 (1.23)

1.79 (0.57)

-0.67 (-1.41 to 0.07)

-27%

Zhibituo

3.40 (0.90)

2.10 (1.10)

-1.30 (-1.81 to -0.79)

-38%

104

3.40 (1.50)

2.30 (1.30)

-1.10 (-1.48 to -0.72)

-32%

Subtotal: 147

-1.10 (-1.38 to -0.82)

< 0.00001

2.56 (0.88)

2.36 (0.64)

-0.20 (-0.91 to 0.51)

-8%

3.40 (1.10)

3.10 (1.20)

-0.30 (-0.88 to 0.28)

-9%

Placebo

101

3.10 (0.40)

2.50 (1.40)

-0.60 (-0.88 to -0.32)

-19%

Subtotal: 140

-0.50 (-0.74 to -0.26)

< 0.0001

LDL-C levels (mmol/L)

Cholestin

4.47 (0.70)

3.49 (0.70)

-0.98 (-1.28 to -0.68)

-22%

< 0.00001

Placebo

4.65 (0.78)

4.53 (0.85)

-0.12 (-0.47 to 0.23)

-3%

0.51

3.94 (0.82)

2.83 (0.88)

-1.11 (-1.54 to -0.68)

-28%

4.13 (0.52)

2.80 (0.52)

-1.33 (-1.58 to -1.08)

-32%

Xuezhikang

101

4.80 (1.60)

3.50 (1.40)

-1.30 (-1.71 to -0.89)

-27%

3.00 (1.03)

2.10 (1.03)

-0.90 (-1.42 to -0.38)

-30%

Subtotal: 194

-1.23 (-1.41 to -1.05)

<0.00001

4.13 (0.94)

4.01 (0.86)

-0.12 (-0.59 to 0.35)

-3%

4.24 (0.53)

3.41 (0.53)

-0.83 (-1.10 to -0.56)

-20%

Placebo

4.20 (1.60)

4.30 (1.60)

0.10 (-0.52 to 0.72)

3.19 (0.87)

2.70 (0.87)

-0.49 (-1.03 to 0.05)

-15%

Subtotal: 129

-0.38 (-0.83 to 0.07)

0.10

Zhibituo

104

3.70 (1.60)

3.50 (1.40)

-0.20 (-0.61 to 0.21)

-5%

0.34

Placebo

101

3.70 (1.20)

3.70 (1.00)

0.00 (-0.30 to 0.30)

1.00

HDL-C levels (mmol/L)

Cholestin

1.29 (0.34)

1.29 (0.36)

0.00 (-0.15 to 0.15)

1.00

Placebo

1.19 (0.26)

1.19 (0.28)

0.00 (-0.12 to 0.12)

1.00

1.50 (0.46)

1.67 (0.54)

0.17 (-0.08 to 0.42)

11%

1.37 (0.21)

1.16 (0.21)

-0.21 (-0.31 to -0.11)

-15%

Xuezhikang

101

1.20 (0.40)

1.40 (0.30)

0.20 (0.10 to 0.30)

17%

1.20 (0.21)

1.22 (0.21)

0.02 (-0.09 to 0.13)

Subtotal: 194

0.04 (-0.17 to 0.24)

0.73

1.57 (0.69)

1.53 (0.32)

-0.04 (-0.32 to 0.24)

-3%

1.36 (0.24)

1.13 (0.24)

-0.23 (-0.35 to -0.11)

-17%

1.30 (0.40)

1.30 (0.30)

0.00 (-0.14 to 0.14)

Placebo

1.22 (0.25)

1.00 (0.25)

-0.22 (-0.37 to -0.07)

-18%

Subtotal: 129

-0.13 (-0.26 to -0.01)

0.04

0.89 (0.41)

1.09 (0.41)

0.20 (-0.12 to 0.52)

22%

1.08 (0.11)

1.31 (0.17)

0.23 (0.16 to 0.30)

21%

Zhibituo

104

0.85 (0.14)

0.98 (0.26)

0.13 (0.07 to 0.19)

15%

Subtotal: 147

0.18 (0.10 to 0.26)

< 0.0001

0.92 (0.19)

0.90 (0.17)

-0.02 (-0.16 to 0.12)

-2%

0.99 (0.20)

1.02 (0.28)

0.03 (-0.09 to 0.15)

Placebo

101

0.89 (0.13)

0.80 (0.30)

-0.09 (-0.15 to -0.03)

-10%

Subtotal: 144

-0.04 (-0.12 to 0.03)

0.26

Table 3

Post-treatment total cholesterol levels (mmol/L) in randomized controlled trials

Interventions

No. of trials [references]

No. of participants

Weighted mean difference (95% confidence interval)

P value

RYR vs. no intervention/placebo

Zhibituo vs. no intervention

2 [22, 23]

112

-1.27 (-1.50 to -1.05)

< 0.00001

RYR supplement vs. placebo

1 [7]

-1.04 (-1.41 to -0.67)

< 0.00001

Xuezhikang vs. placebo

4 [8, 24–26]

323

-1.04 (-1.46 to -0.62)*

< 0.00001

Zhibituo vs. placebo

3 [27–29]

283

-0.80 (-1.03 to -0.57)

< 0.00001

RYR vs. statins

Xuezhikang vs. simvastatin

15 [6, 30–43]

1455

0.05 (-0.27 to 0.37)*

0.76

Xuezhikang vs. pravastatin

7 [44–50]

594

- 0.20 (- 0.47 to 0.06)*

0.14

Xuezhikang vs. lovastatin

3 [51–53]

174

-0.05 (-0.27 to 0.18)

0.69

Xuezhikang vs. atorvastatin

1 [54]

-0.16 (-0.58 to 0.26)

0.46

Xuezhikang vs. fluvastatin

1 [55]

118

0.48 (0.24 to 0.72)

0.0001

Zhibituo vs. simvastatin

9 [32, 56–63]

728

0.11 (-0.03 to 0.25)

0.14

Zhibituo vs. provastatin

1 [22]

0.05 (-0.20 to 0.30)

0.70

Zhibituo vs. lovastatin

1 [57]

-0.11 (-0.48 to 0.26)

0.56

RYR vs. non-statin drugs

Xuezhikang vs. inositol nicotinate

7 [65–71]

624

-0.56 (-0.81 to -0.31)*

< 0.0001

Xuezhikang vs. fenofibrate

5 [32, 73–76]

337

-0.13 (-0.46 to 0.20)*

0.44

Xuezhikang vs. gemfibrozil

3 [77–79]

156

-0.43 (-1.52 to 0.65)*

0.43

Xuezhikang vs. fish oils

2 [80, 81]

116

-0.81 (-1.11 to -0.50)

< 0.00001

Xuezhikang vs. alginic sodium diester

1 [84]

-1.08 (-1.38 to -0.78)

< 0.00001

Xuezhikang vs. conjugated estrogens

1 [85]

-0.87 (-1.20 to -0.54)

< 0.00001

Xuezhikang vs. elastase

1 [86]

107

-0.10 (-0.49 to 0.29)

0.61

Xuezhikang vs. biphenalbid

1 [87]

0.12 (-0.31 to 0.55)

0.59

Zhibituo vs. inositol nicotinate

8 [88–95]

608

-0.73 (-1.13 to -0.33)*

0.0004

Zhibituo vs. fish oils

6 [97–102]

491

-0.76 (-1.04 to -0.49)*

< 0.00001

Zhibituo vs. fenofibrate

2 [32, 104]

248

0.31 (0.04 to 0.59)

0.02

RYR versus RYR

Xuezhikang vs. Zhibituo

7 [32, 106–111]

701

-0.03 (-0.25 to 0.20)*

0.82

* Random effects model

The three RYR preparations significantly reduced serum TC levels and the effect was reached at four weeks after the treatment and remained stable until 12 weeks (Figure 1). The percentage of TC level reduction was 16% for cholestin, 19%–44% for Xuezhikang, and 13%–21% for Zhibituo (Table 2). Compared with no treatment, Zhibituo showed a reduction of serum TC levels (WMD -1.27 mmol/L; 95% CI -1.50 to -1.05; 2 trials, n = 112) 2223. Compared with placebo, significant reduction of serum TC levels was found for Cholestin (WMD -1.04 mmol/L; 95% CI -1.41 to -0.67; 1 trial, n = 83) 7, Xuezhikang (WMD -1.04 mmol/L; 95% CI -1.46 to -0.62; 4 trials, n = 323) 8242526, and Zhibituo (WMD -0.80 mmol/L; 95% CI -1.03 to -0.57; 3 trials, n = 283) 272829. There was no significant heterogeneity among the trials (I²statistic test) (Table 3). Different treatment duration showed similar effect of RYR preparations in reducing TC levels compared with placebo by 4 weeks (WMD -0.96 mmol/L; 95% CI -1.49 to -0.43; 2 trials, n = 113) 2526, 6 weeks (WMD -0.61; 95% CI -1.0 to -0.22; 2 trials, n = 78) 2728, 8 weeks (WMD -1.06; 95% CI -1.39 to -0.73; 5 trials, n = 406) 78242526, and 12 weeks (WMD -1.04; 95% CI -1.41 to -0.67; 1 trial, n = 83) 7.

Figure 1

Total cholesterol levels during the treatment in 8 randomized placebo-controlled trials

Total cholesterol levels during the treatment in 8 randomized placebo-controlled trials.

Xuezhikang and Zhibituo were compared with simvastatin, pravastatin, lovastatin, atorvastatin, or fluvastatin in 37 trials. There was no statistically significant difference in TC levels between RYR preparation and statins except for one trial, in which Xuezhikang was less effective than fluvastatin (WMD 0.48 mmol/L; 95% CI 0.24 to 0.72; n = 118) 55. One trial presented data as number of subjects with at least 10% reduction of TC levels, and it showed no difference between Xuezhikang and lovastatin (64/69 vs. 68/76; RR 1.04; 95% CI 0.94 to 1.15) 64. In these trials, Xuezhikang was used at dosage of 1.2 g/day (containing 10 mg of lovastatin), Zhibituo at 3.15 g/day (containing 9 mg of lovastatin), simvastatin at 10–20 mg/day, pravastatin at 10 mg/day, lovastatin at 20 mg/day, atorvastatin 10 mg/day, and fluvastatin 20 mg/day.

Compared with non-statin lipid-lowering agents, Xuezhikang was more effective in lowering TC levels than inositol nicotinate (WMD -0.56 mmol/L; 95% CI -0.81 to -0.31; 7 trials, n = 624) 65666768697071, fish oils (WMD -0.81 mmol/L; 95% CI -1.11 to -0.50; 2 trials, n = 116) 8081], alginic sodium diester (WMD -1.08 mmol/L; 95% CI -1.38 to -0.78; 1 trial, n = 60) 84, and conjugated estrogens (WMD -0.87 mmol/L; 95% CI -1.20 to -0.54; 1 trial, n = 44) in postmenopausal women85. More participants had 10% reduction of TC levels after treatment of Xuezhikang against inositol nicotinate (16/18 vs. 7/17; RR 2.16; 95% CI 1.20 to 3.90) 72. Xuezhikang was better than fish oils in terms of more participants with 10% reduction of TC levels (WMD 1.36; 95% CI 1.14 to 1.63; 2 trials, n = 146) 8283. No significant difference was found between Xuezhikang and fenofibrate or gemfibrozil, Xuezhikang and elastase or biphenalbid in lowering TC levels. However, Zhibituo was less effective than fenofibrate (WMD 0.31 mmol/L; 95% CI 0.04 to 0.59; 2 trials, n = 248) 32104, but more effective than inositol nicotinate (WMD -0.73 mmol/L; 95% CI -1.13 to -0.33; 8 trials, n = 608) 8889909192939495, and fish oils (WMD -0.76 mmol/L; 95% CI -1.04 to -0.49; 6 trials, n = 491) 979899100101102 by random effect model due to significant heterogeneity (Table 3). More participants treated by Zhibituo had 10% reduction of TC levels compared with those treated by inositol nicotinate (23/30 vs. 13/30; RR 1.77; 95% CI 1.12 to 2.79) 96 or those treated by fish oils (18/25 vs. 7/25; RR 2.57; 95% CI 1.31 to 5.05) 103. Zhibituo appeared superior to alginic sodium diester for the number of participants with 10% reduction of TC levels (105/121 vs. 67/89; RR 1.15; 95% CI 1.00 to 1.32) 105.

Xuezhikang did not differ from Zhibituo in TC-lowering effect (WMD -0.03 mmol/L; 95% CI -0.25 to 0.20; 7 trials, n = 701) 32106107108109110111 (Table 3).

Triglycerides (TG) levels (Tables 2 and 4)

Table 4

Post-treatment triglycerides levels (mmol/L) in randomized controlled trials

Interventions

No. of trials [references]

No. of participants

Weighted mean difference (95% confidence interval)

P value

RYR vs. no intervention/placebo

Zhibituo vs. no intervention

2 [22, 23]

112

-0.54 (-0.77 to -0.32)

< 0.00001

RYR supplement vs. placebo

1 [7]

-0.25 (-0.47 to -0.03)

0.03

Xuezhikang vs. placebo

4 [8, 24–26]

323

-0.40 (-0.70 to -0.10)*

0.008

Zhibituo vs. placebo

3 [27–29]

291

-0.55 (-0.99 to -0.10)

0.02

RYR vs. statins

Xuezhikang vs. simvastatin

14 [6, 30–42]

1251

-0.08 (-0.25 to 0.10)*

0.39

Xuezhikang vs. pravastatin

7 [44–50]

592

0.04 (- 0.29 to 0.38)*

0.79

Xuezhikang vs. lovastatin

3 [51–53]

168

-0.07 (-0.16 to 0.01)

0.09

Xuezhikang vs. atorvastatin

1 [54]

-0.02 (-0.16 to 0.12)

0.78

Xuezhikang vs. fluvastatin

1 [55]

118

0.09 (-0.1 4 to 0.32)

0.44

Zhibituo vs. simvastatin

9 [32, 56–63]

732

0.05 (-0.17 to 0.26)*

0.67

Zhibituo vs. provastatin

1 [22]

-0.02 (-0.19 to 0.15)

0.81

Zhibituo vs. lovastatin

1 [57]

-0.21 (- 0.61 to 0.19)

0.30

RYR vs. non-statin drugs

Xuezhikang vs. inositol nicotinate

7 [65–71]

636

-0.06 (-0.20 to 0.08)

0.38

Xuezhikang vs. fenofibrate

5 [32, 73–76]

337

0.42 (-0.17 to 1.01)*

0.16

Xuezhikang vs. gemfibrozil

3 [77–79]

160

0.41 (0.30 to 0.51)

< 0.00001

Xuezhikang vs. fish oils

2 [80, 81]

112

-0.71 (-0.97 to -0.44)

< 0.00001

Xuezhikang vs. alginic sodium diester

1 [84]

0.04 (-0.21 to 0.29)

0.75

Xuezhikang vs.conjugated estrogens

1 [85]

-0.82 (-1.31 to -0.33)

0.001

Xuezhikang vs. elastase

1 [86]

107

0.00 (-0.31 to 0.31)

1.00

Xuezhikang vs. biphenalbid

1 [87]

-0.43 (-0.8 1 to -0.05)

0.03

Zhibituo vs. inositol nicotinate

7 [88–93, 95]

598

-0.39 (-0.62 to -0.16)*

0.0008

Zhibituo vs. fish oils

5 [97–100, 102]

394

-0.12 (-0.29 to 0.05)

0.17

Zhibituo vs. fenofibrate

2 [32, 104]

248

0.33 (-0.12 to 0.78)

0.15

RYR vs. RTR

Xuezhikang vs. Zhibituo

7 [32, 106–111]

727

0.05 (-0.17 to 0.27)*

0.66

* Random effects model

There was a 13%–44% reduction of TG levels after treatment by Xuezhikang, 27%–38% by Zhibituo, and 7% by Cholestin. Compared with no treatment, Zhibituo showed a significant effect on reducing TG levels (WMD -0.54 mmol/L; 95% CI -0.77 to -0.32; 2 trials, n = 112) 2223. Compared with placebo, all three RYR preparations significantly reduced TG levels (Cholestin: WMD -0.25 mmol/L; 95% CI -0.47 to -0.03; 1 trial, n = 83 7; Xuezhikang: WMD -0.40 mmol/L; 95% CI -0.70 to -0.10; 4 trials, n = 323 8242526; and Zhibituo: WMD -0.55 mmol/L; 95% CI -0.99 to -0.10; 3 trials, n = 283)