Red Yeast Rice Study Not Conclusive: An NLA Statement to Members

Overview: The results of a study published in the June 15, 2008 issue of the American Journal of Cardiology suggest that there may be significant benefits of Xuezhikang, a specific red yeast rice extract. The National Lipid Association (NLA) recommends that physicians and patients be aware that the composition of this product is not yet fully known and that future use of this product will depend on the result of additional ongoing studies. The NLA offers the following opinion and advice to its membership with respect to this trial.*

A recent article about the nutritional supplement red yeast rice was published in the June 15 issue of the American Journal of Cardiology.¹ This was a randomized, double-blind, placebo-controlled study conducted with 4,870 patients in Chinese hospitals who had a documented previous (within 5 years) myocardial infarction (MI). Eligible patients were randomly assigned into 1 of 2 groups for twice-daily treatment with the red yeast rice extract Xuezhikang (XZK) 600 mg or placebo, administered orally for an average of 4.5 years. The primary study end point was the occurrence of a major coronary event, either nonfatal MI or death from coronary or cardiac causes.

The XZK and placebo treatment groups were matched at baseline for plasma lipids, additional medications, cardiovascular risk factors, and other criteria. Mean LDL cholesterol was 129 mg/dL in both groups at baseline and 98% of patients completed the study. The mean on-treatment LDL-C level was 17.6% lower in the XZK group compared to placebo (103 ± 30 vs. 125 ± 33 mg/dL, p<0.001). HDL-C in the XZK group was 4.2% higher than the placebo group (48 ± 12 vs. 46 ± 12 mg/dL, p<0.001), and the ratio of total cholesterol/HDL-C was lower in the XZK group (3.9 ± 1.1 vs. 4.6 ± 1.4, p<0.0001). The results were encouraging: In patients treated with XZK there was a marked decrease in the frequency of major coronary events (10.4% in the placebo group vs. 5.7% in the XZK-treated group, p<0.001), a relative risk reduction of 45% and an absolute risk reduction of 4.7%. The number of treated patients needed to prevent (NNT) one event over the study period of 4.5 years was 21. There was a 30% reduction in cardiovascular mortality [odds ratio, 0.70 (95% CI, 0.54-0.89) p<0.005]. Total mortality declined by 33% [odds ratio 0.67 (95% CI, 0.52-0.82) p<0.0003]. Stroke mortality was the same, 0.5% in both groups. The incidence of non-fatal plus fatal stroke was not reported.

The striking findings of the study are the 45% reduction of the relative risk of major coronary events and the statistically significant reductions in cardiovascular and total mortality. These results have created public and professional interest in red yeast rice. The NLA will monitor the progress of research in this area and, having given this matter consideration, the NLA makes the following recommendations:

What clinicians should consider

Research into red yeast rice extracts is ongoing. The product discussed in the study, Xuezhikang (XZK), is produced by the Beijing WBL Peking University Biotech Co. Ltd (Beijing, Peoples Republic of China), and it is a partially purified extract of red yeast Chinese rice with multiple components. This product is not sold in the United States, it lacks FDA approval and it is not identical to other products sold in the US as "red yeast rice." A major component of XZK is lovastatin, but XZK contains other ingredients, such as lovastatin hydroxy acid, plant sterols, isoflavones, and isoflavone glycosides. At the present time it is not known to what extent lipid lowering accounts for the treatment benefit. It may be that the various ingredients work together in such a manner as to magnify the efficacy of lovastatin, but this has not been studied yet. More research is necessary to determine what ingredients are in XZK and how they might influence atherogenesis.

• The drug used in the study is a unique formulation not sold in the United States. The NLA recommends that clinicians not advise patients to take other red yeast rice extracts, as efficacy has not been proved for any indication.
• Red yeast rice should not be substituted for statins. The active ingredients present in domestically available versions of red yeast rice sold are unknown.
• The patients in this study were a homogenous Chinese population, a group that may metabolize statins less effectively than other populations.² This might account for the 17.6% reduction in LDL-C, about what has been observed in other populations treated with 10-20 mg daily doses of lovastatin. What is striking is the 45% relative risk of sustaining a major coronary event in association with only a 17.6% reduction in LDL-C.
• The prevalence of stroke in Chinese patients in population-based studies is about 3-fold greater than myocardial infarction.³ In the XZK study, total stroke incidence was not reported, but stroke mortality was 0.5% in both the XZK and the placebo group. Most statin clinical trials have demonstrated reductions in the incidence of fatal plus non-fatal strokes. The apparent very low incidence of stroke raises questions about the comparability of the patients in this study relative to the entire Chinese population and about special care that these patients may have received simply because of participation in this study.

What patients need to know

Studies of red yeast rice extracts are in progress. It is premature to reach a conclusion about their benefits and risks in patients who need to manage their cholesterol levels, and who are not ethnic Chinese.

• The drug used in this study is manufactured in China. It is a special formulation not sold in United States drug and nutritional supplement retail outlets.
• If you currently are taking a medication for cholesterol management, continue to take your prescription. Do not add a red yeast rice extract to your current medications. Adverse effects may be more likely.
• Before making any changes in your medication regimen, consult your health care provider first.

1. Lu Z, Kou W, Du B, Wu Y, Zhao S, Brusco O, Morgan J, Capuzzi D. Effect of Xuezhikang, an Extract From Red Yeast Chinese Rice, on Coronary Events in a Chinese Population With Previous Myocardial Infarction. Am J Cardiol. 2008;101: 1689-1693
2. Liao J. Safety and efficacy of statins in Asians. Am J Cardiol. 2007;99:410-414.
3. Liu L. Cardiovascular disease in China. Biochem Cell Biol. 2007;85:157-163

*The NLA contributors to this paper have provided full disclosures and their thoughts on this matter have not been influenced by bias or commercial interest. The viewpoints expressed here represent the clinical experience and opinion of our experts and the scientific evidence, which serves as the basis of clinical lipidology. All members of the organization and others reviewing this document are urged to thoroughly review the study and place this, in addition to other learned comment, in the context of meeting the interests of patient care. The NLA further discloses that the association has received educational grants from multiple manufacturers to support accredited medical educational activities. There was no funding or any interaction with any manufacturer in regard to this statement

Author Disclosures:

Thomas P. Bersot, MD, PhD
Consultant: Merck & Co., Merck-Schering Plough, and Abbott Laboratories. Speaker honoraria from: Merck & Co., Merck-Schering Plough, and Abbott Laboratories.

Vera Bittner, MD
Consultant for Pfizer Inc., CV Therapeutics, and Reliant Pharmaceuticals. Research grants from: Pfizer Inc., Atherogenics, Merck, NIH-Abbott, and CV Therapeutics.

Jerome D. Cohen, MD
Consultant: Bayer and Merck & Co. Speaker honoraria from: Abbott Laboratories, King, Merck & Co., and Novartis.

Anne C. Goldberg, MD
Consultant: Unilever and Abbott Laboratories. Speaker honoraria from: Merck & Co. and Merck/Schering-Plough. Research grants from: Kos Pharmaceuticals, Pfizer Inc., Sankyo Pharma, AstraZeneca, Merck & Co., Takeda Pharmaceuticals, Abbott Laboratories, Reliant Pharmaceuticals, Sanofi-Aventis, ISIS, and Aegerion.

Penny Kris-Etherton, RD, PhD
Consultant: Unilever, and Heinz. Advisor for: Health Fitness Corp. Research grants from: National Cattleman's Beef and CA Walnut Commission.

Mary McGowan, MD
Consultant: Merck/Schering-Plough. Speaker for: Merck & Co. and Merck/Schering-Plough. Honoraria received from: Merck & Co. and Merck/Schering-Plough.