Matthew Klimek, PharmD, Shan Wang, PharmD, and Adeleye Ogunkanmi, PharmD
Abstract
Red yeast rice is a Chinese fermented rice product (Monascus purpureus) that some have claimed improves blood circulation by decreasing cholesterol and triglyceride levels in humans. The supplement contains naturally occurring monacolin K, the active ingredient found in Merck’s prescription agent lovastatin (Mevacor). Lovastatin is associated with various adverse effects such as myopathy and abnormal liver function test results, which can lead to serious problems if patients are not monitored and treated. The inclusion of lovastatin in red yeast rice and the lack of dietary supplement regulation by the FDA raise safety concerns for health care professionals as well as for patients. Studies have shown that red yeast rice products can be beneficial in lowering serum cholesterol levels, but they are not without risk. Furthermore, product uniformity, purity, labeling, and safety cannot be guaranteed.
Keywords:red yeast rice, Monascus purpureus, hyperlipidemia, myopathy, dietary supplement, lovastatin
Background
Despite the increase in FDA-approved prescription medications, alternative therapies have become more prevalent in the U.S. About 42% of Americans use alternative medicine, and the demand for these therapies continues to grow.1,2 In 1997, patients paid approximately 629 million visits to alternative medicine practitioners, a rate that was 47% higher than in 1990. At approximately $27 billion, total out-of-pocket expenditures for alternative therapies exceeded total out-of-pocket expenditures for all hospitalizations in the U.S.1
Red yeast rice, a Chinese dietary supplement, has gained popularity because of its properties as a natural statin. This fermented rice product is used as a medicinal food to improve blood circulation by decreasing cholesterol and triglyceride levels.3,4 The supplement contains varying amounts of natural monacolins as a result of the different strains of Monascus purpureus used in fermentation.5 Monacolins lower cholesterol by inhibiting HMG–CoA (5-hydroxy-3-methylglutaryl-coenzyme A) reductase, the rate-limiting step for cholesterol synthesis in the liver. The primary monacolin in red yeast rice is monacolin K, which has the same chemical structure as lovastatin. Although levels of lovastatin vary in the product, 2.4 g of red yeast rice daily may contain about 4.8 mg of lovastatin, or 0.2% of the total dose. Red yeast rice supplements may also contain isoflavonoids, monounsaturated fats, and sterols that help to reduce cholesterol levels even further.3
The natural inclusion of low-dose lovastatin raises concerns for patient safety. In 2007, the FDA warned consumers to avoid red yeast rice supplements promoted on the Internet (Red Yeast Rice, Red Yeast Rice/Policosonal Complex, and Cholestrix) to lower cholesterol because of the possibility of myopathy, leading to kidney impairment.6 The widespread use of evidence-based medicine has caused health care professionals to become skeptical about dietary supplement use. The lack of studies and regulations to ensure the safety of these products has the result of steering health care professionals away from herbal products and toward prescription medications that have been demonstrated to be safe and efficacious. Health care practitioners should become aware of herbal products that patients might be using in place of commonly prescribed medications. This article reviews the safety and effectiveness of red yeast rice as a “natural” alternative treatment to statins for hypercholesterolemia.
LITERATURE FINDINGS
Before performing a Medline search, we identified the most appropriate search terms using the MeSH (medical subject headings) database provided by the National Library of Medicine (www.pubmed.gov). Instead of using this database to perform the search, we conducted a “text word” search (from 1966 to November 2008) using PubMed to include articles indexed for Medline as well as those not yet indexed (those that do not yet have MeSH terms assigned).
When a relevant article was located, we reviewed the MeSH terms assigned to that article to identify other relevant search terms. To be as complete as possible, we did not use any limitations.
PubMed includes millions of citations from Medline and other life science journals for biomedical articles. We reviewed the bibliographies of all relevant articles to identify any other pertinent articles that the previous searches might have missed. Our article includes some of the more provocative data about red yeast rice but might not include all available relevant literature.
EFFICACY
Lu et al.7
Lu et al. conducted a randomized, double-blind, placebo-controlled clinical trial of 4,870 Chinese subjects over 4.5 years to evaluate the efficacy of Xuezhikang (XZK), an extract of cholestin and derived from fermented red yeast rice. The study medication consisted of 300-mg capsules of XZK. Each capsule contained 2.5 to 3.2 mg of lovastatin and a small amount of hydroxyl acid, ergosterol, and other components. To be included in the study, patients must have had a myocardial infarction (MI) within 60 months of enrollment.
Patients underwent a four-week initial period of a controlled diet beginning with the cessation of all lipid-lowering agents. At the end of four weeks, baseline lipid levels were measured. Baseline characteristics were similar for all treatment groups except for sex (3,986 men and 884 women).
Mean low-density lipoprotein-cholesterol (LDL-C) levels were 129 mg/dL in both groups at baseline. Patients treated with XZK showed a significant decrease in frequency of major coronary events such as nonfatal MI and death from coronary or cardiac causes when compared with those receiving placebo (−10.4% and −5.7%, respectively; P < 0.001). They also experienced a 33% decrease in the need for coronary revascularization compared with the placebo recipients (P = 0.004).
Within eight weeks after randomization, total cholesterol (−10.9%) and LDL-C (−17.6%) levels decreased significantly and were maintained over the duration of the study in the XZK-treated group (P < 0.001). The authors concluded that XZK demonstrated efficacy in decreasing cholesterol, recurrent coronary events, and mortality rates.
Lin et al.8
Lin and coworkers assessed the lipid-lowering effect and safety of M. purpureus in a randomized, double-blind, placebo-controlledstudy of 79 patients 23 to 65 years of age with hyperlipidemia. Subjects received M. purpureus 600 mg twice daily or placebo for eight weeks. The meanbaseline LDL-C level was 203.9 mg/dL. At week eight, M. purpureus therapy significantly reduced concentrations of LDL-C by 27.7%, total cholesterol by 21.5%, triglycerides by 15.8%, and apolipoprotein B (apo-B) by 26%. High-density lipoprotein-C (HDL-C) and apolipoprotein A-I (apo A-I) levels were increased nonsignificantly by 0.9% and 3.4%, respectively.
Gheith et al.9
Gheith and colleagues compared the efficacy and safety of M. purpureus Went rice (red yeast rice) with fluvastatin (Lescol, Novartis) in the management of nephrotic dyslipidemia. The investigators conducted an open-label study of 72 patients with dyslipidemia secondary to idiopathic persistent nephrotic syndrome. Patients were randomly divided into three groups: 20 patients received M. purpureus Went rice 600 mg twice a day for one month, then 600 mg once daily; 30 patients were treated with fluvastatin 20 mg daily; and 22 controls group received no therapy.
The fluvastatin group had average total cholesterol readings of 436, 333, 313, and 302 mg/dL at baseline, three months, six months, and one year, respectively. Similar reductions were observed in the Went rice group, with cholesterol averages of 457 mg/dL at baseline, 408 mg/dL at three months, 283 mg/dL at six months, and 303 mg/dL at one year. A significant reduction in proteinuria was noted in the fluvastatin group (8.3 g/day at baseline vs. 2.4 g/day at one year) and in the Went rice group (8.6 g/day at baseline vs. 3.2 g/day at one year) but not in the control arm.
Compared with baseline evaluations, there was no clinical evidence of myopathy or neuropathy in patients who received statins or Went rice. The authors concluded that M. purpureus Went rice was a safe and effective strategy for treating nephrotic dyslipidemia.
Summary
In each of these studies, M. purpureus provided beneficial effects in hyperlipidemic patients7–9 and might have also positively affected cardiac outcomes.7 Studies like these give confidence to patients seeking alternative cholesterol-lowering therapies in place of more conventional statin therapies.
SAFETY
All three controlled trials (Lu, Lin, Gheith) showed that M. purpureus was well tolerated with few safety concerns.7–9 In the trial conducted by Lin et al.,8 none of the subjects receiving M. purpureus experienced alanine aminotransferase (ALT), aspartate aminotransferase (AST), or creatine phosphokinase (CPK) measurements that were more than three times the upper limit of normal (ULN) at the fourth or eighth week. Gheithet al.9 also found no evidence of significant adverse effects in neuromuscular function associated with M. purpureus.
Despite these findings, published case reports show potential safety problems with the use of red yeast rice. The following case reports of myopathy and rhabdomyolysis illustrate these potential dangers.
Myopathy
Vercelli et al.10
A 76-year-old man with type-2 diabetes received statins for four years; 20 mg of simvastatin (Zocor, Merck) daily for two years, followed by 20 mg of atorvastatin (Lipitor, Pfizer) daily for two years. After four years of therapy, atorvastatin was discontinued upon patient complaints of generalized muscle weakness and serum creatinine kinase (CK) levels of 3,000 U/L. Six months later, generalized muscle weakness improved slightly, but CK levels climbed to 3,700 U/L.
An open quadriceps muscle biopsy revealed muscular atrophy. The patient then admitted that three months after discontinuing atorvastatin, he had begun using a product derived from red yeast rice as an alternative therapy to lower cholesterol. Red yeast rice was discontinued at this point. Muscle weakness improved and CK levels fell to 1,000 U/L three months after he stopped taking red yeast rice. The authors concluded that patients with statin-induced muscle damage should not use red yeast rice as a way to lower cholesterol.
Smith et al.4
Smith and colleagues described a case of symptomatic myopathy associated with the use of Chinese red yeast rice.4 A 50-year-old man visited his primary care physician, reporting joint pain and muscle weakness for two months. At presentation, he had diffuse body aching, upper-extremity weakness, and lower-back stiffness along with a CK level of 358 U/L. He had no history of muscle diseases or problems. According to the patient, the only new medications in his regimen were ginseng, Chinese red yeast rice, and rofecoxib (Vioxx, Merck). The patient had started taking ginseng and Chinese red yeast rice four weeks before his symptoms developed and then started to take rofecoxib after the onset of symptoms. He was instructed to discontinue both of these products. At the three-week follow-up visit, his muscle weakness and joint pain resolved completely and the CK level fell to 179 U/L. Eight months later, the patient resumed taking Chinese red yeast rice, and his CK level increased again to 212 U/L.
Mueller11
A case of symptomatic myopathy was attributed to red yeast rice in a 61-year-old woman with hyperlipidemia.11 She was started on simvastatin 20 mg daily along with estradiol from a transdermal patch at a dose of 0.05 mg/week, aspirin 81 mg daily, and a multivitamin. The patient was otherwise in good health; vital signs and laboratory parameters were within normal limits. After four months of therapy, simvastatin was increased to 40 mg daily. At this point, the CK level was 189 U/L. Within one month, diffuse myalgia and an elevated CK level of 451 U/L were reported.
After simvastatin was discontinued, symptoms resolved and CK levels returned to 170 U/L. Soon afterward, the patient began using red yeast rice 600 mg twice daily as an alternative treatment. Three months later, diffuse myalgia returned and CK levels increased to 475 U/L. Red yeast rice was then discontinued; symptoms resolved, and CK levels decreased to 122 U/L. Like simvastatin, red yeast rice caused diffuse myalgia and elevated CK levels. After these products were discontinued, symptoms resolved soon thereafter.
Summary
Although the effects of red yeast rice are mild, the product can cause muscle pain and weakness similar to that associated with conventional statins. These events can become serious if the patient’s intake is not monitored appropriately. Awareness of the previous two cases can help health care professionals understand the potential for myopathy when red yeast rice is used as a natural alternative to statins.
Rhabdomyolysis
Prasad et al.12
Prasad and coworkers reported on a 28-year-old stable renal transplant recipient who developed rhabdomyolysis after therapy with red yeast rice.12 The patient experienced an asymptomatic elevation of CK to 1,050 IU/L; a second assessment showed a CK level of 2,600 IU/L. After questioning, the patient stated she had taken red yeast rice for the previous two months to lower cholesterol naturally. After she stopped taking the supplement, her CK levels fell to 600 IU/L within two weeks and she remained clinically asymptomatic.
The patient was also taking cyclosporine to prevent transplant rejection. Cyclosporine, a known cytochro
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