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From the Townsend Letter
December 2015

Red Yeast Rice in the Treatment of Hyperlipidemia
by Douglas Lobay, BSc, ND
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This article discusses the use of red yeast rice (RYR) in the treatment of hyperlipidemia. It begins with a brief overview of the history and folk use of this natural product from Asia. It provides information on its chemical composition and active ingredients, pharmacology, and mechanism of action. It then provides analysis of clinical studies and scientific research in the use of RYR to treat hyperlipidemia, hypercholesterolemia, and cardiovascular disease. It also discusses other potential clinical uses of RYR. It reports on adverse side effects and toxicology. It concludes with a discussion of this author's personal experience of using RYR in the treatment of hyperlipidemia and has specific dosage recommendations.

History and Folk Use
Red yeast rice has been used in China for over 1200 years. It has been used to flavor, color, and preserve foods and as a traditional medicine. RYR has been included in fermented rice products, rice wine, rice vinegar, pickled tofu, Peking duck, and Chinese pastries. RYR was first mentioned in traditional Chinese medicine during the Tang dynasty at about 800 AD to invigorate the body, aid in digestion, and revitalize the blood. RYR was included in the Chinese Pharmacopeia of the Ming dynasty in the 1300s.1 It is still widely used in China and other Asian countries, including Japan and Thailand. In more modern times RYR has been used in the treatment of dyslipidemia, high cholesterol, coronary heart disease, diabetes, osteoporosis, cancer, non-alcoholic fatty liver disease, fatigue, poor memory, Alzheimer's disease, and dementia.2

Chemical Composition and Active Ingredients
Red yeast rice is created by fermenting rice with a fungal species called Monascus purpureus. Rice is a food staple that consists of approximately 80% carbohydrates, 7% protein, 2% dietary fiber, and 1% fat. It contains trace amounts of B vitamins, including vitamin B1, B2, B3, B5, and B6, and minor amounts of minerals including calcium, magnesium, potassium, phosphorus, iron, and zinc.3
Monacolins have been identified to be the active ingredients in RYR for its lipid-lowering effects. Fourteen different monacolins have been isolated from RYR with HPLC (high-performance liquid chromatography) and MS (mass spectroscopy). The concentration of the monacolin varies. Monacolin K has been identified to be structurally identical to the cholesterol-reducing drug lovastatin (Mevacor). Twelve different commercial products of RYR were analyzed for monacolin content by HPLC and MS at an independent lab. There was wide variability in total monacolin content ranging from 0.31 to 11.15 milligrams per 600 mg capsule of RYR. There was also wide variability of monacolin K content ranging from 0.10 to 10.09 mg per 600 mg capsule of RYR.4
RYR also contains sterols including beta-sitosterol, campesterol, stigmasterol, sapogenin, isoflavones, monounsaturated fatty acids, decalins and other biphenolic compounds, azaphilones and other lactone ring compounds, GABA (gamma aminobutyric acid), dimerumic acid, and citrin.5,6

Detailed pharmacodynamics and pharmacokinetics on RYR are lacking in the scientific literature. Extrapolation of the data from studies of monacolin K or lovastatin has been suggested. Lovastatin, also known as monacolin K, is a naturally occurring molecule consisting of two bound phenolic rings known as naphthalene and one lactone ring with one or more attached substituent groups. It has a molecular formula of C24H36O5 and a molecular mass of 404.54 grams per mole. Its oral bioavailability has been shown to be less than 5%. Once absorbed it shows 98% protein bound. It has a biological half-life between 2 to 5 hours. It is mainly altered through hepatic degradation via the cytochrome P450 pathway, specifically CYP3A4 and CYP2C8. It is excreted 83% through fecal elimination and 10% through urine excretion.7 One study compared the dissolution rate and oral bioavailability of lovastatin in lovastatin tablets and RYR. The results showed that the lovastatin from RYR was higher and faster than lovastatin tablets alone.8 In another study, the plasma clearance of lovastatin was compared with RYR in 11 healthy volunteers who were randomized to receive 20 mg of lovastatin versus 2400 mg of RYR. The results suggested that the effect of RYR on cholesterol concentration might be caused by the additive or synergistic effects of monacolin K with the other monacolins in RYR.9

Mechanism of Action
Lovastatin or monacolin K inhibits the enzyme hydroxyl methylglutaryl coenzyme A (HMG CoA) reductase that catalyzes the reduction of HMG-CoA to mevalonate during the initial synthesis of cholesterol. There is a naphthalene-lactone complex that forms the basic structure of the monacolins and other allied statin drugs. In the liver, it is believed, the lactone ring of that naphthalene-lactone structure opens and binds to the HMG-CoA reductase enzyme, thereby inhibiting the incorporation of acetate molecules into forming a cholesterol molecule. The other monacolins probably exert cholesterol-lowering effects. RYR also contains phytosterols, isoflavones, and monounsaturated fatty acids that might also contribute to lipid-lowering effects.10

Clinical Studies in Hyperlipidemia
In one study, 40 children between ages 8 and 16 years with familial hyperlipidemia were treated with a product that contained 200 milligrams of RYR with 3 milligrams of monacolins for 8 weeks. Total cholesterol decreased 18.5% on average and LDL decreased 25.1%. Apolipoprotein B decreased 25.3%, and both HDL and Apo A showed no significant changes. No adverse effects were observed when liver and muscle markers including AST, ALT, and CK were monitored.11
In a double-blind, placebo-controlled trial, 52 physicians and their spouses with a total cholesterol greater than 200 milligrams were randomly assigned to receive RYR extract or placebo for 8 weeks. The primary outcome was to measure lipid before and after treatment. Total cholesterol decreased by an average of 37 mg/dl or 15%. LDL cholesterol decreased by an average of 36 mg/dl or 22%. No marked difference in CK levels or other side effects were noted between the groups. The authors concluded that RYR may be an attractive and well-studied alternative in patients who are intolerant to statins or who have objections to pharmacologic lipid lowering.12
In another study, a Mediterranean diet was compared with RYR supplementation for the management of statin-intolerant patients with and without type 2 diabetes. A total of 171 patients were observed over 24 weeks. 46 diabetic patients were treated with MD alone, 44 diabetic patients were treated with MD and RYR, 38 patients with dyslipidemia were treated with MD alone, and 43 patients with dyslipidemia were treated with MD and RYR. The results showed that RYR was superior in lowering LDL levels in both groups. In the diabetic group treated with MD alone, LDL decreased an average of 7.4%. In the diabetic group treated with MD and RYR, LDL decreased an average of 21.0%. In the dyslipidemic group treated with MD alone, LDL decreased 12.5%, and in the dyslipidemic group treated with MD and RYR, LDL decreased an average of 22.0%. RYR was superior to MD alone in modifying lipid parameters in diabetic and nondiabetic dyslipidemic patients.13
The beneficial impact of a RYR product on cardiovascular events and mortality was studied in 1530 elderly hypertensive patients greater than 65 years of age who had a previous myocardial infarction. 772 patients took the RYR product and 758 patients took a placebo for an average of 4.5 years. 68 cases (8.8%) of coronary events occurred in the RYR-treated group and 108 cases (14.3 %) in the placebo group. This translated to a 38.2% risk reduction of coronary events in the RYR-treated group. There were 49 cases (6.4%) of death due to coronary heart diseases in the RYR-treated group and 68 cases (9.0%) in the placebo group. This translates to a 29% risk reduction in the RYR-treated group of death by coronary heart disease. The researchers concluded that this RYR product could effectively and safely reduce cardiovascular events and all-cause death in Chinese elderly hypertensive patients who have had a previous myocardial infarction.14
In an assessment of 93 randomized controlled trials, three different RYR products were compared with placebo on lipid modification in primary hyperlipidemia. A total of 9625 participants were involved in these trials. Total cholesterol decreased an average of 0.91 mmol/L or 35.0 mg/dl, LDL decreased 0.73 mmol/L or 28.1 mg/dl, triglycerides decreased 0.41 mmol/L or 36.3 mg/dl, and HDL increased 0.15 mmol/L or 5.8 mg/dl. No serious adverse side effects such as dizziness and gastrointestinal disturbance were noted. Lipid modification of RYR was similar to statin medication. RYR was superior to fish and vitamin B3 in modifying lipid levels. The researchers concluded that RYR was similar to statins and that more rigorous trials are needed, including long-term safety effects.15
In a clinical prospective trial, the effect of RYR on coronary events was studied in a Chinese population with previous myocardial infarction. Nearly 5000 patients were given a RYR extract or placebo and followed for primary end points of lipid levels and cardiovascular events. 5.7% of the RYR-treated patients experienced a cardiovascular event contrasted to 10.4% of the placebo group. The absolute difference of CV events between the two groups was a 4.7% reduction in the RYR group. The relative different of CV events was a 45% reduction in the RYR group. The RYR group experienced a decrease in cardiovascular and total mortality of 30% and 33%. The need for coronary revascularization also decreased by 33% in the RYR-treated group. The authors concluded that long-term therapy with this RYR product significantly decreased the recurrence of coronary events and the occurrence of new cardiovascular events and death, improved lipoprotein regulation, and was safe and well tolerated.16

Other Potential Clinical Effects
RYR attenuated the development of angiotensin II-induced abdominal aortic aneurysm and the development of atherosclerosis in experimental mice models. RYR suppressed angiotensin II, decreased atherosclerotic lesion in the intima lining, decreased vascular cell adhesion, and regulated inflammatory responses independent of its lipid-lowering effects.17 RYR supplementation upregulated endogenous nitric oxide expression in vascular endothelium and red blood cells, increased plasma nitric oxide, and improved abnormal rheology in high cholesterol–diet induced atherosclerotic rats.18 RYR also has been shown to increase excretion of bile acid by up to 3 or 4 times in hamsters.19 RYR supplementation decreased cellular proliferation and induced apoptosis in colon cancer growth. Epidemiological studies show that individuals who take statins have a lower risk of colon cancer. The chemoprotective effects of RYR were postulated to exist beyond the effects of the monacolins alone.20 RYR supplementation inhibited prostate cancer cell growth in mice. RYR decreased tumor volume in both androgen-dependent and -independent prostate tumor lines. RYR decreased expression of androgen-synthesizing enzymes and cholesterol-dependent hormones. These effects were postulated to be independent from monacolins in RYR.21 Several azaphilones from RYR showed selective toxicity against various human cancer cell lines in in vitro experimentation.22 RYR supplementation enhanced bone formation through improved osteoblast cell proliferation and differentiation. Alkaline phosphatase enzyme activity increased, reflecting improved bone activity.23 RYR supplementation improved collagen matrix and bone formation in rabbits.24

Adverse Side Effects
Monacolin K and other statins can potentially cause hepatotoxicity, nephrotoxicity, and peripheral neuropathy. Myopathy was reported in 4 individuals from 2002 to 2007 in the Italian Surveillance System of Natural Products.25 Another report discussed a middle-aged man with joint pain and myopathy who had been taking RYR for several months. Laboratory testing showed moderately elevated CPK levels. His symptoms and lab abnormalities returned to normal after the RYR was discontinued.26
A case of rhabdomyolysis was reported in a stable renal transplant recipient who had been taking a RYR product. The muscle damage stopped once the RYR product was discontinued. The interaction of the immune-suppressing transplant drugs and the RYR on the cytochrome P450 pathway was believed to be the cause of this problem. It was further recommended that transplantation patients should use caution when using RYR products.27 One 63-year-old female who had been taking RYR for several months showed acutely elevated liver enzymes and hepatotoxicity. The liver enzymes and inflammation returned to normal after the RYR product was discontinued.28
RYR use is likely unsafe during pregnancy and is not recommended while breast-feeding. It has caused birth defects at high doses in animal models. It should be used with caution in patients with liver and kidney disease. It uses the cytochrome P4503A4 pathway and can potentially interact with other drugs and foods. These drugs include gemfibrozil, cyclosporine, protease inhibitors, acetaminophen, amiodarone, carbamezapine, isoniazid, methotrexate, methyldopa, fluconazole, itraconazole, erythromycin, phenytoin, lovastatin, pravastatin, and other statin drugs. These foods include alcohol, grapefruit, and herbal medicines such as St. John's wort.29

Citrin is a mycotoxin that is produced by several genera of fungal species, including Monascus. Citrin has been shown to be nephrotoxic to certain animal species. Its LD (lethal dose) 50 is 100 milligrams per kg in animal models. Its effect on humans is not clearly known. It has shown to be genotoxic to human lymphocytes  in in vitro experiments. The EFSA (European Food and Safety Authority) has suggested that the daily citrin content be limited to an average of 30 mcg/kg in children and 60 mcg/kg in adults.30 In an independent evaluation of 12 commercially available RYR products, 4 showed variable amounts of citrin. The citrin content ranged from 0 to 114.2 mcg/capsule. The four products showed 14.3, 57.5, 70.4, and 114.2 mcg/600 mg capsule of RYR. The other 8 products showed 0 mcg of citrin. Increasing the temperature by several degrees Celsius during the fermentation process of RYR dramatically stops the production of citrin.4 Red yeast rice can contain a trace amount of arsenic.3

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