A Review and Update of Red Yeast Rice

Transcription

1 Topical Review Article A Review and Update of Red Yeast Rice Megan E. Musselman, PharmD, BCPS 1, Rebecca S. Pettit, PharmD, MBA, BCPS 2, and Karrie L. Derenski, PharmD, BCNSP, CNSC 3 Journal of Evidence-Based Complementary & Alternative Medicine 17(1) ª The Author(s) 2012 Reprints and permission: sagepub.com/journalspermissions.nav DOI: / Abstract Dyslipidemia is a growing concern causing significant morbidity and mortality. High cholesterol levels increase the risk of individuals developing heart disease, stroke, and other disease states. Dietary modification is the initial approach for treatment, but many patients require statins (3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors) to reduce cardiovascular risk. Unfortunately, a number of patients cannot tolerate statins, leading to practitioners searching for alternative regimens. One alternative that has been extensively studied is red yeast rice (Monascus purpureus), a dietary supplement. In patients with dyslipidemia, red yeast rice was efficacious and safe for short-term use (<16 weeks). Red yeast rice has also been studied head to head with statins and was shown to be noninferior in reducing cholesterol levels and cardiovascular risk. Because of the positive clinical effects seen in dyslipidemia, researchers have begun to study its use in other disease states. Keywords red yeast rice, statins, dyslipidemia, Monascus purpureus, cholesterol, polyketides, monacolins Accepted for publication October 21, Red yeast rice, also known as Red Koji, Hong Qu, Ang-kak, red mold rice, and Beni-Koji, is a traditional Chinese food product used as a flavoring, colorant, and preservative in cooking and medicinally for its blood circulation and food digestion promoting properties. The development of red yeast rice is believed to date back more than a thousand years; its use has been documented during the Chinese Tang dynasty (around 800 AD) and continues to be a dietary staple in numerous Asian countries today. Red yeast rice is the fermented product of rice inoculated with red yeast, Monascus purpureus. 1,2 The traditional method of making red yeast rice is based on a fermentation process whereby the yeast is allowed to ferment naturally on a bed of cooked nonglutinous whole rice kernel. When red yeast rice is prepared by this traditional method of solid-state fermentation under controlled conditions, it produces a family of polyketides called monacolins that can inhibit cholesterol production. 3,4 Red yeast rice contains several monacolins, all of which have the ability to inhibit the enzyme 3-hydroxy-3-methylglutaryl co-enzyme A (CoA) reductase, which is an essential step in cholesterol biosynthesis. Specifically, monacolin K, also known as mevicolin or lovastatin, is the monacolin in red yeast rice that has the same chemical structure as the purified, aspergillus-derived monacolin K known as the pharmaceutical drug Mevacor (Merck & Co, Inc). 5 Closely related to monacolin K is the hydroxy acid form called monacolin KA, which is the activated form of lovastatin after it passes through the liver. Monacolin K (lovastatin) and monacolin KA (hydroxyl acid form of lovastatin) are typically the predominant active ingredients in most commercially available red yeast rice preparations (Table 1). 6 Other active ingredients in red yeast rice include plant sterols (b-sitosterol, campesterol, stigmasterol, and sapogenin), isoflavones and isoflavone glycosides, zinc, selenium, and monounsaturated fatty acids. 7 Pharmacology Clinical observations have shown that red yeast rice has the ability to lower total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides in both animal models and humans. 3-5 This is largely a result of enzymatic inhibition of the conversion of 3-hydroxy-3-methylglutaryl CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis (Figure 1). Although it is known that monacolin K is effective at lowering cholesterol because of this enzymatic inhibition, one study in humans found that it is unlikely to be solely the result of a single species of monacolin but rather the result of 1 Saint Luke s Health System, Kansas City, MO, USA 2 Indiana University Health, Riley Hospital for Children, Indianapolis, IN, USA 3 CoxHealth, Springfield, MO, USA Corresponding Author: Megan E. Musselman, PharmD, BCPS, Saint Luke s Health System, 4401 Wornall Road, Kansas City, MO 64111, USA meganmusselman@gmail.com

2 34 Journal of Evidence-Based Complementary & Alternative Medicine 17(1) Table 1. Analysis of Commercially Available Red Yeast Rice Preparations 6 Product (Manufacturer) RYR Dosage/Administration Total Daily Dosage (Lovastatin/capsule) Choleast (Thorne Research, Inc) 600 mg/capsule; no frequency suggested None suggested (1.7 mg/capsule) Cholestene (HPF, Inc) 600 mg/capsule a ; 2 capsules twice daily 2.4 g/d (3.4 mg/capsule) Chole-sterin (Atrium, Inc) 600 mg/capsule; 2 capsules twice daily 2.4 g/d (2.3 mg/capsule) Doctors Best RYR (Doctors Best, Inc) 1200 mg/capsule; 1 capsule daily 1.2 g/d (3 mg/capsule) Healthy America RYR (Healthy 600 mg/capsule; 2 capsules once or g/d (0.6 mg/capsule) America) twice daily Nature s Sunshine RYR (Nature s 570 mg/capsule; 2 capsules 2 or 3 times g/d (1.3 mg/capsule) Sunshine Products, Inc) daily NSI RYR (Nutraceutical Life Sciences) 600 mg/capsule; 1 capsule daily 0.6 g/d (3.5 mg/capsule) Solaray RYR (Nutraceutical Corp) 600 mg/capsule; 1 capsule daily 0.6 g/d (0.8 mg/capsule) Spring Valley RYR (US Nutrition, Inc) 600 mg/capsule; 2 capsules once or g/d (0.9 mg/capsule) twice daily Stop Aging Now Extra Strength RYR 600 mg/capsule; 2 capsules daily 1.2 g/d (0.3 mg/capsule) (Stop Aging Now, LLC) Swanson Traditional RYR (Swanson Health Products) 600 mg/capsule; 1 capsule twice daily 1.2 g/d (0 mg/capsule) Abbreviations: RYR, red yeast rice. a Claimed to contain 600 mg of red yeassst rice; however, when tested only contained 443 mg/capsule. Acetyl CoA + Acetoacetyl-CoA HMG CoA HMG CoA Reductase Red Yeast Rice (Monacolin-K) Mevalonate Isopentenyl Pyrophosphate Co Q-10 Geranyl Pyrophosphate Farnesyl Pyrophosphate Phenylated Proteins Cholesterol Lanosterol Squalene Figure 1. Red yeast rice effects on cholesterol biosynthesis Abbreviations: CoA, co-enzyme A; HMG, 3-hydroxy-3-methylglutaryl; CoQ-10, coenzyme Q-10. a synergy of the action of monacolins and other substances in red yeast rice. 3 Other mechanisms could involve diminished absorption of cholesterol, presumably as a result of competition between sterols in red yeast rice and cholesterol for incorporation into micelles or for transport across the intestinal cell membrane. 7-9 Clinical Efficacy of Red Yeast Rice for Dyslipidemia Multiple clinical trials have been conducted to determine the efficacy of red yeast rice and red yeast rice extracts for dyslipidemia. In the United States, a clinical trial was conducted that included 83 healthy adults with dyslipidemia. Patients were randomized to receive either red yeast rice supplementation (2.4 g/d) or placebo for a total of 12 weeks. Supplementation with red yeast rice significantly reduced total cholesterol (P <.001), triglycerides (P <.05), and LDL cholesterol (P <.001) in comparison with placebo. High-density lipoprotein (HDL) did not significantly differ from baseline in either group. 9 Another study, performed in China, included 79 patients with a mean baseline LDL cholesterol of mg/dl. Patients were randomized to receive either red yeast rice 600 mg twice daily or placebo for a total of 8 weeks.

3 Musselman et al 35 Compared with baseline, LDL cholesterol was reduced by 27.7% (P <.001), total cholesterol by 21.5% (P <.001), triglycerides by 15.8% (P <.05), and apolipoprotein B by 26% (P <.001) in the red yeast rice supplementation group. An increase of HDL in the red yeast rice group of 0.9% from baseline did occur; however, this result was not significant. 10 A specific red yeast rice product, HypoCol, was evaluated for its effects on plasma lipids, fasting plasma glucose, glycosylated hemoglobin, and C-reactive protein for 16 weeks. Patients were randomized to receive either 4 capsules of HypoCol or placebo. Patients in the study group had a significant reduction in LDL cholesterol by 23% and total cholesterol by 15.5% compared with the placebo group (P <.001). However, no significant results were observed in glucose and inflammatory parameters. 11 Liu et al 4 conducted a meta-analysis of 93 randomized trials (9625 participants) that compared red yeast rice with placebo, statins, and other lipid-lowering therapies in patients with dyslipidemia. There were 3 different preparations of red yeast rice (Cholestin, Xueshikang, and Zhibituo) in the trials analyzed. All preparations showed significant reductions in total cholesterol, triglycerides, and LDL cholesterol compared with placebo (P <.00001). Only the participants receiving the Zhibituo preparation showed a significant improvement of HDL levels (P <.00001). 4 Based on positive results in using red yeast rice compared with placebo in patients with dyslipidemia, trials have been conducted to evaluate the lipid-lowering effects of red yeast rice compared with statins. Becker et al 12 evaluated simvastatin at a dose of 40 mg daily versus red yeast rice, fish oil, and lifestyle changes for a period of 12 weeks. Significant reduction in LDL cholesterol from baseline was found in both groups (P <.001), but no significant differences were found between the 2 groups. However, the group receiving red yeast rice, fish oil, and lifestyle changes had significant reduction in triglycerides (P ¼.003) in comparison to the simvastatin group. 12 Another study by the same group of researchers was conducted comparing red yeast rice at a dose of 2400 mg twice daily with pravastatin 20 mg twice daily for 12 weeks. The purpose of the study was to determine the tolerability of red yeast rice in patients considered intolerant to statin therapy (defined as having a prior history of myalgias while receiving a statin). Tolerability was similar in both groups with <10% of patients experiencing myalgias. A reduction in LDL cholesterol was found to be similar in both groups: 30% in the red yeast rice group and 27% in the pravastatin group from baseline. 13 A trial evaluating the safety and efficacy of red yeast rice in patients with dyslipidemia was conducted. A total of 62 patients with a prior history of statin-associated myalgias were randomized to receive either red yeast rice 1800 mg twice daily or placebo twice daily for 24 weeks. The LDL cholesterol decreased by 23%, and total cholesterol decreased by 16% in the red yeast rice group compared with baseline at the end of 24 weeks. In the red yeast rice group, the LDL cholesterol levels at week 12 and week 24 were significantly lower than that in the placebo group: P <.001 and P ¼.011, respectively. There was no difference in liver transaminase and creatine phosphokinase levels, and presence of myalgias in either group compared with baseline levels. 14 A recent trial retrospectively evaluated the use of red yeast rice for dyslipidemia in 25 patients with a history of statinassociated myalgias, elevated transaminases, and/or gastrointestinal intolerance. Patients were included if they received 1200 mg of red yeast rice at bedtime for at least 4 weeks. The total cholesterol decreased by 13% and the LDL cholesterol by 19% from baseline. The majority of patients (92%) tolerated red yeast rice and achieved their LDL cholesterol goal (56%). 15 Multiple studies evaluating a specific red yeast rice extract, Xuezhikang, on dyslipidemia and coronary events have been conducted in China. Liu et al 16 randomized 50 patients with coronary heart disease to receive the study medication Xuezhikang at a dose of 1200 mg daily or placebo for 6 weeks. After 6 weeks, the Xuezhikang group had significantly decreased C- reactive protein concentrations (P <.05), serum lipoprotein A(P <.05), and triglyceride levels (P <.001) compared with baseline levels. A large clinical study was conducted in patients with previous myocardial infarction. Approximately 5000 patients were enrolled and monitored for 4.5 years. Patients were randomized to receive either Xuezhikang 300 mg or placebo. Patients treated with Xuezhikang had a significant 20% reduction in LDL cholesterol (P <.01) and a significant decrease in frequency of major coronary events (P <.001) from baseline. 17 A subgroup analysis of this study was conducted to evaluate the lipid-lowering effects of Xuezhikang in elderly patients (>65 years of age) with coronary heart disease, over a 4-year period. The patients receiving Xuezhikang had a 37% reduction in coronary events (P ¼.001), 44% reduction in stroke (P ¼.04), 31% decrease in cardiac-related mortality (P ¼.04), and 32% decrease in all-cause mortality (P ¼.01) compared with the placebo group. 18 The study researchers also conducted another subgroup analysis in patients with type 2 diabetes. A total of 591 diabetic patients with cardiovascular disease were randomized to either receive Xuezhikang or placebo and followed for 4 years. In the Xuezhikang group, the risk reduction for cardiovascular heart disease events was 51% (P <.001), decreasing nonfatal myocardial infarction by 64%, fatal myocardial infarction by 59%, and cardiovascular sudden death by 27% from baseline. 19 More recent studies have shown that the Xuezhikang extract is beneficial in improving left-ventricular diastolic function in patients with hypertension as well as efficacious in lowering morbidity and mortality in elderly patients with a history of myocardial infarction, independent of its lipid-lowering effects. 20,21 Safety of Red Yeast Rice for Dyslipidemia Because of the presence of lovastatin (monacolin K and monacolin KA) in red yeast rice, the US Food and Drug Administration (FDA) ruled that red yeast rice was not a dietary supplement but rather a drug. They asked companies producing red yeast rice to reformulate their products to no longer contain lovastatin. 2 Despite these rulings from the FDA, red yeast rice continues to be produced in the United States with trace amounts of lovastatin, and multiple formulations and strengths

4 36 Journal of Evidence-Based Complementary & Alternative Medicine 17(1) exist (Table 1). 6 One study evaluated 9 red yeast rice preparations and found great variation in the amount and type of monacolins among the products. 3 Therefore, determining clinical response and effectiveness with these products becomes extremely difficult. Multiple clinical studies have indicated that red yeast rice is a safe option for patients, with limited side effects; however, case reports have implicated red yeast rice in causing acute hepatitis, myopathy, and rhabdomyolysis Development of myopathy or myalgias is believed to be a result of monacolins also blocking the production of coenzyme Q 10 leading to deficiency and the development of atrophic muscular changes. 25 Another concern is the potential for the toxin citrinin to be included in the final red yeast rice product. Citrinin, a by-product of the red yeast rice fermentation process, has been found in available preparations, and studies conducted in animals have found that it has nephrotoxic capabilities. 6 Other Clinical Implications for Red Yeast Rice Most commonly, red yeast rice is used to treat dyslipidemia, but recent research suggests other potential indications for its clinical applicability. Research is being conducted investigating the use of red yeast rice in diabetes mellitus, hypertension, obesity, depression, cancer, and osteoporosis. Red yeast rice has antioxidant and anti-inflammatory properties that could be useful in other disease states. Studies in this area involve mainly cellular and animal research; however, further investigation could translate these findings to human medicine. Diabetes affects 8.3% of the US population and can lead to complications such as heart attack and stroke. 26 Type II diabetes mellitus patients exhibit insulin resistance leading to hyperglycemia. A study in rats found that orally administered red yeast rice can decrease plasma glucose, delay insulin resistance, and increase insulin sensitivity. 27 Red yeast rice increases the release of acetylcholine, resulting in increased insulin secretion in rats. 28 These studies suggest that red yeast rice could be useful in prediabetic patients, although further research is needed to confirm this benefit in humans. Hypertension is another chronic disease state affecting a large percentage of the population. Red yeast rice is reported to produce antihypertensive effects by 3 mechanisms. The first mechanism is through g-aminobutyric acid (GABA) content in Monascus purpureus M When red yeast rice was compared with pure GABA in rats with fructose-induced hypertension, the red yeast rice had a more potent antihypertensive effect. 29 The study indicated that other components besides the GABA content contributed to the antihypertensive effect of red yeast rice. The second mechanism is through acetylcholine chloride that was identified in Monascus pilosus IFO Finally, the third mechanism is through inhibition of angiotensin I converting enzyme by 4 active peptides that were found in Monascus purpureus IFO Based on these results, red yeast rice could be helpful in reducing blood pressure in diabetic patients and in the general population; however, human studies are needed before it can be recommended for the treatment of hypertension. Another potential use of red yeast rice is in obesity, and this was first observed in 3T3-L1 cells where red yeast rice extract was found to inhibit adipocyte differentiation and enhance lipolysis. 32,33 The effect was further tested in Wistar rats on a highfat diet. The rats that were fed red yeast rice had less weight gain and decreased cholesterol and insulin levels. 33 The antiobesity effects of red yeast rice could be a result of its appetite suppression activity and increased lipolysis. 33 These effects of red yeast rice have not been tested in humans, although use as an appetite suppressant would be particularly useful. Also, components of red yeast rice were found to have monoamine oxidase inhibitory activity. 34 Monankarins A to D had monoamine oxidase inhibiting activity, with monankarin C showing strong monoamine oxidase-b inhibition in mice brain cells. 34 Monoamine oxidase inhibitors have therapeutic use in the treatment of depression. Cellular and animal studies have used red yeast rice to promote bone growth In a cellular study, red yeast rice was found to increase the proliferation of osteoblasts, thus promoting the synthesis of collagenous proteins and factors essential for bone growth. 36 These bone-promoting qualities of red yeast rice were further tested on parietal bones of white rabbits. Red yeast rice was mixed with a collagen matrix and applied to the damaged bone. There was more bone formation in rabbits treated with the red yeast rice mixture than in those treated with just a collagen matrix alone. 35 Although bone formation is an exciting new area for potential red yeast rice use, research has not moved beyond animal studies, and more research is needed to determine if this effect translates into human medicine. An epidemiological study revealed that patients taking statins had a reduced risk of developing colorectal cancer. 38 This potential benefit from statins has promoted investigation into the ability of red yeast rice to alter cancer risk. A study investigated which components of red yeast rice helped decrease the growth of colon cancer cells. 39 Lovastatin and monacolin-rich red yeast rice had similar abilities to stop colon cancer cell proliferation; however, whole red yeast rice and pigment-rich red yeast rice also decreased colon cancer cell proliferation. This suggests that there are components in red yeast rice, other than just monacolins, that inhibit cancer cell proliferation. 39 Other than colorectal cancer, red yeast rice is being investigated for use in risk reduction for prostate cancer. Similar to the colorectal cancer results, there is evidence to suggest that components other than the monacolins in red yeast rice decreased androgendependent and -independent prostate cancer growth. 40 A study in mice with prostate cancer showed that there was a decrease in tumor size in those receiving red yeast rice in comparison to those mice that received placebo. 41 Because some prostate cancers are slow growing, the treatment regimen includes watchful waiting. This group of prostate cancer patients could benefit from the use of red yeast rice to prevent tumor progression. 42 Patients with slow-growing prostate cancer, where watchful waiting is being used, could particularly benefit from chronic treatment with red yeast rice. Other studies have shown red

5 Musselman et al 37 yeast rice to have cytotoxic properties. One study on human cancer cells established that a specific compound called ankaflavin, a component of red yeast rice, exhibited cytotoxic effects. 43 Also, a study in mice with lung cancer cells and induced skin cancer also showed cytotoxic effects. 44,45 However, the use of red yeast rice to prevent cancer or slow tumor progression is still in the early stages, and more research needs to be done to delineate its role in cancer. Red yeast rice has been shown to have antioxidant properties. Dimerumic acid, a component of red yeast rice, has been used. In molecular studies, dimerumic acid donates an electron to produce its antioxidant effect, and when dimerumic acid (12 mg/kg) was administered to mice, it was able to reduce druginduced liver toxicity. 46,47 Constituents of red yeast rice were tested for anti-inflammatory ability in mice with chemically induced inflammation. 48 All 10 tested constituents exhibited anti-inflammatory properties with varying potency. 47 In addition, these antioxidant and anti-inflammatory properties could be protective against amyloid b peptide induced plaques. 49 Amyloid b peptide plaque formation in the brain can contribute to the development of Alzheimer s disease. A cellular study found that red yeast rice protected cells from the effects of the amyloid b peptide. 49 When studied in rats, red yeast rice was found to reverse the memory loss caused by amyloid b peptide. 50 The antioxidant and anti-inflammatory properties of red yeast rice could also be applicable in other disease states. Summary Red yeast rice has been shown in multiple clinical studies to be an efficacious option in decreasing serum lipid levels in patients with dyslipidemia, with the greatest effect being on LDL cholesterol. Also, it seems to be a safe, viable option in patients unable to tolerate statins because of myalgias and/or other statin-related side effects. Currently, red yeast rice is the only supplement that has been proven to reduce the occurrence of adverse cardiac events in a comparable degree to statins. Recent research has been conducted that points to increase in the potential use of red yeast rice in other disease states. These studies have amplified its clinical applicability and role as a dietary supplement. Despite these favorable effects, a limitation to using red yeast rice is the lack of consistency in ingredients between different manufacturers and the inability to determine appropriate dosing. Author Contributions All authors have contributed to this article. MEM completed the first draft, outline, abstract, and references. RSP completed other clinical implications of red yeast rice and provided edits. KLD completed the introduction and pharmacology and provided edits. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The authors received no financial support for the research, authorship, and/or publication of this article. References 1. Ma J, Li Y, Ye Q, et al. Constituents of red yeast rice, a traditional Chinese food and medicine. J Agric Food Chem. 2000;48: Nijjar PS, Burke FM, Bloesch A, Rader DJ. Role of dietary supplements in lowering low-density lipoprotein cholesterol: a review. J Clin Lipidol. 2010;4: Heber D, Lembertas A, Lu QY, Bowerman S, Go VL. An analysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents. J Altern Complement Med. 2001;7: Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fonnebo V. Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials. Chin Med. 2006: Alberts AW, Chen J, Kuron G, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA. 1980;77: ConsumerLab.com Page. Red-Yeast-Rice-Supplements-Review/Red_Yeast_Rice/. Updated May 20, Accessed October 14, Journoud M, Jones PJ. Red yeast rice: a new hypolipidemic drug. Life Sci. 2004;74: Ma KY, Zhang ZS, Zhao SX, et al. Red yeast rice increases excretion of bile acids in hamsters. Biomed Environ Sci. 2009;22: Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go VL. Cholesterol-lowering effects of a proprietary Chinese red-yeastrice dietary supplement. Am J Clin Nutr. 1999;69: Lin CC, Li TC, Lai MM. Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia. Eur J Endocrinol. 2005;153: Bogsrud MP, Ose L, Langslet G, et al. HypoCol (red yeast rice) lowers plasma cholesterol: a randomized placebo controlled study. Scand Cardiovasc J. 2010;44: Becker DJ, Gordon RY, Morris PB, et al. Simvastatin vs therapeutic lifestyle changes and supplements: randomized primary prevention trial. Mayo Clin Proc. 2008;83: Halbert SC, French B, Gordon RY, et al. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol. 2010; 105: Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009;150: , W147-W Venero CV, Venero JV, Wortham DC, Thompson PD. Lipidlowering efficacy of red yeast rice in a population intolerant to statins. Am J Cardiol. 2010;105:

6 38 Journal of Evidence-Based Complementary & Alternative Medicine 17(1) 16. Liu L, Zhao SP, Cheng YC, Li YL. Xuezhikang decreases serum lipoprotein(a) and C-reactive protein concentrations in patients with coronary heart disease. Clin Chem. 2003;49: Lu Z, Kou W, Du B, et al. 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: Ye P, Lu ZL, Du BM, et al. Effect of Xuezhikang on cardiovascular events and mortality in elderly patients with a history of myocardial infarction: a subgroup analysis of elderly subjects from the China Coronary Secondary Prevention Study. J Am Geriatr Soc. 2007;55: Zhao SP, Lu ZL, Du BM, et al. Xuezhikang, an extract of cholestin, reduces cardiovascular events in type 2 diabetes patients with coronary heart disease: subgroup analysis of patients with type 2 diabetes from China coronary secondary prevention study (CCSPS). J Cardiovasc Pharmacol. 2007;49: Ye P, Wu CE, Sheng L, Li H. Potential protective effect of longterm therapy with Xuezhikang on left ventricular diastolic function in patients with essential hypertension. J Altern Complement Med. 2009;15: Li JJ, Lu ZL, Kou WR, et al. Beneficial impact of Xuezhikang on cardiovascular events and mortality in elderly hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS). J Clin Pharmacol. 2009;49: Grieco A, Miele L, Pompili M, et al. Acute hepatitis caused by a natural lipid-lowering product: when alternative medicine is no alternative at all. J Hepatol. 2009;50: Polsani VR, Jones PH, Ballantyne CM, Nambi V. A case report of myopathy from consumption of red yeast rice. J Clin Lipidol. 2008;2: Roselle H, Ekatan A, Tzeng J, Sapienza M, Kocher J. Symptomatic hepatitis associated with the use of herbal red yeast rice. Ann Intern Med. 2008;149: Vercelli L, Mongini T, Olivero N, Rodolico C, Musumeci O, Palmucci L. Chinese red rice depletes muscle coenzyme Q10 and maintains muscle damage after discontinuation of statin treatment. J Am Geriatr Soc. 2006;54: Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, Atlanta, GA: Department of Health and Human Services; Accessed October 18, Su CF, Liu IM, Cheng JT. Improvement of insulin resistance by Hon-Chi in fructose-rich chow-fed rats. Food Chem. 2007;104: Chen CC, Liu IM. Release of acetylcholine by Hon-Chi to raise insulin secretion in Wistar rats. Neurosci Lett. 2006;404: Hsieh PS, Tai YH. Aqueous extract of Monascus purpureus M9011 prevents and reverses fructose-induced hypertension in rats. J Agric Food Chem. 2003;51: Xue-Mei LX-HS, Zhen-Wen D, Shu-Ren G. Advances on the pharmacological effects of red yeast rice. Chin J Nat Med. 2011;9: Kuba MTK, Sesoko M, Inoue F, Yasuda M. Angiotensin I-converting enzyme inhibitory peptides in red-mold rice made by Monascus purpureus. Process Biochem. 2009;44: Jeon T, Hwang SG, Hirai S, et al. Red yeast rice extracts suppress adipogenesis by down-regulating adipogenic transcription factors and gene expression in 3T3-L1 cells. Life Sci. 2004;75: Chen WP, Ho BY, Lee CL, Lee CH, Pan TM. Red mold rice prevents the development of obesity, dyslipidemia and hyperinsulinemia induced by high-fat diet. Int J Obes (Lond). 2008;32: Hossain CF, Okuyama E, Yamazaki M. A new series of coumarin derivatives having monoamine oxidase inhibitory activity from Monascus anka. Chem Pharm Bull (Tokyo). 1996;44: Wong RW, Rabie B. Chinese red yeast rice (Monascus purpureusfermented rice) promotes bone formation. Chin Med. 2008;3: Cho YE, Alcantara E, Kumaran S, et al. Red yeast rice stimulates osteoblast proliferation and increases alkaline phosphatase activity in MC3T3-E1 cells. Nutr Res. 2010;30: Gutierrez GE, Mundy B, Rossini G, Garrett IR, Chen ST, Mundy GR. Red yeast rice stimulates bone formation in rats. Nutr Res. 2006;26: Poynter JN, Gruber SB, Higgins PD, et al. Statins and the risk of colorectal cancer. N Engl J Med. 2005;352: Hong MY, Seeram NP, Zhang Y, Heber D. Chinese red yeast rice versus lovastatin effects on prostate cancer cells with and without androgen receptor overexpression. J Med Food. 2008;11: Hong MY, Seeram NP, Zhang Y, Heber D. Anticancer effects of Chinese red yeast rice versus monacolin K alone on colon cancer cells. J Nutr Biochem. 2008;19: Hong MY, Henning S, Moro A, Seeram NP, Zhang Y, Heber D. Chinese red yeast rice inhibition of prostate tumor growth in SCID mice. Cancer Prev Res (Phila). 2011;4: Moyad MA, Klotz LH. Statin Clinical Trial (REALITY) for prostate cancer: an over 15-year wait is finally over thanks to a dietary supplement. Urol Clin North Am. 2011;38: Su NW, Lin YL, Lee MH, Ho CY. Ankaflavin from Monascusfermented red rice exhibits selective cytotoxic effect and induces cell death on Hep G2 cells. J Agric Food Chem. 2005;53: Akihisa T, Tokuda H, Yasukawa K, et al. Azaphilones, furanoisophthalides, and amino acids from the extracts of Monascus pilosus-fermented rice (red-mold rice) and their chemopreventive effects. J Agric Food Chem. 2005;53: Ho BY, Pan TM. The Monascus metabolite monacolin K reduces tumor progression and metastasis of Lewis lung carcinoma cells. J Agric Food Chem. 2009;57: Taira J, Miyagi C, Aniya Y. Dimerumic acid as an antioxidant from the mold, Monascus anka: the inhibition mechanisms against lipid peroxidation and hemeprotein-mediated oxidation. Biochem Pharmacol. 2002;63: Aniya Y, Ohtani II, Higa T, et al. Dimerumic acid as an antioxidant of the mold, Monascus anka. Free Radic Biol Med. 2000;28:

7 Musselman et al Akihisa T, Tokuda H, Ukiya M, et al. Anti-tumor-initiating effects of monascin, an azaphilonoid pigment from the extract of Monascus pilosus fermented rice (red-mold rice). Chem Biodivers. 2005;2: Lee CL, Wang JJ, Pan TM. Red mold rice extract represses amyloid beta peptide-induced neurotoxicity via potent synergism of anti-inflammatory and antioxidative effect. Appl Microbiol Biotechnol. 2008;79: Lee CL, Kuo TF, Wu CL, Wang JJ, Pan TM. Red mold rice promotes neuroprotective sappalpha secretion instead of Alzheimer s risk factors and amyloid beta expression in hyperlipidemic Abeta40- infused rats. J Agric Food Chem. 2010;58: