Call us at (877) 284-3976 Monday-Friday 9am-5pm PST

My Cart (0)

Statin Clinical Trial (REALITY) for Prostate Cancer: an Over 15-Year Wait is Finally Over Thanks to a Dietary Supplement

Mark A. Moyad, MD, MPHa,b,*, Laurence H. Klotz, MDc

a Department of Urology, University of Michigan Medical Center, 1500 East Medical Center Drive , Ann Arbor,
MI 48109-0330, USA
b Eisenhower Wellness Institute, Eisenhower Medical Center, Rancho Mirage, CA, USA
c Sunnybrook Health Science Centre, 2075 Bayview Avenue, #MG408, Toronto, ON M4N 3M5, Canada
* Corresponding author. Department of Urology, University of Michigan Medical Center, 1500 East Medical
Center Drive, Ann Arbor, MI 48109-
0330.
E-mail address: moyad@umich.edu

KEYWORDS: Prostate cancer, Red yeast rice, Statins, REALITY trial

Urol Clin N Am 38 (2011) 325–331
doi:10.1016/j.ucl.2011.05.002
0094-0143/11/$ 2011 Elsevier Inc.

Efforts to initiate a prospective study of cholesterol-lowering agents have been unsuccessful to date. Many designs, including the evaluation of lipid reduction for the prevention of prostate cancer in average and high-risk patients, formenwith prostate cancer on active surveillance, or as a neoadjuvant or adjuvant treatment, have been proposed over the last 15 years. Lack of interest in such a trial has been due to multiple barriers, including: perceived lack of a compelling scientific rationale, concerns over unpredictable toxicity, lack of funding, corporate
instability, competition from generics, and a perception that other micronutrients (vitamin E, selenium, and so forth) may be of more interest.1–3
    However, over the last 7 years a great deal of epidemiologic and observational data has renewed interest in the relationship between cholesterol-lowering agents and prostate cancer progression.4–17 The authors believe the time has come to formally evaluate this relationship in a prospective randomized trial.


RED YEAST RICE
The field of dietary supplements has evolved, and offers new opportunities for clinical trials. One such area is lipid-lowering treatment.18 Most lipid-lowering dietary supplements are ineffective, particularly compared with pharmacologic statins.18–21  
    An important exception is red yeast rice (RYR) extract. This compound favorably competes with lovastatin, pravastatin, and simvastatin in terms of potency, and is a realistic alternative for statin-intolerant patients.18,22–24 

RYR has demonstrated a significant reduction in cardiovascular events (primary end point) in a randomized controlled trial of almost 5000 participants followed for a median of 4.5 years.25
    RYR is a traditional Chinese herbal medicine first mentioned in 800 AD in the Tang Dynasty for blood circulation.18,26,27 It is produced by the fermentation of the fungal strain Monascus purpureus Went (red yeast) overmoist and sterile rice.RYR is also actually a common dietary compound and food colorant utilized in numerous Asian countries. In China, Japan, and several other countries it is used as an additive and preservative for fish and meat. It has a vibrant red color, flavor, and aroma, thus it is also used as a flavoring agent in several Chinese recipes and dishes, and is even used for brewing red rice wine. RYR is also known by several synonyms as a food product, including HongQu, Hung-Chu, Angkak, Ankak rice, red mold rice, and Beni-Koji.
    In the late 1970s, Akira Endo28 found that a Monascus yeast strain naturally produced a substance that inhibits cholesterol synthesis. He named it “monacolin K.” This compound was later isolated and is now known to be of the same structure as lovastatin, the first marketed statin. Thus, RYR is the first statin used in medical history. Like RYR, a fungus, 3 of the first prescribed statins utilized in the United States were derived from fungi (lovastatin, pravastatin, and simvastatin).18,29 Certain fungi use statin-like compounds to block the synthesis of cholesterol required by intruders (bacteria) for their cell wall synthesis, thus in part deactivating or eliminating the intruder. The analysis of this fascinating protective mechanism led to the isolation of a class of medications (statins) that have benefitted patients substantially. RYRcontains 10 different compounds known as “monacolins” (statin-like compounds) that block the rate-limiting enzyme for cholesterol synthesis,22,30 and these are listed in Box 1. Of these, Monacolin K is likely most responsible for the low-density lipoprotein (LDL) cholesterol reduction associated with RYR.

CLINICAL EFFICACY OF RYR
A meta-analysis of 9625 patients in 93 randomized trials involving 3 different commercial variants of RYR has summarized this large experience.31 The mean reduction in total cholesterol, LDL cholesterol, triglyceride, and increase in high-density lipoprotein (HDL) cholesterol was respectively the following: -35 mg/dL (-0.91 mmol/L), -28 mg/dL (-0.73 mmol/L), -36 mg/dL (-0.41 mmol/L), and 16 mg/dL (10.15 mmol/L).

Box 1
Monacolin compounds that can be detected in red yeast rice (RYR)

Dihydromonacolin K
Monacolin J
Monacolin JA
Monacolin K (lovastatin equivalent)
Monacolin KA
Monacolin L
Monacolin LA
Monacolin M
Monacolin X
Monacolin XA

Total monacolin content (sum of the 10 detectable monacolins)

 

Xuezhikang is a commercial RYR product evaluated in a large, randomized, placebo-controlled clinical trial with robust end points.25,32 The China Coronary Secondary Prevention Study (CCSPS) enrolled 4870 participants (3986 men, 884 women) withapreviousmyocardial infarction (MI),andabaseline mean total cholesterol, LDL cholesterol, triglyceride, and HDL cholesterol of approximately 208 mg/dL (5.38 mmol/L), 129 mg/dL (3.34 mmol/L), 165 mg/dL (1.85 mmol/L), and 46 mg/dL (1.19 mmol/L). Participants received RYR, 600 mg twice
daily (1200 mg total, monacolin K 2.5–3.2 mg/capsule) or matching placebo and were followed for 4.5 years. The trial was conducted from May 1996 to December 2003 in 65 hospitals in China. The primary end point was nonfatal MI or death from coronary or cardiac causes. Secondary end points included total mortality from cardiovascular disease, total all-cause mortality, need for coronary revascularization procedure, and change in lipid levels. Fasting blood samples were drawn at baseline, 6 to 8 weeks after randomization, and at 6-month intervals.
    There were 2 interim analyses, and the second one demonstrated a significant difference for the primary end point. The study was stopped in June 2003. A total of 98% of the participants completed the study. Synopses of the results are found in Tables 1 and 2. It is of interest that a plethora of clinical end points were significantly reduced with the exception of a nonsignificant reduction in fatal MI. Cancer mortality and all cause mortality were reduced. Lipids were alsomodestly and significantly reduced. No serious adverse events were observed during this trial.

Table 1
Multiple clinical end-point observations in the largest randomized trial (CCSPS) of RYR

 


Total adverse events and treatment cessation numbers were similar for RYR and placebo. The number needed to treat (NNT) to prevent a primary end point over the 4.5-year duration of the trial is 21, which favorably compares with the NNT range (19–56) observed in previous secondary prevention trials.33 Subsequent subgroup evaluations from the CCSPS trial have found equivalent benefits with RYR among diabetic,34 elderly (mean age 69 years),35 and hypertensive participants.36 Potential anticancer benefits found in the overall trial
with RYR were also found among the elderly (significant reduction in cancer deaths),25,35 and included a 51% reduction in cancer incidence.35 Thus, the data have been consistent in that RYR reduces lipid parameters, especially LDL,37–39 and appears to have a favorable impact on clinical end points.25 

    A randomized trial of 74 dyslipidemia patients comparing 40 mg/d of simvastatin to a highpotency RYR (2.53 mg monacolin K per capsule, total monacolins, 5.3 mg/capsule) and lifestyle changes with fish oil found that the LDL reductions between both groups were similar after 12 weeks (-40% for simvastatin, -42% for RYR).30 Participants consuming RYR needed to consume 4 to 6 capsules (2400–3600 mg RYR total) per day compared with 1 tablet per day for the prescription-drug group. No dropouts occurred, and there was no difference in adverse events reported. In the simvastatin arm 3 patients experienced musculoskeletal symptoms with 1 having elevated liver function tests (LFTs). RYR group  had 1 patient with elevated creatine kinase numbers. This abnormality may have been caused by excessive exercise.
    Another trial (N562) by the same principal author utilized a less potent RYR (1.02 mg monacolin K per capsule, total monacolins, 2.16 mg/capsule) at a dose of 6 capsules (3600 mg total RYR) per day compared with placebo for statin-intolerant (myalgia-induced) patients for 24 weeks and found a significant (P5.01) LDL reduction of -21.3%.22 It should also be of interest that 93% of the subjects on RYR in this trial with a history of statin intolerance were able to tolerate this supplement without myalgia.
    Another group of 43 statin-intolerant adults with dyslipidemia were randomized in a separate trial to prescription pravastatin at 20 mg (40 mg total) or RYR, 2400 mg twice daily (4800 mg total, monacolin K at 1.245 mg per capsule, 8 capsules/d), and both groups were asked to adhere to weekly healthy lifestyle educational sessions.24 After 12 weeks a 30% reduction in LDL was observed for RYR and a 27% reduction for pravastatin. Only 1 of 21 in the RYR (5%) and 2 of 22 (9%) participants in the pravastatin group discontinued because of myalgia recurrence. Mean pain severity, and muscle strength at weeks 4, 8, and 12 did not differ. Other recent publications report similar results.23,40 A recently published crossover study of children (aged 8–16 years) with heterozygous familial hypercholesterolemia (n524) and familial combined hyperlipidemia (n516) found that an RYR supplement significantly (P<.001) reduced LDL by 25%.41 There were no adverse events in terms of liver or muscle enzyme abnormalities over the 8-week treatment period. The authors can propose multiple reasons for a low rate of toxicity with RYR overall in the literature (none proven): the diluted monacolin K in a supplement that contains mostly other ingredients, lower dose and potency of monacolin K/lovastatin compared with the previous statin utilized, multiple capsules during the day compared with one bolus at one specific time, which reduces the risk of excessive blood concentrations or impact with CYP3A4 inhibitors, other compounds that may deter myalgia in RYR (coenzyme Q–like effects), lack of aggressive monitoring, the desire to report fewer side effects from patients on a supplement compared with a drug, and so forth.

Prostate Cancer
RYR has direct effects on androgen-dependent LNCaP cells and androgen-independent cells over expressing androgen receptor.42 RYR inhibited prostate cancer growth compared with a prescription statin (lovastatin). Whole RYR inhibited proliferation to a greater extent than monacolin K and pigment-enriched fractions isolated from RYR (P<.001). These results suggested that intact RYR, beyond the monacolin content, may favorably inhibit androgen-dependent and androgenindependent prostate cancer growth. A recent study showed that RYR significantly reduced androgen-dependent and androgen-independent xenograft tumors in SCID mice (P<.05).43 Intact whole RYR again provided more inhibition than monacolin K alone. RYR also significantly (P<.05)
reduced gene expression of several androgensynthesizing enzymes (AKR1C3, HSD3B2, and SRD5A1) in both androgen-dependent and androgen-independent tumors. A significant (P<.001) association was seen between tumor volume and serum cholesterol. Similar findings have been demonstrated in colon cancer cell lines.44 Other studies have demonstrated that RYR has pleiotropic actions on a variety of pathways and markers beyond LDL cholesterol,45–48 which could have an impact on prostate cancer proliferation and progression.49–51 Thus RYR has the appeal of an inexpensive nontoxic natural compound that is equivalent to many statins and may have further inhibitory effects on prostate cancer.
    The authors believe that the active surveillance population is ideal for an initial clinical trial of RYR.7,52 Repeat biopsy and prostate-specific antigen kinetic data can be gleaned rapidly without the interference of other treatment manipulations. In addition, a preventive agent that is heart healthy and can prevent the progression of a minimal volume low-grade tumor to a more clinically significant disease would be of enormous value in this population of men. Heart disease is the number one cause of mortality in men with prostate cancer, so an agent that simultaneously improved heart and prostate health in active surveillance patients is a rational choice.7 The observational data suggest that if statins provide benefit, they do so by preventing progression or transformation to an aggressive disease state. One literature review stated

One interesting option that could be used to study the efficacy of statins in the prevention
of prostate cancer is a randomized clinical trial that includes men with localized and
well-differentiated prostate cancer who have chosen to be managed by active surveillance
instead of intervention. Such patients could be randomly allocated to receive either a statin
or placebo, with disease progression as the study end point. This kind of trial is made
possible by the currently increasing trend for active surveillance to be considered as an
acceptable management strategy for small, well-differentiated, prostate tumors.52

    The quotation referred to ongoing data on active surveillance from Klotz.53
    The authors will be conducting their trial in Toronto, Canada. Men will receive 3600 mg daily of RYR with a potency of monacolin K that is approximately 2.5 mg per capsule, based on previous clinical trials. It is expected that compliant participants will experience a 20% to 35% LDLcholesterol reduction. Active surveillance patients will be followed for at least 1 year and have at least 2 biopsies in this 12-month period.54,55 The level of LDL is not predictive for response, and therefore will not be an eligibility criterion.

LIMITATIONS OF RYR
Quality control with this over-the-counter product is an issue.56–59 Different commercial products of RYR have different concentrations of monacolins. Some contain a potentially harmful by-product of yeast fermentation known as “citrinin.”59 The REALITY trial will contain a monacolin K content similar to that used in the largest randomized trial of RYR, and be confirmed to be void of citrinin and other contaminants.
    RYR has been promoted as a safe and effective alternative to statins.60–63 Myopathy on statins is not a contraindication to RYR.22–24,60–63 However, RYR requires medical oversight. Case reports of hepatotoxicity,64,65 myopathy,66–71 and rhabdomyolysis have been reported.72 The contraindications for RYR should be similar to lovastatin, including hepatic or renal impairment, and allergies to yeast or fungus. RYR should be taken with or especially after meals, because lovastatin absorption is significantly improved under these circumstances, but only as long as pectin or oat bran (high fiber) is not consumed with it because these products specifically reduce absorption.73–75 There has been no consistent mention of this potentially positive and negative interaction with RYR and food in the medical literature or data relating to RYR specifically (only lovastatin).

SUMMARY
RYR is a safe, inexpensive, widely used natural compound, which acts as an effective statin and appears to inhibit prostate cancer proliferation in preclinical studies. It is very compelling as a preventive agent for both heart disease and prostate cancer. The active surveillance population is ideally suited for evaluating the effect of
this agent on prostate cancer progression.

References

1. van Adelsberg J, Gann P, Ko AT, et al. The VIOXX in Prostate Cancer Prevention study: cardiovascular events observed in the rofecoxib 25 mg and placebo treatment groups. Curr Med Res Opin 2007;23:2063–70.
2. Thompson IM, Tangen CM, Klein EA, et al. Phase III prostate cancer prevention trials: are the costs justified? J Clin Oncol 2005;23:8161–4.
3. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. Selenium and Vitamin E Cancer Prevention Trial. J Urol 2001; 166:1311–5.
4. Moyad MA. Heart healthy equals prostate healthy equals statins: the next cancer chemoprevention trial. Part I. Curr Opin Urol 2005;15:1–6.
5. Moyad MA. Why a statin and/or another proven heart healthy agent should be utilized in the next major cancer chemoprevention trial: part I. Urol Oncol 2004;22:466–71.
6. Moyad MA. Why a statin and/or another proven heart healthy agent should be utilized in the next major cancer chemoprevention trial: part II. Urol Oncol 2004;22:472–7.
7. Moyad MA, Merrick GS. Statins and cholesterol lowering after a cancer diagnosis: why not? Urol Oncol 2005;23:49–55.
8. Moyad MA, Merrick GS, Butler WM, et al. Statins, especially atorvastatin, may favorably influence clinical presentation and biochemical progression-free survival after brachytherapy for clinically localized prostate cancer. Urology 2005;66:1150–4.
9. Shannon J, Tewoderos S, Garzotto M, et al. Statins and prostate cancer risk: a case-control study. Am J Epidemiol 2005;162:318–25.
10. Cyrus-David MS, Weinberg A, Thompson T, et al. The effect of statins on serum prostate specific antigen levels in a cohort of airline pilots: a preliminary report. J Urol 2005;173:1923–5.
11. Zhuang L, Kim J, Adam RM, et al. Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. J Clin Invest 2005;115:959–68.
12. Platz EA, Leitzmann MF, Visvanathan K, et al. Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst 2006;98:1819–25.
13. Jacobs EJ, Rodriguez C, Bain EB, et al. Cholesterollowering drugs and advanced prostate cancer incidence in a large U.S. cohort. Cancer Epidemiol Biomarkers Prev 2007;16:2213–7.
14. Colli JL, Amling CL. Exploring causes for declining prostate cancer mortality rates in the United States. Urol Oncol 2008;26:627–33.
15. Murtola TJ, Pennanen P, Syvala H, et al. Effects of simvastatin, acetylsalicylic acid, and rosiglitazone on proliferation of normal and cancerous prostate epithelial cells at therapeutic concentrations. Prostate 2009;69:1017–23.
16. Loeb S, Kan D, Helfand BT, et al. Is statin use associated with prostate cancer aggressiveness? BJU Int 2010;105:1222–5.
17. Farwell WR, D’Avolio LW, Scranton RE, et al. Statins and prostate cancer diagnosis and grade in (CCSPS)-lipid regulating therapy with xuezhikang for secondary prevention of coronary heart disease. Chin J Cardiol (Chin) 2005;33:109–15. a Veterans population. J Natl Cancer Inst 2011; 103:885–92.
18. Nijjar PS, Burke FM, Bloesch A, et al. Role of dietary supplements in lowering low-density lipoprotein cholesterol: a review. J Clin Lipidol 2010;4:248–58.
19. Marinangeli CP, Jones PJ, Kassis AN, et al. Policosanols as nutraceuticals: fact or fiction. Crit Rev Food Sci Nutr 2010;50:259–67.
20. Khoo YS, Aziz Z. Garlic supplementation and serum cholesterol: a meta-analysis. J Clin Pharm Ther 2009;34:133–45.
21. Thompson Coon JS, Ernst E. Herbs for serum cholesterol reduction: a systematic review. J Fam Pract 2003;52:468–78.
22. Becker DJ, Gordon RY, Halbert SC, et al. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med 2009;150:830–9.
23. Venero CV, Venero JV, Wortham DC, et al. Lipidlowering efficacy of red yeast rice in a population intolerant to statins. Am J Cardiol 2010;105:664–6.
24. Halbert SC, French B, Gordon RY, et al. Tolerability of red yeast rice (2400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol 2010;105:198–204.
25. Lu Z, Kou W, Du B, et al, Chinese Coronary Secondary Prevention Group. Effects of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol 2008;101:1689–93.
26. Li C, Zhu Y, Wang Y, et al. Monascus purpureus fermented rice (red yeast rice): a natural food product that lowers blood cholesterol in animal models of hypercholesterolemia. Nutr Res 1998;18:71–81. Red yeast rice. Med Lett Drugs Ther 2009;51:71–2.
27. Lin Y-L, Wang T-H, Lee M-H, et al. Biologically active components and nutraceuticals in the Monascusfermented rice: a review. Appl Microbiol Biotechnol 2008;77:965–73.
28. Endo A. Monacolin K, a new hypocholesterolemic agent produced by a Monascus species. J Antibiot (Tokyo) 1979;32:852–4.
29. Landers P. Stalking cholesterol. How one scientist intrigued by molds found first statin. Feat of Japan’s Dr. Endo led to heart-care revolution but brought him nothing. Nature as a drug laboratory. Wall Street Journal. New York: Dow Jones and Company;
2006. p. A1, A8.
30. Becker DJ, Gordon RY, Morris PB, et al. Simvastatin vs therapeutic lifestyle changes and supplements: randomized primary prevention trial. Mayo Clin Proc 2008;83:758–64.
31. Liu J, Zhang J, Shi Y, et al. Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials. Chin Med 2006;1:4.
32. China Coronary Secondary Prevention Study Group. China coronary secondary prevention study33. Ong HT. The statin studies: from targeting hypercholesterolemia to targeting the high risk patient. QJM 2005;98:599–614.
34. Zhao SP, Lu ZL, Du BM, et al, China Coronary Secondary Prevention Study. 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 Chian coronary secondary prevention study (CCSPS). J Cardiovasc Pharmacol 2007;49:81–4.
35. Ye P, Lu ZL, Du BM, et al, CCSPS Investigators. Effects of xuezhikang on cardiovascular events and mortality in elderly patients with a history of myocardial infarction: a subgroup analysis of elderly subjects from China coronary secondary prevention study. J Am Geriatr Soc 2007;55:1015–22.
36. Li JJ, Lu ZL, Kou WR, et al, Chinese Coronary Secondary Prevention Study (CCSPS) Group. Long-term effects of Xuezhikang on blood pressure in hypertensive patients with previous myocardial infarction: data from the Chinese Coronary Secondary Prevention Study (CCSPS). Clin Exp Hypertens 2010;32(8):491–8.
37. Huang CF, Li TC, Lin CC, et al. Efficacy of Monascus purpureus Went rice on lowering lipid ratios in hypercholesterolemic
patients. Eur J Cardiovasc Prev Rehabil 2007;14:438–40.
38. Lin CC, Li TC, Lai MM. Efficacy and safety of Monascus purpureus Went rice in subjects with hyperlipidemia. Eur J Endocrinol 2005;153:679–86.
39. Heber D, Yip I, Ashley JM, et al. Cholesterol-lowering effects of a proprietary Chinese redyeast-rice dietary supplement. Am J Clin Nutr 1999;69:231–6.
40. Bogsrud MP, Ose L, Langslet G, et al. HypoCol (red yeast rice) lowers plasma cholesterol-a randomized placebo controlled study. Scand Cardiovasc J 2010; 44:197–200.
41. Guardamagna O, Abello F, Baracco V, et al. The treatment of hypercholesterolemic children: Efficacy and safety of a combination of red yeast rice extract and policosanols. Nutr Metab Cardiovasc Dis 2011; 21:424–9.
42. Hong MY, Seeram NP, Zhang Y, et al. Chinese red yeast rice versus lovastatin effects on prostate  cancer cells with and without androgen receptoroverexpression. J Med Food 2008;11:657–66.
43. Hong MY, Henning S, Moro A, et al. Chinese red yeast rice inhibition of prostate tumor growth in SCID mice. Cancer Prev Res (Phila) 2011;4:608–15.
44. Hong MY, Seeram NP, Zhang Y, et al. Anticancer effects of Chinese red yeast rice versus monacolin K alone on colon cancer cells. J Nutr Biochem 2008;19:448–58.
45. MaKY, Zhang ZS, Zhao SX, et al. Red yeast increases excretion of bile acids in hamsters. Biomed Environ Sci 2009;22:269–77.
46. Li JJ, Hu SS, Fang CH, et al. Effects of xuezhikang, an extract of cholestin, on lipid profile and C-reactive protein: a short-term time course study in patients with stable angina. Clin Chim Acta 2005; 352:217–24.
47. Zhao SP, Liu L, Cheng YC, et al. Xuezhikang, an extract of cholestin, protects endothelial function through anti-inflammatory and lipid-lowering mechanisms in patients with coronary heart disease. Circulation 2004;110:915–20.
48. Liu L, Zhao SP, Cheng YC, et al. Xuezhikang decreases serum lipoprotein(a) and C-reactive protein concentrations in patients with coronary heart disease. Clin Chem 2003;49:1347–52.
49. Eisberger B, Lankston L, McMillan DC, et al. Presence of tumoural C-reactive protein correlates with progressive prostate cancer. Prostate Cancer Prostatic Dis 2011;14:122–8.
50. Lehrer S, Diamond EJ, Mamkine B, et al. C-reactive protein is significantly associated with prostatespecific antigen and metastatic disease in prostate cancer. BJU Int 2005;95:961–2.
51. Solomon KR, Pelton K, Boucher K, et al. Ezetimibe is an inhibitor if tumor angiogenesis. Am J Pathol 2009; 174:1017–26.
52. Murtola TJ, Visakorpi T, Lahtela J, et al. Statins and prostate cancer prevention: where we are now, and future directions. Nat Clin Pract Urol 2008;5:376–87.
53. Klotz L. Active surveillance versus radical treatment for favorable-risk localized prostate cancer. Curr Treat Options Oncol 2006;7:355–62.
54. Gotto AM Jr, Whitney E, Stein EA, et al. Relation between baseline and on treatment lipid parameters and first major acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:
477–84.
55. Nakamura H; MEGA Study Group. Primary prevention of cardiovascular diseases among hypercholesterolemic Japanese with a low dose of pravastatin. Atheroscler Suppl 2007;8:13–7.
56. Gordon RY, Cooperman T, Obermeyer W, et al. Marked variability of monacolin levels in commercial red yeast rice products: buyer beware. Arch Intern Med 2010;170:1722–7.
57. Harding A. Contamination common in red yeast rice products. New York: Thompson Reuters; 2008. Available at:  www.reuters.com/article/healthNews/idUSCOL97022820080709. Accessed April 25, 2011.
58. Klimek M, Wang S, Ogunkanmi A. Safety and efficacy of red yeast rice (Monascus purpureus) as an alternative therapy for hyperlipidemia. P T 2009;
59. Heber D, Lembertas A, Lu QY, et al. An analysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents. J Altern Complement Med 2001;7:133–9.
60. Abd TT, Jacobson TA. Statin-induced myopathy: a review and update. Expert Opin Drug Saf 2011; 10:373–87.
61. Eckel RH. Approach to the patient who is intolerant of statin therapy. J Clin Endocrinol Metab 2010;95: 2015–22.
62. Kelly RB. Diet and exercise in the management of hyperlipidemia. Am Fam Physician 2010;81: 1097–102.
63. Lin JS. An alternative treatment of hyperlipidemia with red yeast rice: a case report. J Med Case Reports 2010;4:4.
64. Roselle H, Ekatan A, Tzeng J, et al. Symptomatic hepatitis associated with the use of herbal red yeast rice [letter]. Ann Intern Med 2008;149:516–7.
65. 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;50:1273–7.
66. Polsani VR, Jones PH, Ballantyne CM, et al. A case report of myopathy from consumption of red yeast rice. J Clin Lipidol 2008;2:60–2.
67. Lapi F, Gallo E, Bernasconi S, et al. Myopathies associated with red yeast rice and liquorice: spontaneous reports from the Italian Surveillance System of Natural Health Products [letter]. Br J Clin Pharmacol 2008;66:572–4.
68. Mueller PS. Symptomatic myopathy due to red yeast rice [letter]. Ann Intern Med 2006;145:474–5.
69. Smith DJ, Olive KE. Chinese red rice-induced myopathy. South Med J 2003;96:1265–7.
70. Vercelli L, Mongini T, Olivero N, et al. Chinese red rice depletes muscle coenzyme Q10 and maintains muscle damage after discontinuation of statin treatment [letter]. J Am Geriatr Soc 2006;54:718–20.
71. Cartin-Ceba R, Lu LB, Kolpakchi A. A “natural” threat [letter]. Am J Med 2007;120:e3–4.
72. Prasad GV, Wong T, Meliton G, et al. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient. Transplantation 2002;74:1200–1.
73. Garnett WR. Interactions with hydroxymethylglutarylcoenzyme A reductase inhibitors. Am J Health Syst Pharm 1995;52:1639–45.
74. Schacter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 2005;19:117–25.
75. Moghadasian MH. Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Life Sci 1999;65:1329–37