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

Mark A. Moyad, MD, MPH^a,b,*, Laurence H. Klotz, MD^c

<sup>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</sup>

^{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