Red yeast rice

The field of dietary supplements has evolved, and offers new opportunities for clinical trials. One such area is lipid-lowering treatment. Most lipid-lowering dietary supplements are ineffective, particularly compared with pharmacologic statins.

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. 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.

RYR is a traditional Chinese herbal medicine first mentioned in 800 ad in the Tang Dynasty for blood circulation. It is produced by the fermentation of the fungal strain Monascus purpureus Went (red yeast) over moist 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 Hong Qu, Hung-Chu, Ang-kak, Ankak rice, red mold rice, and Beni-Koji.

In the late 1970s, Akira Endo 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). 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. RYR contains 10 different compounds known as “monacolins” (statin-like compounds) that block the rate-limiting enzyme for cholesterol synthesis, 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. 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 +6 mg/dL (+0.15 mmol/L).

Xuezhikang is a commercial RYR product evaluated in a large, randomized, placebo-controlled clinical trial with robust end points. The China Coronary Secondary Prevention Study (CCSPS) enrolled 4870 participants (3986 men, 884 women) with a previous myocardial infarction (MI), and a baseline 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 also modestly and significantly reduced. No serious adverse events were observed during this trial. 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. Subsequent subgroup evaluations from the CCSPS trial have found equivalent benefits with RYR among diabetic, elderly (mean age 69 years), and hypertensive participants. Potential anticancer benefits found in the overall trial with RYR were also found among the elderly (significant reduction in cancer deaths), and included a 51% reduction in cancer incidence. Thus, the data have been consistent in that RYR reduces lipid parameters, especially LDL, and appears to have a favorable impact on clinical end points.

A randomized trial of 74 dyslipidemia patients comparing 40 mg/d of simvastatin to a high-potency 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). 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 (N = 62) 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 ( P = .01) LDL reduction of −21.3%. 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. 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. A recently published crossover study of children (aged 8–16 years) with heterozygous familial hypercholesterolemia (n = 24) and familial combined hyperlipidemia (n = 16) found that an RYR supplement significantly ( P <.001) reduced LDL by 25%. 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.