UCLA Center for Human Nutrition

There are 57 million Americans with cholesterol levels greater than 200 mg/dl who are at increased risk of heart disease, which remains the primary cause of mortality in the U.S. with 500,000 deaths per year due to heart attack. However, cholesterol-lowering drugs are only recommended for individuals with cholesterol levels above 240 mg/dl, and it is estimated that only 3 to 4 million Americans take these drugs currently. For 30 million Americans with cholesterol levels in the 200 to 240 mg/dl range, natural remedies combined with diet and lifestyle changes may offer a great public health benefit at reasonable cost and low risk. The botanical dietary supplement Monascus Purpureus Went yeast or Chinese red yeast rice contains a family of monacolins (polyketides) with the ability to inhibit cholesterol synthesis and lower plasma cholesterol levels independent of diet. One of the monacolins (Monacolin K) is identical in chemical structure to Lovastatin, which is widely sold as a prescription cholesterol-lowering drug, but the other monacolins in this botanical supplement may also have cholesterol-lowering activity. Evidence of the activity of multiple components of this yeast clearly will differentiate this product as a dietary supplement rather than a drug. Preliminary work has extensively characterized these potentially bioactive components of the yeast, and we have successfully conducted a recently published double-blind, placebo-controlled trial of this supplement in 80 individuals demonstrating a significant decrease in cholesterol levels from ca. 250 mg/dl to 210 mg/dl over 8 weeks independent of diet.

Red yeast rice is a traditional food consumed throughout Asia. Its food value and medicinal value is believed to date back more than a thousand years, with the first documentation of its use recorded in 800 A.D. The fungus Monascus isolated from red yeast rice first became known in Western society through the work of Dutch scientists, who noted its use by local populations in Java in 1884. A species isolated from red Koji or Honqu (as red rice yeast is known in East Asia) was named Monascus Purpureus Went in 1895, in recognition of the purple coloration. Today there are more than 30 Monascus strains on deposit with the American Type Culture Collection.

The traditional method of making red yeast rice is to ferment the yeast naturally on a bed of cooked non-glutinous whole rice kernels, and this method has been industrialized to produce a dietary supplement marketed in the United States (Cholestin, Pharmanex, Inc., Simi Valley, CA). The supplement contains only the rice and the Monascus fungus and the yeast in a capsule. There are a number of constituents in the natural product including pigments, fatty acids, and polyketides (monacolins). These monacolins are believed to account for the majority of the cholesterol-lowering activity of the yeast.

We examined the cholesterol-lowering effects of Chinese red yeast rice supplement in an American population consuming a diet similar to the American Heart Association Step I diet using a double-blind placebo-controlled, prospectively randomized twelve-week controlled trial (32). Eighty-three healthy subjects (46 men, 37 women, aged 34-78) with hyperlipidemia (total cholesterol (TC) 204-338 mg/dL), LDL cholesterol (LDL) 128-277 mg/dL, triglycerides 55-246 mg/dL, and HDL cholesterol (HDL) 30-95 mg/dL) not being treated with lipid-lowering drugs participated. Subjects were treated with this supplement (2.4 g/day) or placebo and instructed on a diet providing 30% of energy from fat, less than 10 % saturated fat, and less than 300 mg of dietary cholesterol.

The total cholesterol (TC) level was significantly decreased between baseline and 8 weeks in the red yeast rice-treated group compared to the placebo treated group (p<0.05). TC levels at 8 and 12 weeks differed significantly (p< 0.05) between the two groups. At 8 weeks, mean TC was 208 ± 31 mg/dL in the red yeast rice-treated group compared to 254 ± 36 mg/dL in the placebo-treated group. Furthermore, TC at both 8 and 12 weeks differed significantly from baseline (p<0.05) in the red yeast rice-treated group. At 8 weeks, every patient in the red yeast rice-treated group experienced a reduction in TC, while there was no significant difference in TC at 8 and 12 weeks compared to baseline in the placebo-treated group. The difference between baseline and 12 weeks was 40 ± 21 mg/dL in the red yeast rice-treated group and 5 ± 20 mg/dL in the placebo-treated group.

Low density lipoprotein (LDL) cholesterol levels at 8 and 12 weeks differed significantly (p<0.001) between the two groups. At 12 weeks, mean LDL cholesterol in the red yeast rice-treated group was 135 ± 27 mg/dL compared to 175 ± 33 mg/dL in the placebo-treated group. Furthemore, LDL levels at 8 and 12 weeks within the red yeast rice-treated group differed significantly (p<0.001) from baseline levels. At 8 weeks, all but one of the red yeast rice-treated subjects experienced a drop in LDL cholesterol. On the other hand, in the placebo-treated group there was no significant difference between baseline and 8 weeks or between baseline and 12 weeks. The difference in the red yeast rice-treated group between baseline and 12 weeks 39 ± 19 mg/dL compared to 5 ± 22 mg/dL in the placebo-treated group (Table 1).

Table 1	Cholesterol (mg.dL)	Triglycerides (mg/dL)	HDL (mg/dL)
Baseline
Control	254 + 29	143 + 46	46 + 10
Red Yeast	250 + 30	133 + 48	50 + 13
Week 8
Control	254 + 36	142 + 52	46 + 10
Red Yeast	208 + 31	118 + 41	50 + 13
Week 12
Control	250 + 36	146 + 47	46 + 11
Red Yeast	210 + 31	124 + 44	50 + 14

Triglyceride levels at 8 and 12 weeks differed significantly (p<0.05 and p<0.05, respectively) between the two groups. At 12 weeks, mean triglyceride levels in the red yeast rice-treated group were 124 ± 44 mg/dL compared to 146 ± 47 mg/dL in the placebo-treated group. Mean triglyceride levels within the red yeast rice-treated group differed from baseline at 8 weeks (p<0.05), but not at 12 weeks (p<0.054). On the other hand, in the placebo-treated group there was no significant difference between baseline and 8 weeks or baseline and 12 weeks. The difference in the red yeast rice-treated group between baseline and 12 weeks was 9 ± 30 mg/dL and for the placebo-treated group it was 3 ± 36 mg/dL.

HDL cholesterol levels did not differ significantly within or between the groups at baseline, 8 weeks, or 12 weeks.

There were no significant differences in dietary intake within or between groups at 8 weeks. Blood lipid differences between the red yeast rice-treated and placebo-treated groups were already evident at a time (8 weeks), when there were no differences in dietary intake. Differences in dietary intake cannot, therefore, account for the observed decrease in cholesterol. Furthermore, there were no differences in body weight between or within groups at any time. At 12 weeks, the treatment group reported reduced intake of total calories, saturated fat, monounsaturated fat, and fiber intake compared to baseline, but not when compared to the placebo-treated group. Reported total fat intake and polyunsaturated fat intake were lower than reported at baseline, as well as when compared to the placebo-treated group.

There were no serious adverse effects in any of the 88 subjects randomized. In the placebo-treated group, three subjects reported minor adverse effects, including: 1) development of a rash which responded to prednisone and antihistamine; 2) headaches; and 3) concurrent development of pneumonia while on study. There were no reported adverse events in the red yeast rice-treated group, except for one subject who reported an intercurrent hospitalization for musculoskeletal chest pain at his 12th week visit. He continued the dietary supplement while hospitalized and had a normal electrocardiogram stress treadmill performed by his outside doctor. His chest pain resolved and was not related to the dietary supplement.

Liver function tests were measured at baseline and 12 weeks. There were no significant differences between the groups at baseline or 12 weeks. Within treatment groups, BUN and GGTP differed significantly between baseline and 12 weeks. Both were lower at 12 weeks than at baseline. There were no abnormal liver function or renal function tests obtained at any time in any subject under study.

In this double-blind randomized, placebo-controlled prospective study, red yeast rice significantly reduced cholesterol levels beyond effects that could be accounted for by diet alone, and without significant adverse effects. The content of Monacolin K is only 0.2%, or about 5 mg. Therefore, 5 mg is the relevant comparison to 20 to 40 mg of lovastain. At this level, the mixture of monacolins and other substances present in the red yeast may have some effect on cholesterol biosynthesis not explained by the Monacolin K content. It is unlikely to be due solely to a single species of Monacolin, but rather to result from a combination of actions of monacolins and other substances in the red yeast rice.

Studies in humans have been conducted in China with both greater and lesser concentrated extracts of the red yeast rice than in our red yeast rice-treated group. In 324 hypercholesterolemic subjects treated with Xuezhikang (1.2 g/day containing 13.5 mg total monacolins) for 8 weeks, serum cholesterol levels decreased by 23 %, triglycerides reduced by 36.5 %, and HDL cholesterol levels increased by 19.6%. Two to four weeks before the initiation of this study, subjects were instructed to cease taking all medications and were provided dietary counseling. In a second study, an earlier version of the red yeast rice supplement containing 10 to 13 mg total monacolins was given to 101 hypercholesterolemic subjects. Total cholesterol decreased by 19.5 % and triglycerides decreased by 36.1% in the treated group. HDL cholesterol levels increased by 16.7% in this study. These and other Chinese studies were similar to this study in showing a marked effect of the constituents of this traditional seasoning on cholesterol levels. However, there were differences in the ethnicity and serum lipid levels of the populations studied. Furthermore, a rice placebo was used in the present study conducted in a double-blind fashion, while the Chinese studies used different natural preparations in the comparison group rather than a matched placebo capsule.

The benefits of statin drugs on the primary prevention of heart disease and in the secondary prevention of recurrent heart disease have been demonstrated in several large prospective clinical trials. These studies have increased interest in the use of statins for heart disease prevention, such as for individuals with hypercholesterolemia and modest cholesterol elevations. While it is acknowledged that side effects with statins are rare and are dose-related, there are data indicating that some statins may cause liver function abnormalites, and under certain circumstances rhabdomyolysis.

A clinical trial in 5608 men and 997 women with average cholesterol levels demonstrated that Lovastatin reduced the risk for a first acute major coronary event. The authors suggested a "need for reassessment of the national Cholesterol Education Program guidelines regarding pharmacological intervention." However, an accompanying editorial raised concerns regarding the economic impact of using cholesterol-lowering drugs, if used in the general population with average cholesterol levels. The currently available Chinese red yeast rice preparation used in the present study costs $20-$30/mo, while cholesterol-lowering drugs cost $120-$300/mo, with an average cost of $187/mo (32) . When considering a population-based public health approach to lowering cholesterol and preventing coronary artery disease, the reduced costs of the red yeast rice dietary supplement compared to prescription drugs could provide a new and novel approach for the maintenance of healthier cholesterol levels.

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