Cholestin for the Treatment of Hypercholesterolemia
April 1, 1999 9 minutes read
Cholestin for the Treatment of Hypercholesterolemia
April 1999; Volume 2: 37-41
By Dónal P. O’Mathúna, PhD
Reducing saturated and trans fat intake and increasing aerobics just aren’t enough—never mind possible—for everyone. Drug therapy with fibrates or bile acid sequestrants is neither as effective nor as safe as physicians had hoped.
Then the statin era arrived. Shown to adjust cholesterol levels appropriately,1 many believe the biggest problem with statin therapy, as with other preventive approaches, is its underutilization.2 Part of this issue is financial. Lovastatin therapy costs between $63-$228 per month, depending on dosage.3 In China, the prohibitive cost and limited availability of statins led to a search for a natural statin alternative among traditional Chinese medications.4 The search yielded what is now marketed in the United States as Cholestin.
History and Production
Cholestin is made by fermenting rice with a particular strain of yeast called Monascus purpureus, Went.5 Called red yeast rice, it has been used for centuries in China to make red rice wine, preserve food, enhance flavor, and act medicinally. Written records from the Ming Dynasty (1368-1644) state that it was believed to improve blood circulation and reduce clotting.5 The dried red yeast rice is either powdered and called Zhitai, or extracted with alcohol and called Xuezhikang.
Red yeast rice is produced in China and imported by Pharmanex, Inc. which packs the rice into gelatin capsules. Pharmanex sells Cholestin as a dietary supplement, to which the FDA objects, claiming it is a drug.
Regulatory Status
Federal courts have preliminarily declared Cholestin to be a dietary supplement and not a drug.
Mechanism of Action
The red yeast rice used in Cholestin contains a number of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. HMG-CoA reductase catalyzes an essential step in the biosynthesis of cholesterol. HMG-CoA reductase inhibition decreases the production of cholesterol in the liver. The pharmaceutical statins are, of course, also HMG-CoA reductase inhibitors. Their chemical structures are very similar, varying in only three places. (See Figure 1.)
Of the many strains of Monascus purpureus, only three produce HMG-CoA inhibitors when fermented under specific controlled conditions.5 Cholestin contains nine HMG-CoA reductase inhibitors, of which monacolin K (or mevinolin or lovastatin) is the most abundant.6 Merck & Co., Inc. markets lovastatin in its purified crystalline form as Mevacor®.7
Animal and Clinical Studies
Searches of Medline, International Pharmaceutical Abstracts, and Toxline (using the terms "Cholestin," "red yeast rice," "Monascus purpureus," "Zhitai," and "Xuezhikang") revealed three studies.4,8,9 A Chinese study using rabbits and quail showed that Xuezhikang significantly lowered cholesterol levels.8,10 Heber reports examining eight controlled studies and nine uncontrolled studies in Chinese medical papers. In these studies, eight weeks of either Zhitai or Xuezhikang led to total cholesterol reductions of 11.2-32.2%.5 The available studies are summarized in Table 1.
| Table 1 | |||||||||||
| Blood lipid levels (mg/dL) in subjects taking various red yeast rice products | |||||||||||
| Study | Formulation |
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HDL-cholesterol |
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| Ref. 11 | Zhitai |
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| Ref. 12 | Xuezhikang |
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| Ref. 4 | Xuezhikang |
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| Ref. 6 | Cholestin |
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| Ref. 6 | Cholestin |
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One double-blind clinical trial was published using Zhitai capsules, the formulation most similar to Cholestin.11 The 152 subjects were randomly divided into three groups (90 men, 62 women; average age, 55 years). One group of 51 subjects received a placebo, while the 101 subjects in the two other groups received five Zhitai capsules daily for two months. Mean total cholesterol concentration in the treatment group dropped 19.2%; LDL-cholesterol dropped 27.4%; triglycerides dropped 36.1%; and HDL-cholesterol increased 16.7% (all P < 0.01). Serum lipids did not change significantly in the placebo group.
One clinical trial using the alcoholic extract of red yeast rice, Xuezhikang, was reported in both a Chinese publication12 and a more recent American publication.4 Both report the same randomized, single-blind trial, but differ in the number of samples reported for each type of lipid analyzed. The discrepancies occurred because the data were reanalyzed according to Western standards.13
The subjects received either 0.6 g Xuezhikang twice daily or Jiaogulan, another Chinese herbal medicine reported as having antihyperlipidemic properties. The concentration of HMG-CoA reductase inhibitors was not reported, although elsewhere 1 g Xuezhikang is reported to contain 20 mg lovastatin.10 The treatment group contained 324 subjects and the control group 122 subjects (total of 261 men, 185 women; average age, 56 years).4,12
The Chinese publication reported that in the treatment group, the mean total cholesterol dropped 23%; LDL-cholesterol dropped 28.5%; triglycerides dropped 36.5%; HDL-cholesterol increased 19.6% (P < 0.001).12 The American publication reported a 22.7% drop in total cholesterol; a 30.9% drop in LDL-cholesterol; a 34.1% drop in triglycerides; and a 19.9% rise in HDL-cholesterol (P < 0.001).4 The lipid concentrations for those receiving Jiaogulan also changed significantly, but to a smaller extent than with Xuezhikang.
The first clinical trial on Pharmanex’s Cholestin was reported recently.6 Eighty-eight patients were randomly assigned to receive either four 600 mg Cholestin capsules daily or a placebo. All subjects adhered to the American Heart Association Step I diet. Excluding drop-outs, 42 completed the treatment and 41 the control (46 men, 37 women; average age, 62 years). Blood lipid analysis was conducted after eight and 12 weeks, with changes summarized here respectively.
With treatment, total cholesterol was 16.8% lower after 8 weeks and 16.0% lower after 12 weeks (P < 0.05); LDL-cholesterol dropped 21.4% (8 weeks) and 22.0% (12 weeks) (P < 0.001); triglycerides dropped 11.3% (8 weeks; P = 0.05) and 6.8% (12 weeks; no longer significant); HDL-cholesterol remained un-changed throughout, as did all values in the placebo group.
Adverse Effects
No significant adverse effects were observed during clinical trials, but a small number of people had digestive tract discomfort. The manufacturer’s literature recommends taking Cholestin with food to minimize these effects.14 Cholestin should not be taken by pregnant or nursing women, women planning to become pregnant, or anyone younger than 20 years. The manufacturer also advises that Cholestin not be taken by people with or at risk for liver disease, by those consuming more than two alcoholic beverages daily, by anyone with a serious infection, disease or physical disorder, or by anyone who has undergone organ transplantation or recent major surgery.14 No rationale is given for these warnings.
Purified lovastatin has been found to cause liver damage, myalgia, weakness, and nephrotoxicity in 1-2% of patients.14 People taking lovastatin should have regular liver examinations. Statins are not recommended for women of child-bearing age for fear of fetal harm since developing fetuses require cholesterol in unique ways.
Toxicity studies with rats revealed no adverse effects with a single dose of Xuezhikang 533 times the normal dose, or over four months at 33 or 66 times the normal dose.15 However, Monascus purpureus can produce citrinin, a nephrotoxic metabolite.9
Drug Interactions
No drug interactions have been reported for Cholestin. However, grapefruit juice gives a 15-fold increase in serum concentrations of lovastatin and its active metabolite, lovastatin acid.16 Consumers of Cholestin should be made aware of this interaction.
Formulation/Dosage
Each gram of Cholestin contains 4 mg HMG-CoA reductase inhibitors: 2 mg as lovastatin, 1 mg as lovastatin acid, and 1 mg as a mixture of seven other statins. The recommended dose of Cholestin is two 600 mg capsules bid. This is equivalent to 7.2 mg lovastatin plus 2.4 mg of other statins. With approximately 10 mg of statins, the 16% reduction in LDL-cholesterol found for Cholestin6 parallels the 17% reduction usually found with 10 mg purified lovastatin.17
Conclusion
Cholestin’s ability to reduce serum cholesterol levels without adverse effects has been demonstrated in a small number of clinical trials. Since its active ingredients are statins, the voluminous research available adds support to Cholestin’s efficacy. Four Cholestin capsules give patients the daily equivalent of about 10 mg lovastatin. Further studies are warranted to determine why Cholestin did not change HDL levels but the Chinese products did. Long-term safety needs to be evaluated.
Recommendation
Whatever its regulatory status, physicians and patients would do well to treat Cholestin as a drug, not as a medicinal food or dietary supplement. At a cost of $20-$30 per month, Cholestin use could help hyperlipidemic patients realize significant cost savings. Some patients may substitute Cholestin for more expensive or more bothersome medications; clinicians should be alert to this possibility and be aware that Cholestin carries the same cautions as the statins, especially lovastatin. In general, Cholestin should not be combined with other cholesterol-reducing medications. Although Cholestin is a standardized product, no federal standards exist for its manufacture, and close scrutiny of red yeast rice preparations will be needed to evaluate quality.
Dr. O’Mathúna is a Professor of Bioethics and Chemistry at Mt. Carmel College of Nursing, Columbus, OH.
References
1. Farmer JA. Aggressive lipid therapy in the statin era. Prog Cardiovasc Dis 1998;41:71-94.
2. Smith SC Jr. Need for a paradigm shift: The importance of risk factor reduction therapy in treating patients with cardiovascular disease. Am J Cardiol 1998;82:10T-13T.
3. Perreault S, et al. Treating hyperlipidemia for the primary prevention of coronary disease. Are higher doses of lovastatin cost-effective? Arch Intern Med 1998;158:375-381.
4. Wang J, et al. Multicenter clinical trial of the serum lipid-lowering effects of a Monascus purpureus (red yeast) rice preparation from traditional Chinese medicine. Curr Ther Res 1997;58:964-978.
5. Heber D. Natural Remedies for a Healthy Heart. Garden City Park, NY: Avery; 1998.
6. Heber D, et al. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr 1999;69:231-236.
7. Havel RJ. Dietary supplement or drug? The case of Cholestin. Am J Clin Nutr 1999;69:175-176.
8. Li C, 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.
9. Blanc PJ, et al. Characterization of monascidin A from Monascus as citrinin. Int J Food Microbiol 1995;27:201-213.
10. Zhu Y, et al. Effects of Xuezhikang on blood lipids and lipoprotein concentrations of rabbits and quails with hyperlipidemia. Chin J Pharmacol 1995;30:4-8.
11. Zhiwei S, et al. A prospective study on Zhitai capsule in the treatment of primary hyperlipidemia. Natl Med J China 1996;76:156-157.
12. Wang J, et al. Clinical trial of extract of Monascus purpureus (red yeast) in the treatment of hyperlipidemia. Chin J Exp Ther Prep Chin Med 1995;12:1-5.
13. In a conversation with Dr. Michael Chang, Pharmanex, Inc. (February 1999).
14. Physicians’ Desk Reference. Montvale, NJ: Medical Economics Company; 1998.
15. Li C, et al. Xuezhikang toxicity study. Bull Chin Pharmacol Soc 1995;12:3.
16. Kantola T, et al. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998;63:397-402.
17. Havel RJ, et al. Lovastatin (Mevinolin) in the treatment of heterozygous familial hypercholesterolemia: A multicenter study. Ann Intern Med 1987;107:609-615.
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