More on the Chinese red-yeast-rice supplement and its cholesterol-lowering effect.

I follow with great interest the heated legal, ethical, and purely medical controversies surrounding the therapeutic value of fermented Chinese red yeast rice in cardiovascular diseases. Some of the debated issues are addressed by the authors of a recent publication in the Journal (1). The study by Heber et al (1) indicates that very short-term supplementation of patients with hyperlipidemia with red yeast rice reduced total cholesterol, LDL-cholesterol, and total triacylglycerol concentrations modestly. Unfortunately, only 42 patients were included in the treatment group. Differences in total cholesterol, LDL-cholesterol, and triacylglycerol between the treatment and control groups were modestly significant (P < 0.05; Table 2 from reference 1). Total cholesterol decreased from baseline by 16.8% at week 8 and by 16.1% at week 12 in the treatment group and was 18.1% lower at week 8 and 16.1% lower at week 12 in the treatment group than in the control group. An analysis of the Chinese red-yeast-rice supplement by Heber et al indicated the presence of nine 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in addition to sterols, isoflavones, glycerides, and other substances. The authors’ conclusion was that the effect of red yeast rice on the cholesterol concentration could not be explained by its constituent monacolin K alone (also known as mevinolin or lovastatin), but was the combined effect of monacolins and other substances in the red-yeast-rice supplement. The inhibition of cholesterol biosynthesis by statins (including lovastatin) is a well-accepted fact and Heber et al assumed that the effect of the red-yeast-rice supplement followed the same pathway; however, they presented no evidence in support of this assertion. In the United states, 6 different HMG-CoA reductase inhibitors (known as statins) are currently marketed, all of which control endogenous cholesterol biosynthesis at the mevalonate level. A schematic representation of this complex pathway was presented by Bliznakov and Wilkins (2). Yet, this multistep process can be affected at various other levels, with different biochemical and clinical consequences. The potent effect of statins at the mevalonate level is, unfortunately, not specific and results in parallel inhibition of several nonsterol isoprenoid end products, including coenzyme Q10 (CoQ10) and dolichol. If the cholesterol biosynthetic pathway is impaired below the farnesyl pyrophosphate branch point of the mevalonate pathway, CoQ10 biosynthesis is not inhibited. The CoQ10-lowering effect of statins and its compensation by administration of CoQ10 was described 10 y ago and since then has been confirmed in numerous studies of animals and humans. CoQ10, also designated ubiquinone, is a naturally occurring, fat-soluble, vitamin-like nutrient—a quinone—with characteristics common to vitamins. Like vitamins, CoQ10 is essential to the healthy functioning of all cells in an organism. The fundamental role of CoQ10 as an electron and proton carrier for the cellular energy transduction in mitochondria is well established. In addition, CoQ10 is involved in the stabilization of cell membranes, thus preserving cellular integrity and function, and is a potent scavenger of reactive oxygen species, preventing oxidative injury to DNA, lipids, proteins, and other molecules. This action retards or prevents the development of many cardiovascular and possibly neoplastic and neurodegenerative disease states. The biomedical and clinical aspects of CoQ10 have been the subject of 14 international symposia, and the clinical effectiveness of CoQ10 in cardiovascular diseases (a system with high energy demand) was reviewed recently (3, 4). A compilation of the indications for clinical use of CoQ10 was presented by Bliznakov and Wilkins (2). In summary, many studies substantiate the strong relations between CoQ10 deficiency, disease states, and clinical improvement after CoQ10 treatment. Despite numerous clinical trials documenting a generally good safety profile, side effects resulting from treatment with statins occur. Some of the adverse reactions—myalgia; myopathies; rhabdomyolysis; gastrointestinal symptoms, including hepatic injury; and the initiation or accelerated progression of cataracts and neoplasia— could be a direct or indirect consequence of the CoQ10-deficiency state associated with statin treatment. It was suggested that CoQ10 supplementation should be considered during extended therapy with statins to support cellular bioenergetic demands (2). Moreover, the possibility of an additive or synergistic therapeutic effect of CoQ10 when administered with statins should be considered. Heber et al disclose that “there were no serious adverse effects in any of the 88 subjects randomly assigned” to treatment with the red-yeast-rice supplement or placebo. Note that there were only 42 subjects in the red-yeast-rice treatment group and the length of the treatment, unfortunately, was only 12 wk. It is premature to assume the lack of toxicity on the basis of this short-term study. Cendella (5) attests that the ocular safety of statins can be established only after 10–20 y of clinical experience. Recently, Jeppesen et al (6) reported 7 cases of peripheral neuropathy associated with longer-term (1–7 y) statin therapy. The fact that fermented red yeast rice has been used in China since 800 AD is an interesting part of bygone medical folklore, but is not an indication of efficacy or of the lack of toxic effects. Obviously, it is important to measure blood CoQ10 concentrations in patients treated with the Chinese red-yeast-rice supplement. If the CoQ10 concentration is not affected, this will imply a mechanism different from the mechanism accepted for cholesterol reduction by statins and will heighten the clinical interest in this product.